All relevant data are within the paper.

Introduction {#sec001}
============

Human cytomegalovirus (HCMV), a member of the *Betaherpesvirinae* subfamily of herpesviruses, is a ubiquitous pathogen with a seroprevalence of 45--100% \[[@pone.0154100.ref001]\]. Primary HCMV infection is usually asymptomatic in healthy individuals and is followed by a persistent infection. In contrast, HCMV is a major reason of multiorgan disease in immunocompromised patients and a leading cause of congenital infection, occurring in 0.5--2% of pregnancies in the United States and Europe \[[@pone.0154100.ref002], [@pone.0154100.ref003]\]. Among congenitally infected neonates, approximately 10--15% exhibit signs and symptoms of disease at birth, and these symptomatic infants have an increased risk for sensorineural hearing loss and central nervous system damage \[[@pone.0154100.ref004], [@pone.0154100.ref005]\]. However, the factors that dictate whether HCMV infection is asymptomatic or symptomatic are not clear. Innate immunity plays a crucial role in preventing the acquisition of HCMV infections, whereas its failure may contribute to an increased risk of infection. It is suggested that variations in the genes that modulate innate immune responses, including *TLRs* genes, may result in distinct clinical presentations of infection.

Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens and have been implicated in infectious and autoimmune processes. There is evidence that interactions between some TLRs with viruses influence both the immune response and outcome of HCMV infection. HCMV activates host cells *via* multiple TLRs, predominantly those that reside on cell surface or in endosomes. TLR2 is pattern recognition receptor (PRR) for HCMV glycoproteins B (gB) and gH \[[@pone.0154100.ref006]\]. TLR2 and CD14 participate in HCMV attachment, uptake, and subsequent signaling, leading to the expression of pro-inflammatory cytokine genes \[[@pone.0154100.ref006], [@pone.0154100.ref007]\]. TLR4 induces THP-1 cells signaling via the TLR4/MD2/CD14 complex which initiates and regulates additional downstream signaling \[[@pone.0154100.ref008]\]. It has been also demonstrated that TLR4-ligand complexes enhance the ability of dendritic cells to present viral antigen \[[@pone.0154100.ref009]\]. Endosomal TLR3, TLR7, and TLR9 are involved in HCMV-elicited signaling, which leads to a pro-inflammatory and antiviral response, such as type I interferons (IFNs) \[[@pone.0154100.ref006], [@pone.0154100.ref007], [@pone.0154100.ref010]\]. TLR3 recognizes dsRNA, also generated during the life cycle of viruses, whereas TLR7 and 8 recognize single-stranded RNA (ssRNA). TLR9, localized intracellularly within endolysosomes, recognizes unmethylated CpG dinucleotide motifs located in viral DNA and plays a central role in host defense against viral infection \[[@pone.0154100.ref011], [@pone.0154100.ref012]\]. HCMV strongly up-regulates *TLR9* mRNA levels in human fibroblasts \[[@pone.0154100.ref013]\]. TLR9 mediates the recognition of murine CMV (MCMV), as evidenced by experiments using a mutated form of TLR9. A missense mutation in the receptor domain of the *TLR9* gene (TLR9CpG1) can be induced by N-ethyl-N-nitrosourea and results in unresponsiveness to CpG-containing oligonucleotides. Mice homozygous for the TLR9CpG1 allele are highly susceptible to infection with MCMV and display impaired (infection-induced) IFN-α/ß secretion and NF-κB activation \[[@pone.0154100.ref014]\]. The TLR9-mediated activation of MyD88 and TLR3-dependent induction of TRIF signaling are activated *in vivo* upon inoculation of MCMV, leading to type I IFN production. Notably, neither of the pathways alone---in the absence of the other---offers complete protection against MCMV infection, but they instead act in an additive or codependent manner \[[@pone.0154100.ref014]\].

Little is known about the role of TLR polymorphisms in the pathogenesis of HCMV infection in humans. The R753Q single-nucleotide polymorphism (SNP) in the *TLR2* gene was shown to be associated with increased HCMV replication and disease in transplant recipients \[[@pone.0154100.ref015], [@pone.0154100.ref016]\]. *In vitro* experiments showed that the R753Q SNP abolishes TLR2-mediated immune signaling in response to HCMV \[[@pone.0154100.ref017]\]. No association between *TLR2* Arg753Gln SNP with HCMV infection was detected in both infants and immunocompromised adult patients \[[@pone.0154100.ref018]\]. Although the relationship between the mutation in the highly polymorphic *TLR4* gene and the incidence of HCMV disease has been described in transplant patients \[[@pone.0154100.ref019]\], no effect of the *TLR4* Asp299Gly SNP on viral infection in infancy was found \[[@pone.0154100.ref018]\]. Few studies have described the association between *TLR9* polymorphisms and HCMV infection \[[@pone.0154100.ref020]--[@pone.0154100.ref022]\]. Increasing studies have found that specific *TLR* SNPs have an association with congenital HCMV infection \[[@pone.0154100.ref023], [@pone.0154100.ref024]\]. Taniguchi et al. \[[@pone.0154100.ref023]\] found that the homozygous CC genotype of the 1350T/C SNP (rs3804100) in the *TLR2* gene was associated with congenital HCMV infection, while no associations between *TLR4* and *TLR9* SNPs with HCMV infection and disease in infants were found. Recently, *TLR4* and *TLR9* polymorphisms were found to play a role in the development of congenital HCMV infection in fetuses and neonates \[[@pone.0154100.ref024]\].

Our study explored the genotype distribution of *TLR9* -1237T/C (rs5743836), -1486T/C (rs187084), 1174G/A (rs352139), and 2848C/T (rs352140) SNPs in infants and the correlation between polymorphisms in the *TLR9* gene and HCMV infection in infants.

Materials and Methods {#sec002}
=====================

Ethics statement {#sec003}
----------------

The study protocols were approved by the Bioethics Committee of the Medical University of Lodz (RNN/120/09/KE), and the Ethics Committee of the Polish Mother's Memorial Hospital Research Institute. Written informed consents were obtained from all parents or guardians on behalf of the children involved in the study.

Study population {#sec004}
----------------

Between 2008 and 2011, 72 infants were selected as HCMV-positive at the 3rd Department of Pediatrics of the Polish Mother's Memorial Hospital Research Institute in Lodz, Poland. HCMV infection was confirmed by HCMV DNA (*UL55* gene) detection in whole-blood and/or urine samples after 3 weeks of life and by the presence of HCMV-specific antibodies. Because infants were examined after that time, children were classified as having postnatal or unproven congenital HCMV infection. However, clinical data suggest that the majority of the studied infants were infected congenitally ([Table 1](#pone.0154100.t001){ref-type="table"}). Serum samples from the infants were assessed for anti-HCMV IgG and IgM antibodies with the use of CLIA LIASON CMV IgM and IgG assays (DiaSorin, Sallugia, Italy). HCMV-positive infants were compared with 70 healthy newborn infants (seronegative and aviremic), which were used as controls for the association studies. All of the study subjects were Caucasians and there were no ethnic differences between the cases and control group.

10.1371/journal.pone.0154100.t001

###### Demographic and clinical characteristics of study subjects with HCMV infection.

![](pone.0154100.t001){#pone.0154100.t001g}

  Characteristics
  -------------------------------------------------------------------- -----------
  **Total No.**                                                        72
  **Mean ± SD age (months)**                                           3.9 ± 2.4
  **Gender number; n (%)**[^**a**^](#t001fn001){ref-type="table-fn"}
  Female                                                               30 (41.7)
  Male                                                                 42 (58.3)
  **Symptoms; n (%)**[^**a**^](#t001fn001){ref-type="table-fn"}
  Hematological disorders                                              28 (38.9)
  Pneumonia                                                            19 (26.4)
  Jaundice                                                             16 (22.2)
  Neurological dysfunction                                             16 (22.2)
  CNS damage                                                           15 (20.8)
  Psychomotor retardation                                              14 (19.4)
  Liver damage                                                         11 (15.3)
  Hearing loss                                                         7 (9.7)
  IUGR                                                                 5 (6.9)
  Hepatosplenomegaly                                                   5 (6.9)
  Hepatitis                                                            5 (6.9)
  Heart disease                                                        3 (4.2)
  Ocular defects                                                       2 (2.8)
  **Anti-HCMV serologic status**
  IgG positive, IgM negative                                           40 (55.5)
  IgG positive, IgM positive                                           29 (40.3)
  IgG negative, IgM negative                                           3 (4.2)

^a^ Values are the number of infants (%).

All infants with HCMV infection were symptomatic due to the selection bias. Clinical samples were collected from children at diagnosis or after exacerbation of cytomegaly symptoms. The children were classified as having a symptomatic infection based on clinical or laboratory findings, including hematological disorders (anemia, thrombocytopenia), pneumonia, neurological dysfunction, central nervous system damage, psychomotor retardation, liver damage, intrauterine growth restriction, and other symptoms; the classification was made after other causes had been excluded. Of the 72 patients, 30 (41.7%) were female and 42 (58.3%) were male, and their mean age at evaluation was 3.9 ± 2.4 months (median: 3.3 months, range: 1--12 months). The demographic and clinical characteristics of infants with HCMV infection were summarized in [Table 1](#pone.0154100.t001){ref-type="table"}. Laboratory personnel were blinded to the demographic characteristics and clinical findings of the study subjects.

Genotyping of *TLR9* polymorphisms {#sec005}
----------------------------------

All genotyping was performed on genomic DNA extracted from whole-blood samples using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) according to manufacturer's recommendations. The concentration and purity of DNA were assessed using a NanoDrop 2000c UV-vis Spectrophotometer (Thermo Scientific, Wilmington, DE, USA). The identification of *TLR9* SNPs was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using primers described previously by Hamann et al. \[[@pone.0154100.ref025]\] (-1237T/C, rs5743836; -1486T/C, rs187084), Fang et al. \[[@pone.0154100.ref026]\] (1174G/A, rs352139) and Roszak et al. \[[@pone.0154100.ref027]\] (2848C/T, rs352140). Briefly, PCR was performed in a total volume of 50 μL containing 200 ng of genomic DNA, primers (1 μM each), dNTPs (2.5 mM), 10 x *Taq* buffer (100 mM Tris-HCl, 500 mM KCl, 0.8% Nonidet P40; pH 8.8), 2 mM MgCl~2~, and 1 U of *Taq* DNA Polymerase (Fermentas, Glen Burnie, MD, USA). The thermal cycling conditions for -1237T/C were 4 min at 95°C and 40 cycles each of 30 s at 95°C, 20 s at 50°C, and 30 s at 72°C. The PCR parameters for -1486T/C and 2848C/T were as follows: 4 min at 95°C and 35 cycles each of 30 s at 95°C, 20 s at 60°C, and 30 s at 72°C. The final extension in both PCR profiles was at 72°C for 5 min. The reactions were carried out using a Veriti thermal cycler (Applied Biosystems, Foster City, CA, USA). The PCR-amplified fragments corresponding to the *TLR9* -1237T/C, -1486T/C, 1174G/A, and 2848C/T polymorphisms were digested with the restriction enzymes MvaI, AflII, FspBI, and Bsh1236I, respectively (Fermentas, Hanover, MD, USA). The digested fragments were separated using the QIAxcel system (Qiagen). The *TLR9* SNPs variants were identified by different fragment lengths ([Table 2](#pone.0154100.t002){ref-type="table"}; [Fig 1](#pone.0154100.g001){ref-type="fig"}). The results were confirmed by the direct sequencing of selected samples of each *TLR9* genotype using the MiSeq system (Illumina, San Diego, CA, USA). The results of the PCR-RFLP and sequencing methods were in agreement.

![Visualization of selected PCR-RFLP products for *TLR9* -1486T/C genotyping.\
Gel image: 1 and 2, heterozygous TC genotype (192, 327, 490 bp); 3 and 4, TT genotype (192, 327 bp); 5 and 6, CC genotype (490 bp). Alignment markers (15 bp, 1 kbp).](pone.0154100.g001){#pone.0154100.g001}

10.1371/journal.pone.0154100.t002

###### Restriction enzymes and length of the restriction fragments.

![](pone.0154100.t002){#pone.0154100.t002g}

  SNP            Restriction enzyme   Genotype   Length of the restriction fragments, base pairs (bp)
  -------------- -------------------- ---------- ------------------------------------------------------
  **-1237T/C**   MvaI                 TT         29 bp, 113 bp
                                      TC         29 bp, 113 bp, 142 bp
                                      CC         142 bp
  **-1486T/C**   AflII                TT         192 bp, 327 bp
                                      TC         192 bp, 327 bp, 490 bp
                                      CC         490 bp
  **1174G/A**    FspBI                GG         206 bp
                                      GA         28 bp, 178 bp, 206 bp
                                      AA         28 bp, 178 bp
  **2848C/T**    Bsh1236I             CC         114 bp, 217 bp
                                      CT         114 bp, 217 bp, 331 bp
                                      TT         331 bp

Assessment of HCMV replication {#sec006}
------------------------------

Real-time PCR quantification of the HCMV DNA copy number in DNA isolates from whole-blood and urine samples was performed by using a 7900HT Fast Real-Time PCR System (Applied Biosystems) \[[@pone.0154100.ref028]\]. For amplification of the HCMV genome, a pair of primers and a TaqMan probe labeled at the 5' end with FAM (6-carboxyfluoroscein) and at the 3' end with TAMRA (6-carboxytetramethylrhodamine) targeting the gB sequence were used. The primers and probe used were the following: primer gB1, 5'-GAGGACAACGAAATCCTGTTGGGCA-3', primer gB2, 5'-GTCGACGGTGGAGATACTGCTGAGG-3', and probe, 5'-CAATCATGCGTTTGAAGAGGTAGTCCA-3'. The samples for real-time PCR were prepared in a volume of 25 μL containing 5 μL of the DNA extract or calibrated plasmid dilution (standard curve), 0.4 μM of each primer, 0.2 μM of the fluorogenic probe, and the TaqMan Universal PCR Master Mix (Applied Biosystems). The PCR amplification reaction used the condition: 95°C for 10 min, 60 cycles at 95°C for 15 s, followed by 60°C for 1 min. Standard curves for the plasmid DNA were obtained from serial 10-fold dilutions from 10^5^ to 5. The number of target copies was determined from the threshold cycle CT.

Statistical analysis {#sec007}
--------------------

The calculation of Hardy-Weinberg equilibrium (HWE), linkage disequilibrium (LD) and additional genotype and haplotype associations with HCMV infection status were performed by using the SNPSTATS program (<http://bioinfo.iconcologia.net/index.php?module=Snpstats>) \[[@pone.0154100.ref029]\]. The association between the polymorphisms and HCMV infection was estimated using an odds ratio (OR) and 95% confidence intervals (95% CIs) with unadjusted and adjusted multivariate models. *P* values were corrected (*Pc*) for multiple testing with the Bonferroni's correction and the *Pc*-values of ≤ 0.05 were considered to be significant. Logistic regression models to evaluate the association between the *TLR* genotype and the symptoms was performed using the SPSS statistical software package for Windows 17.0 (SPSS, Chicago, IL, USA). The distribution of genotypes and alleles in the patient groups was examined by using the Fisher's exact test. The Mann-Whitney U test was used to study the association between *TLR* polymorphisms and viral load. The level of significance for all statistical tests was defined as *P* ≤ 0.05.

Results {#sec008}
=======

Frequency of *TLR9* SNPs in infants {#sec009}
-----------------------------------

*TLR9* -1237T/C, -1486T/C, 1174G/A, and 2848C/T SNPs were typed in 142 infants, including the 72 subjects with HCMV infection. Almost all individuals (139/142, 97.9%) possessed the wild-type -1237TT genotype, while the CC genotype was only found in three HCMV-infected cases (3/72, 4.2%; *P* \> 0.05). As the -1237T/C SNP is non-polymorphic in our population, it was excluded from further analyses. The distribution of the -1486T/C, 1174G/A, and 2848C/T SNPs was different between HCMV-infected and uninfected infants (see [Table 3](#pone.0154100.t003){ref-type="table"}). In infants with HCMV infection, the frequencies of the TT, TC, and CC genotypes at the -1486T/C SNP were 22.2%, 62.5%, and 15.3%, respectively. The wild-type TT genotype was detected in 40.0% and the heterozygous TC genotype in 45.7%, while the homozygous CC genotype was detected in 14.3% of healthy individuals. Similar genotype frequencies in HCMV-infected and uninfected infants were observed in the *TLR9* 2848C/T SNP ([Table 3](#pone.0154100.t003){ref-type="table"}). The frequency of wild-type genetic variants of both -1486T/C and 2848C/T SNPs was significantly higher in uninfected infants than in HCMV-infected cases (*P* = 0.029; Fisher's exact test). It should be noted that, the heterozygous variant carriers of the 2848C/T and -1486T/C SNPs were detected more frequently among infants with HCMV infection (*P* = 0.044 and *P* = 0.064, respectively; Fisher's exact test). In case of 1174G/A SNP, the frequencies of the GG, GA, and AA genotypes in children with HCMV infection were 1.4%, 40.3%, and 58.3%, respectively. The GG genotype at this SNP was identified more frequently in uninfected than HCMV-infected infants (14.3% vs 1.4%; *P* = 0.004; Fisher's exact test). In the group of infants without HCMV infection, the frequencies of genotypes at all *TLR9* SNPs were in HWE (*P* \> 0.05; [Table 4](#pone.0154100.t004){ref-type="table"}).

10.1371/journal.pone.0154100.t003

###### The distribution of genotypes frequencies of *TLR9* SNPs in infants and relationship between polymorphisms and the risk of HCMV infection.

![](pone.0154100.t003){#pone.0154100.t003g}

  *TLR9* SNPs    Model          Genotype   Genotype frequencies; n (%)[^a^](#t003fn001){ref-type="table-fn"}   Unadjusted                       Adjusted[^b^](#t003fn002){ref-type="table-fn"}
  -------------- -------------- ---------- ------------------------------------------------------------------- ------------ ------------------- ------------------------------------------------ ----------- ---------------------- ----------- -----------
  **-1486T/C**   Codominant     TT         16 (22.2)                                                           28 (40.0)    1.00                0.063                                            0.189       1.00                   **0.012**   **0.036**
                                TC         45 (62.5)                                                           32 (45.7)    2.46 (1.15--5.28)                                                                4.23 (1.53--11.67)
                                CC         11 (15.3)                                                           10 (14.3)    1.92 (0.67--5.52)                                                                2.80 (0.73--10.72)
                 Dominant       TT         16 (22.2)                                                           28 (40.0)    1.00                **0.021**                                        0.063       1.00                   **0.004**   **0.012**
                                TC-CC      56 (77.8)                                                           42 (60.0)    2.33 (1.12--4.86)                                                                3.89 (1.45--10.46)
                 Recessive      TT-TC      61 (84.7)                                                           60 (85.7)    1.00                0.870                                            ns          1.00                   0.960       ns
                                CC         11 (15.3)                                                           10 (14.3)    1.08 (0.43--2.74)                                                                1.03 (0.34--3.07)
                 Overdominant   TT-CC      27 (37.5)                                                           38 (54.3)    1.00                **0.044**                                        0.132       1.00                   **0.010**   **0.030**
                                TC         45 (62.5)                                                           32 (45.7)    1.98 (1.01--3.87)                                                                2.87 (1.26--6.52)
  **1174G/A**    Codominant     AA         42 (58.3)                                                           30 (42.9)    1.00                **0.005**                                        **0.015**   1.00                   **0.005**   **0.015**
                                GA         29 (40.3)                                                           30 (42.9)    0.69 (0.35--1.38)                                                                0.71 (0.32--1.58)
                                GG         1 (1.4)                                                             10 (14.3)    0.07 (0.01--0.59)                                                                0.00 (0.00-NA)
                 Dominant       AA         42 (58.3)                                                           30 (42.9)    1.00                0.065                                            0.195       1.00                   0.110       0.330
                                AG-GG      30 (41.7)                                                           40 (57.1)    0.54 (0.28--1.04)                                                                0.53 (0.24--1.16)
                 Recessive      AA-AG      71 (98.6)                                                           60 (85.7)    1.00                **0.002**                                        **0.006**   1.00                   **0.002**   **0.06**
                                GG         1 (1.4)                                                             10 (14.3)    0.08 (0.01--0.68)                                                                0.00 (0.00-NA)
                 Overdominant   AA-GG      43 (59.7)                                                           40 (57.1)    1.00                0.760                                            ns          1.00                   0.890       ns
                                AG         29 (40.3)                                                           30 (42.9)    0.90 (0.46--1.75)                                                                0.94 (0.43--2.06)
  **2848C/T**    Codominant     CC         16 (22.2)                                                           28 (40.0)    1.00                **0.049**                                        0.147       1.00                   **0.014**   **0.042**
                                CT         43 (59.7)                                                           29 (41.4)    2.59 (1.20--5.63)                                                                4.02 (1.43--11.28)
                                TT         13 (18.1)                                                           13 (18.6)    1.75 (0.65--4.68)                                                                3.59 (1.07--12.00)
                 Dominant       CC         16 (22.2)                                                           28 (40.0)    1.00                **0.021**                                        0.063       1.00                   **0.004**   **0.012**
                                CT-TT      56 (77.8)                                                           42 (60.0)    2.33 (1.12--4.86)                                                                3\. 89 (1.45--10.46)
                 Recessive      CC-CT      59 (81.9)                                                           57 (81.4)    1.00                0.940                                            ns          1.00                   0.470       ns
                                TT         13 (18.1)                                                           13 (18.6)    0.97 (0.41--2.26)                                                                1.41 (0.56--3.60)
                 Overdominant   CC-TT      29 (40.3)                                                           41 (58.6)    1.00                **0.029**                                        0.087       1.00                   **0.046**   0.138
                                CT         43 (59.7)                                                           29 (41.4)    2.10 (1.07--4.09)                                                                2.21 (1.01--4.85)

^a^ Values are the number of examined infants (%)

^b^ Adjusted analysis was carried out for HCMV DNA copy number in whole-blood samples

^c^ The significance level after Bonferroni's correction for multiple testing is 0.05

OR: odds ratio; 95% CI: 95% confidence interval; *P*, logistic regression model; *Pc*, value after Bonferroni's correction accounting for multiple SNPs (raw *P*-value × 3); ns: not statistically significant; NA: not available.

10.1371/journal.pone.0154100.t004

###### *TLR9* SNP variance from Hardy-Weinberg equilibrium.

![](pone.0154100.t004){#pone.0154100.t004g}

  *TLR9* SNPs    Infant group    Genotype/allele frequencies; n[^a^](#t004fn001){ref-type="table-fn"}   *P*-value
  -------------- --------------- ---------------------------------------------------------------------- ----------- ---- ----- ----- ----------
  **-1237T/C**                   TT                                                                     TC          CC   T     C
                 HCMV-infected   69                                                                     0           3    138   6     \<0.0001
                 Uninfected      70                                                                     0           0    140   0     1
  **-1486T/C**                   TT                                                                     TC          CC   T     C
                 HCMV-infected   16                                                                     45          11   77    67    0.056
                 Uninfected      28                                                                     32          10   88    52    1
  **1174G/A**                    GG                                                                     GA          AA   G     A
                 HCMV-infected   1                                                                      29          42   31    113   0.16
                 Uninfected      10                                                                     30          30   50    90    0.61
  **2848C/T**                    CC                                                                     CT          TT   C     T
                 HCMV-infected   16                                                                     43          13   75    69    0.16
                 Uninfected      28                                                                     29          13   85    55    0.32

^a^ Values are the number of observed genotypes/alleles

*P*, chi-square test.

In the examined infants, the frequencies of the wild-type -1486 T, 1174 G and 2848 C alleles were 58.1%, 28.5% and 56.3%, respectively, while the frequencies of the -1486 C, 1174 A and 2848 T alleles were 41.9%, 71.5% and 43.7%, respectively. In both HCMV-infected and uninfected infant groups, no significant differences in the frequency of *TLR9* -1486T/C and 2848C/T alleles were observed ([Table 5](#pone.0154100.t005){ref-type="table"}, *P* \> 0.05). In contrast, the A allele of 1174G/A SNP was detected more frequently in infants with HCMV infection compared with uninfected cases (*P* = 0.009). Among HCMV-infected infants, in the -1237 locus, the C alleles were significantly more frequent than in uninfected individuals (*P* = 0.030).

10.1371/journal.pone.0154100.t005

###### The distribution of allele frequencies of *TLR9* SNPs in infants with and without HCMV infection.

![](pone.0154100.t005){#pone.0154100.t005g}

  *TLR9* SNPs    Allele   Allele frequencies; n (%)[^a^](#t005fn001){ref-type="table-fn"}   *P*-value
  -------------- -------- ----------------------------------------------------------------- ------------ -----------
  **-1237T/C**   T        138 (95.8)                                                        140 (100)    **0.030**
                 C        6 (4.2)                                                           0 (0)
  **-1486T/C**   T        77 (53.5)                                                         88 (62.90)   0.119
                 C        67 (46.5)                                                         52 (37.1)
  **1174G/A**    G        31 (21.5)                                                         50 (35.7)    **0.009**
                 A        113 (78.5)                                                        90 (64.3)
  **2848C/T**    C        75 (52.1)                                                         85 (60.7)    0.153
                 T        69 (47.9)                                                         55 (39.3)

^a^ Values are the number of alleles (%)

*P*, Fisher's exact test.

*TLR9* polymorphisms associated with HCMV infection {#sec010}
---------------------------------------------------

Statistically significant differences between infants with and without HCMV infection were observed for the *TLR9* -1486T/C, 1174G/A, and 2848C/T polymorphisms (see [Table 3](#pone.0154100.t003){ref-type="table"}). For the -1486T/C, 1174G/A, and 2848C/T SNPs, the wild-type genotypes occurred more frequently in the uninfected infants compared to the HCMV-infected group. When considered separately, *TLR9* SNPs were significantly associated with risk of HCMV infection. Heterozygous and homozygous CC genotypes at the -1486 locus were associated with a 2-fold increased risk of HCMV infection (OR 2.33, 95% CI 1.12--4.86, *P* = 0.021 in dominant model). Similarly, at least a 2-fold increased risk of infection was found for the heterozygous and homozygous TT genotypes at the 2848 locus in almost all genetic models (OR 2.33, 95% CI 1.12--4.86, *P* = 0.021 and OR 2.10, 95% CI 1.07--4.09, *P* = 0.029 in the dominant and overdominant models, respectively). These two SNPs showed a trend to association with HCMV infection after Bonferroni's correction for multiple testing (*Pc* = 0.063). In infants with double heterozygous -1486T/C and 2848C/T polymorphisms, a trend towards increased risk of cytomegaly was found (OR 1.95, 95% CI 0.92--4.13, *P* = 0.077). In contrast, the GG genotype of the 1174G/A SNP compared to GA and AA genotypes decreased the risk of HCMV infection (OR 0.08, 95% CI 0.01--0.68, *P* = 0.002 in recessive model). These *P* value remained significant even after Bonferroni\'s correction (*Pc* = 0.006).

For the *TLR9* -1486T/C and 2848C/T SNPs, a mutation present in at least one allele may lead to HCMV infection in infants. No association between specific *TLR9* genotypes and the presence of specific symptoms in HCMV-infected children was found.

Associations between *TLR9* SNPs and HCMV load {#sec011}
----------------------------------------------

We correlated the SNPs with HCMV DNA concentration in peripheral blood during exacerbation of cytomegaly symptoms. The viremia levels ranged from 0 to 1.41 × 10^5^ copies/mL (mean 2.73 × 10^3^ ± 1.68 × 10^4^ copies/mL) in HCMV-infected infants. However, the mean copy number of HCMV DNA was statistically higher in blood samples from infants with the heterozygous variant of *TLR9* -1486T/C than those with the wild-type genotype ([Fig 2](#pone.0154100.g002){ref-type="fig"}, *P* = 0.039). In addition, the children with heterozygous and homozygous recessive genotypes at the -1486 and 2848 locus had almost 4-fold increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number (OR 3.89, 95% CI 1.45--10.46, *P* = 0.004 in dominant model; [Table 3](#pone.0154100.t003){ref-type="table"}). This association reach statistical significance after Bonferroni's correction (*Pc* = 0.012). No association was observed between the HCMV DNAemia and *TLR9* 1174G/A SNP (*P* \> 0.05).

![Comparison of viremia levels in HCMV-infected infants without or with the *TLR9* -1486T/C SNP (N = 72).\
Bars in the scatter dot plot represent the mean viral loads. Bars in the box plots represent median viral loads, upper and lower borders represent the 25th and 75th percentiles, and whiskers represent the minimum to maximum values. *P* ≤ 0.05, Mann-Whitney U test.](pone.0154100.g002){#pone.0154100.g002}

Haplotype analysis {#sec012}
------------------

Multiple-SNP analysis showed that the most common haplotype for *TLR9* -1237T/C, -1486T/C, 1174G/A and 2848C/T was TCAC (21.62% and 18.46% for HCMV-infected and uninfected cases, respectively). The CCAT, CTGC, and CCAC haplotypes were detected only in infants with HCMV infection, while CTAC haplotype was not detected in any children. We found an association between -1486T/C and 1174G/A SNPs (*Pc* \< 0.001). Linkage disequilibrium analysis revealed that -1237T/C, -1486T/C, 1174G/A, and 2848C/T SNPs were not in LD with each other (correlation coefficient r^2^ \< 0.2). In addition, the haplotypes were not observed to influence the risk for HCMV infection.

An additional multiple-SNP analysis for *TLR9* -1237T/C, -1486T/C, and 2848C/T showed that the TCT haplotype was observed at a lower frequency in both infant groups (24.3% and 14.7% for HCMV-infected and uninfected cases, respectively) and it was associated with 2.5-fold increased the risk of HCMV infection (OR 2.47, 95% CI 1.14--5.33, *P* = 0.023). However, association did not reach statistical significance after Bonferroni's correction (*Pc* \> 0.05).

Discussion {#sec013}
==========

In this study, we demonstrated that the heterozygous genotype of *TLR9* -1486T/C and 2848C/T occurred more frequently in infants with HCMV infection than in uninfected cases. The heterozygous or homozygous recessive genotypes of the *TLR9* SNPs were consistently associated with a 2-fold higher risk of HCMV infection and disease development. This study provides the first demonstration that the 2848C/T and -1486T/C genotype might be important markers of HCMV infection. Furthermore, the GG genotype of the 1174G/A locus showed a significantly reduced risk for HCMV infection. No association between a polymorphism in the promoter of the *TLR9* gene (-1237T/C) and HCMV infection was found. We speculate that genetic variations in *TLR9* lead to a functional deficiency of the receptor signaling pathway and they are partially responsible for the development of cytomegaly.

TLR9 has been implicated in the recognition of different families of DNA viruses, all of which contain genomes rich in CpG DNA motifs, including herpesviruses \[[@pone.0154100.ref030]--[@pone.0154100.ref033]\]. The intracellular localization of TLR9 is critical for the discrimination of self and non-self nucleic acids. TLR9 recognizes unmethylated CpG dinucleotide motifs in DNA, a feature that is enriched in viruses and not present in host genomes. After stimulation with CpG DNA, TLR9 redistributes from the endoplasmic reticulum to lysosomes, where the receptor undergoes proteolytic cleavage of its ectodomain. Only the cleaved receptor is able to recruit MyD88 \[[@pone.0154100.ref034], [@pone.0154100.ref035]\], which signals through a protein complex consisting of TRAF6 and IL-1 receptor-associated kinase 1/4 (IRAK1/4), leading to the activation of IRF7, NF-ĸB, and mitogen-activated protein kinase \[[@pone.0154100.ref036]--[@pone.0154100.ref038]\]. Thus, TLR9 activates the production of type I IFNs and inflammatory cytokines. Because TLR9 signaling leads to the activation of IRF7, the recognition of herpesviruses by dendritic cells leads to the expression of type I IFNs \[[@pone.0154100.ref030], [@pone.0154100.ref032], [@pone.0154100.ref039]\].

We studied the -1237T/C and -1486T/C SNPs, which are located within the putative promoter region, 1174G/A SNP located in intron 1, and the 2848C/T SNP located in exon 2 of *TLR9* gene. *TLR9* polymorphisms that are located in the promoter region most likely alter the functional ability of the receptor, as reported in other studies \[[@pone.0154100.ref040]--[@pone.0154100.ref042]\]. These *TLR9* SNPs have been reported to show high heterozygosity in other population \[[@pone.0154100.ref043]\]. We observed a low prevalence of the -1237T/C SNP in the examined population and an incidence of HCMV disease in individuals carrying the *TLR9*--1237 C allele. An analysis of the second polymorphism of the *TLR9* promoter -1486T/C revealed that the mutation present in at least one allele enhanced risk of HCMV disease. There are no functional data available for the *TLR9* -1486T/C polymorphism but it likely alters the function of the promoter. The combination of the C allele at position -1486 with a G allele at position 1174 has the ability to downregulate *TLR9* expression, and the C allele predisposes patients to systemic lupus erythematosus \[[@pone.0154100.ref044]\]. Kikuchi et al. \[[@pone.0154100.ref045]\] reported that the 2848G/A SNP was associated with alterations in gene expression. This polymorphism does neither results in an amino acid change nor modification of a regulatory site, implying functional linkage with another proximal SNPs \[[@pone.0154100.ref046]\]. We found that infants with double heterozygous 2848C/T and -1486T/C genotypes had a trend towards increased risk of HCMV infection. Similar to the -1486T/C SNP, a mutation present in at least one allele of 2848C/T was associated with HCMV infection. We speculate that genetic variations of *TLR9* that down regulate its expression could reduce the function of the innate immune response against HCMV infection. The previous study showed that the *TLR9* 2848 heterozygous status predisposes fetuses and newborns to HCMV infection and increases the risk of cytomegaly development \[[@pone.0154100.ref024]\]. Although the frequency of the heterozygous genotype of *TLR9* SNP rs352140 was also higher in Japanese children congenitally infected with HCMV, no significant association between genotype variants and viral infection was found \[[@pone.0154100.ref023]\]. The present study revealed a significant association between 2848C/T genotype and the higher risk of HCMV infection in infants with postnatal or unproven congenital HCMV infection. Our findings indicate no significant association of *TLR9* 1174G/A polymorphism with cytomegaly among Polish infants. Nevertheless, we observed that the 1174 GG carriers had a reduced risk of HCMV infection. The genotype and allele distribution of *TLR9* SNPs was comparable to that in other European populations \[[@pone.0154100.ref020], [@pone.0154100.ref027], [@pone.0154100.ref047]--[@pone.0154100.ref049]\] but was different than in Asian and American ethnic groups \[[@pone.0154100.ref048], [@pone.0154100.ref050]--[@pone.0154100.ref052]\]. These results indicate the existence of a geographic difference in *TLR9* genotypes that may explain the variability to pathogen susceptibility or other conditions under which TLR9 pathways may be involved.

Specific haplotypes for the *TLR9* gene might affect host defense mechanisms and influence the susceptibility or resistance to infections. *TLR9*--1486 C allele carriers are associated with an increased risk and poor prognosis of gastric carcinoma in the Chinese population \[[@pone.0154100.ref053]\], and the 2848C/T polymorphism may be associated with Hodgkin's lymphoma \[[@pone.0154100.ref054]\] and cervical cancer \[[@pone.0154100.ref027], [@pone.0154100.ref055]\]. Previous studies have shown that *TLR9* polymorphisms are associated with various viral infections, including HIV-1 \[[@pone.0154100.ref056]--[@pone.0154100.ref060]\], HPV16 \[[@pone.0154100.ref055]\], and HCMV \[[@pone.0154100.ref023], [@pone.0154100.ref024]\]. Two *TLR9* SNPs, 1174G/A (rs352139) and 2848C/T, were linked to viral load and disease progression in HIV-1-infected adults \[[@pone.0154100.ref056], [@pone.0154100.ref057], [@pone.0154100.ref059]\]. A significant correlation between these genetic variants and the risk of mother-to-child transmission of HIV-1 infection was found \[[@pone.0154100.ref058]\]. Moreover, the heterozygous 2848 AG genotype and G haplotype were strongly associated with rapid disease progression in HIV-1-infected children \[[@pone.0154100.ref060]\]. The role of *TLR9* polymorphisms in HCMV infection is only beginning to be appreciated. It was previously reported that the -1237T/C mutated C allele was highly predictive of susceptibility to HCMV infection in stem cell transplant recipients \[[@pone.0154100.ref020]\]. However, there was no effect of *TLR9* -1237T/C and 2848C/T polymorphisms on HCMV infection in renal transplant recipients \[[@pone.0154100.ref022]\]. Two other SNPs in the *TLR9* gene in the donor, 1174G/A and 1635C/T (rs352140), influenced the risk of both acute graft-versus-host disease and HCMV reactivation in allogeneic hematopoietic recipients \[[@pone.0154100.ref021]\]. In contrast, no correlation was found between these SNPs and congenital HCMV infection or disease \[[@pone.0154100.ref023]\]. The current and previously described results indicated that *TLR9* polymorphisms have an impact on the development of HCMV disease.

Our finding that *TLR9* -1486T/C and 2848C/T SNPs are associated with HCMV infection suggests an important role of TLRs and TLR-mediated signaling in the pathogenesis and outcomes of cytomegaly. Studying SNPs among the receptors involved in viral recognition will be essential to define the genetic background associated with risk of HCMV infection and disease. Further studies that focus on gene expression and functional consequences of polymorphisms in cytomegaly are needed to determine the exact consequence of *TLR9* SNPs. Increased understanding of how *TLR9* polymorphisms affect congenital cytomegaly may provide a means of identifying high risk groups among newborns and their mothers.

In conclusion, it was found that the heterozygous genotypes of *TLR9* -1486T/C and 2848C/T SNPs as well as the homozygous AA genotype of the intronic 1174G/A SNP were prevalent in infants with HCMV infection. An association between the heterozygous and homozygous recessive genotypes of the -1486T/C and 2848C/T SNPs and predisposition to viral infection was found. Our observations provide new insight into the role of *TLR9* polymorphisms in HCMV infection and may suggest that the presence of the mutation in at least one allele may lead to disease development.

[^1]: **Competing Interests:**The authors have declared that no competing interests exist.

[^2]: Conceived and designed the experiments: EP AJ. Performed the experiments: AJ MS KS PS. Analyzed the data: EP AJ. Contributed reagents/materials/analysis tools: EP AJ MS PS ZJL. Wrote the paper: EP AJ MS. Contributed clinical samples: MWL TWG DN ZG JW. Final approval of the version to be published: EP AJ MS KS PS MWL TWG DN ZG JW ZJL.

[^3]: Current address: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland


1. Field of the Invention
This invention is related to read amplifiers which have at least one load component, at least one differential amplifier and a compensation transistor.
The read amplifier of the invention primarily is utilized in static memories (SRAMs). A SRAM forms a memory wherein after the address has been prescribed, data can be stored under such address and can be read out again with random access. For technical reasons, individual memory cells are not linearly arranged, but are arranged in a quadratic matrix form. Static memories (SRAMs) are preferably utilized in smaller computer systems wherein there are higher costs as compared to dynamic memories (DRAMs) which are offset due to the simpler and cheaper system architect.
2. Description of the Prior Art
Earlier developments in static memories resulted in three different semiconductor technologies. First, bipolar technology; second, NMOS technology; and third, CMOS technology. The CMOS technology is utilized for the read amplifier of the invention which is considered to be an important functional component part of static memories.
Due to the simple peripheral circuits, over 60% of the chip area is covered with memory cells. The remainder of the chip area is principally for row and column decoders as well as for input amplifiers and for read amplifiers.
The circuit oriented arrangement of the read amplifier has a strong influence on important characteristics of the static memory. Thus, for example, the access time and the amount of power dissipated are determined by the properties of the read amplifier.
The following publications disclosed read amplifiers for static CMOS memories:
1. Childs et al, IEEE Journal of Solid State Circuits, Vol. SC-19, Pages 545 through 551, October 1984; and
2. Okazaki et al IEEE Journal of Solid State Circuits, Vol. SC-19, Pages 552 through 556 of October 1984.
The first publication by Childs et al, discloses a 4Kx 4 CMOS static RAM which is produced with a single polysilicon layer and the second publication by Okazaki et al discloses a very fast 2Kx 8 bit CMOS SRAM which enables an access time of 16ns which is comparable to bipolar SRAMs of the same complexity. Both of these publications disclose circuits for read amplifiers which have load components as well as the actual memory cell portion shown in FIG. 10 in the Childs et al publication and in FIG. 6 in the Okazaki et al publication.
FIGS. 1 and 2, except for FIG. 2c, in combination with FIG. 1 show prior art read amplifiers. The read amplifier is divided into a p-channel load component and into a differential amplifier component and there are a number of different circuit possibilities for the p-channel load component. The differential amplifier component is composed of three n-channel field effect transistors which are interconnected in a traditional manner and utilizes an additional p-channel compensation transistor. When clocked memories which have preloading phase are utilized, the compensation transistor improves the compensation of the read amplifier outputs LA and LA during the preloading phase at the first two load component circuits illustrated in FIGS. 2b and 2c. The turn-on of the compensation transistor P4 during the preloading phase and the turn-off during interpretation phase are controlled with a signal at the input AG.
When using the different load components for read amplifier shown in FIGS. 2b, 2c and 2d, the preloading potential V.sub.DD or, respectively, V.sub.DD -V.sub. THP exists at the output LA and LAduring the preloading phase (AG="0", EN="0"). V.sub.THP of about 0.8 volts identifies the threshold voltage of a p-channel transistor. Such a high preloading potential, however, prevents short access times.


Gastric epithelial dysplasia and sulphomucin-type intestinal metaplasia.
The HID-AB histologic staining technique, which distinguishes sulphomucin from sialomucin types of intestinal metaplasia, was employed in endoscopic gastric mucosal biopsies to evaluate their frequency of association with epithelial dysplasia. Sulphomucin-type intestinal metaplasia was found in 33% of the cases under observation; moderate or severe dysplasia was only associated with this type of intestinal metaplasia. Its precancerous significance can be ascertained only by means of prospective studies.


We are in the process of updating parts of our hire fleet meaning we will have machinery coming up for sale as and when. At the moment we have 2x: Etesia Attila AV88 (see pictures/video). If you would like any additional information please give us a call: 01273 494939

Etesia Attila AV88 – cutting width of 88cm / 35” - 1 of 2 for sale

The Etesia Brush cutters have a proven track record to cope with the most demanding of jobs including brushwood, brambles, bracken and long grass.

This ex-hire mower was purchased in 2013 and has been fully maintained whilst on the hire fleet

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I have to give a talk for my mushroom club in May. I would like it to be something that
the members can do in their kitchens without any special equipment. I've pretty well
exhausted Pleurotus.
What else can be grown with just pasteurization and no HEPA filtering?
Reishi? Shiitake?
---- Mark
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You Name It , I have It

Pizza Hut Chinese New Year CHEES-SANG 2018 , Malaysia

Pizza Hut Serves up happiness this Chinese New Year with the All- New CHEESE-SANG Cheesy Bites

Sharing happiness this festive season and encouraging Malaysians to spread the joy with others .

Petaling Jaya , 12 Febuary 2018 - Pizza Hut Malaysia , Malaysia's No.1 pizza chain launches its first ever Cheese-Sang Cheesy Bites , as a way of bringing happiness to the table this Chinese New Year season . With this launch . Pizza Hut invites Malaysians to spread a little happiness to their loved ones and share in each other's joy . This limited edition pizza will be available nationwide in January and Febuary 2018 and through dine in , delivery and take away .

The Cheese-Sang Cheesy Bites comes complete with eighteen generous bites full of cozing cheddar and mozzarella cheese and topped with crispy fried tempura king prawns , pineapple on a bed of creamy salted egg sauce .

The Chinese New Year , Pizza Hut is encouraging Malaysians to pause and take time to do something that makes them or others happy wherever that may be . Malaysians live in a multicultural society where everyone regardless of race or religion can enjoy some happy times together .

Merrill Pereyra , Chief Executive officer of QSR Brands (M) Holdings Bhd said , " As the leading Pizza chain in Malaysia , we pride ourselves in being the brand that connects people to enjoy the happy times as they share a great pizza together , This Chinese New Year shouldn't be any different .

With the festive season upon us , you'll notice many people taking part in the 'Yee Sang' tradition , otherwise known as the Prosperity Toss to usher in the New Year . It's in this season where family and friends come together to toss a dish while sharing in each other's joy . Our Cheese-Sang Cheesy Bites is inspired by that and part of our decision to marry the 'Yee Sang' concept with pizza . It's our own way of bringing cheer to our customers . We know that happiness is contagious . It spreads to people and amplifies regardless of race or religion and that's how we believe we can impact society , Through the Cheese-Sang Cheesy Bites , " he added .

Whether it's being purchased ala carte at RM 38.00 for a regular size or as a combo , the Cheese-Sang Cheesy Bites is the perfect meal for Malaysians to get in the festive spirit and celebrate the New Year with a fun and unique twist to the 'Yee Sang' tradition .

Pizza Hut generously offers three combos . Golden Porsperity Meal . Double Happiness Meal and Double Fortune Meal that are priced reasonably at RM78.80 , RM45.80 and RM42.80 , respectively , The Golden Prosperity Meal for four to five people includes a regular sized Cheese-Sang Cheesy Bites pizza , a plate of salted egg prawns , an appetiser , four drinks and four ice cream . The Double Happiness Meal for two to three people includes a choice of either a regular sized Cheese-Sang Cheesy Bites pizza , a pan/hand stretched Supreme pizza pf Favourite pizza , one appetiser and two drinks while the Double Fortune Meal for two cream of mushroom soups , one appetiser and two drinks

*Prices for the Cheese-Sang Cheesy Bites pizza and its combos may vary depending on location .

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In a discussion with Scientific American Mind executive editor Mariette DiChristina, three noted experts on creativity, each with a very different perspective and background, reveal powerful ways to unleash your creative self.


Q:

How to implement this notification design and have it sensibly responsive

I am attempting to implement this, simple enough design for a notification block.

Including the ability to respond by wrapping the text block on smaller screens, similar to the below;

The intention here is to center align the notification to the parent row, and preferably when the viewport is too small, have the text wrap and height of the horizontal banner on which it sits increase in height accordingly. This will be included in a bootstrap project (may affect floats etc).
Here is a pen showing one of the more simple approaches (and probably closest so far) I've been trying to achieve this.

*,
html {
  font-family: arial;
  font-size: 20px;
}
.extra-row {
  text-align: center;
  padding: 1em;
  border: 1px solid #eee;
  background-color: #ccc;
}
.notification {
  text-align: center;
  color: #fff;
  white-space: nowrap;
}
.notification-circle {
  width: 150px;
  height: 150px;
  background-color: #3D7A1A;
  -moz-border-radius: 75px;
  -webkit-border-radius: 75px;
  border-radius: 75px;
  position: relative;
  display: -webkit-flexbox;
  display: -ms-flexbox;
  display: -webkit-flex;
  display: inline-flex;
  -webkit-flex-align: center;
  -ms-flex-align: center;
  -webkit-align-items: center;
  align-items: center;
  justify-content: center;
}
.notification-icon {
  font-size: 5em;
}
.notification-block {
  min-height: 150px;
  line-height: 150px;
  display: inline-block;
  margin-left: -30px;
  vertical-align: top
}
.notification-block span {
  background-color: #54A127;
  padding: 1em;
  padding-left: 50px;
}
<link href="https://maxcdn.bootstrapcdn.com/bootstrap/3.3.6/css/bootstrap.min.css" rel="stylesheet"/>

This is a row above

i

Lorem ipsum dolor sit amet, consectetur adipiscing elit.

This is a row below

There's quite a few suggestions for vertically centering text in this manner, most appear to rely on line-height which is an issue here with wrapping the text.
This may not be the best approach due to using line-height, but the problems here are;

Preventing the circular container and text container from
wrapping.
Wrapping the text within the container while still
maintaining the overall height/vertically centered position of the text block.
Wrapping the text with a sensible line-height.

Adding white-space: nowrap; to the .notification element does prevent #1, but prevents the text from wrapping, which simply extends past the viewport.
Can anyone shed any light on a better approach? Any thoughts would be appreciated.
Many thanks,
Baps.

A:

Hopefully this sets you on the right path.
I've removed a lot of unnecessary code. I've also removed the prefixes for the demo.
This adjustment may be all you need:
.notification {
     display: flex;                  /* 1 */
     align-items: center;            /* 2 */
     color:#fff;
}
.notification-circle {
     flex: 0 0 150px;                /* 3 */
     height: 150px;
     background-color: #3D7A1A;
     border-radius: 75px;
     display: flex;
     align-items: center;
     justify-content: center;
}
.notification-block {
     margin-left: -50px;             /* 4 */
     background-color: #54A127;      /* 5 */
     padding: 1em;                   /* 5 */
     padding-left: 75px;             /* 5 */
     z-index: -1;                    /* 6 */
}
.notification-block span { }
.notification-icon { font-size: 5em; }

Revised Codepen
Notes:

Make wrapper a flex container
Vertically center both flex children (.notification-circle and .notification-block)
Don't grow. Don't shrink. Remain fixed at 150px width.
Changed from margin-left: -30px
Relocated code from span child
Ensure .notification-block doesn't overlap .notification-circle


Q:

Can I run custom firmware on a pre-certified RF module without needing to redo full FCC certification?

I need BLE connectivity in a product, so to save costs on FCC certification, Bluetooth SIG membership, etc. it will use a pre-certified module for this purpose.
Usually such modules work in one or multiple of the following ways:

Controlled through an external interface (e.g. AT commands over UART)
Programmable using some proprietary scripting language (e.g. Bluegiga modules)
Fully user programmable

The first two approaches seem logical, the manufacturer of the module has very tight control over what can be done with the hardware (especially RF parameters, etc.).
The third approach is very appealing - most BLE chips already contain powerful microcontrollers, so it make sense to do all the processing on them. However I'm not sure whether one still gets the simplified FCC certification. I was under the impression that firmware is part of FCC testing too, especially since RF parameters (usually) can be changed significantly by software. However I wasn't able to find any warnings/clarifiactions about that in the datasheets/app notes/other docs. Could anyone clarify this a bit?
I'm mainly looking at nRF52 based and Cypress EZ-BLE modules.

A:

It has been my experience that you would have to re-certify if you are replacing the firmware in the module.
Be aware that despite the pre-certified nature of certain modules that ultimately you or your company are responsible for meeting the legal requirements for emissions and immunity of the product as a whole. So even though a module may be pre-certified you still need to test your system with the module present.
The only place I know of where a pre-certified type module may have some decided advantages are as follows:

For an embedded module you at least know that the pre-certified module is much less likely to be the source of issues for your system.
A module like an analogue telephone line modem that probably carries several pre-certs may excuse you from testing the analogue phone line requirements whereas the emissions and immunity part may need to still be qualified with your system as a whole.
Externally applied attachments to your product such as power bricks and cords can come pre-certified and safety inspection labeled such that you do not have to deal with that over again for your product. (A very common reason so many products today have external power bricks or wall warts).


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 *  you may not use this file except in compliance with the License.
 *  You may obtain a copy of the License at
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 *
 *  Unless required by applicable law or agreed to in writing, software
 *  distributed under the License is distributed on an "AS IS" BASIS,
 *  WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
 *  See the License for the specific language governing permissions and
 *  limitations under the License
 *
 *
 * @file        Certificates.cs
 * @author      Ernest Borowski (e.borowski@partner.samsung.com)
 * @version     1.0
 * @brief       This file contains interface for connecting ViewModel with Model
 */

namespace SecureRepository
{
    using System.Collections.Generic;

    /// <summary>
    /// Interface for platform dependent MainModel.
    /// </summary>
    public interface IMainInterface
    {
        /// <summary>
        /// Gets Decrypted text.
        /// </summary>
        string DecryptedText
        {
            get;
        }

        /// <summary>
        /// Gets Encrypted text.
        /// </summary>
        string EncryptedText
        {
            get;
        }

        /// <summary>
        /// Gets Item List.
        /// </summary>
        List<ListViewGroup> ItemList
        {
            get;
        }

        /// <summary>
        /// Adds Items to Managers.
        /// </summary>
        void Add();

        /// <summary>
        /// Encrypts then Decrypts data.
        /// </summary>
        void EncryptDecrypt();

        /// <summary>
        /// Gets Selected Item Prefix.
        /// </summary>
        /// <param name="selectedItem">Currently selected item in UI.</param>
        /// <returns>Selected Item prefix.</returns>
        string GetSelectedItemPrefix(Item selectedItem);

        /// <summary>
        /// Gets Selected Item type.
        /// </summary>
        /// <param name="selectedItem">Currently selected item in UI.</param>
        /// <returns>Selected Item type.</returns>
        string GetSelectedItemType(Item selectedItem);

        /// <summary>
        /// Removes all Items from Managers.
        /// </summary>
        void Remove();
    }
}


Immunity to diphtheria in young British adults.
Of 906 recruits aged between 16 and 20 years who were Schick-tested upon entry to the Royal Air Force, 775 were tested for circulating Corynebacterium diphtheriae antitioxin by means of an indirect haemagglutination (IHA) method. Of the total population, 95.7% were Schick-test negative, 3.5% were Schick-test positive and 0.8% gave pseudo-reactions. Of those tested by the IHA test, 37.7% were regarded as immune, 47.0% as 'immune-susceptible' and 15.3% as non-immune. Discrepancies between the two tests were discovered. Of those persons found to be Schick-test positive, 34.6% possessed circulating antitoxin; of those Schick-test negative, 13.5% were regarded as non-immune. A history of diphtheria immunisation in childhood was found to be a poor predictor of immunity. A protocol for selective diphtheria immunisation of adults is proposed.


Unemployment benefits applications fall but joblessness remains high

Unemployment benefits: Fewer people applied for unemployment benefits last week, though some of that was due to technical factors. And the economy grew slightly more in the April-June quarter than previously estimated.

Rick Bowmer/AP

Job seekers stand in line during US Rep. Jaime Herrera Beutler's 'Getting Southwest Washington Back to Work Job Fair,' on Sept. 28, in Vancouver, Wash. The number of people seeking unemployment benefits fell to the lowest level in 5 months.

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September 30, 2011

By Christopher S. Rugaber and Martin CrutsingerAssociated Press

WASHINGTON

The economy is showing signs of modest improvement — not enough to reduce highunemployment but enough to ease fears that another recession might be near.

Fewer people applied for unemployment benefits last week, though some of that was due to technical factors. And the economy grew slightly more in the April-June quarter than previously estimated. Growth is also expected to tick up in coming months.

Investors drew some hope from the latest data, as well as from news that Germany's government approved a plan to bolster Europe's response to its debt crisis. The Dow Jones industrial average finished up 143 points, or 1.3 percent, after a day of volatile trading.

Some of the news Thursday wasn't encouraging. Chief executives of the nation's largest companies are more pessimistic than they were just three months ago, according to a survey by a trade group, the Business Roundtable.

Only about one-third of the CEOs said they plan to hire or boost spending in the next six months. That's down from about half who said so in June.

And fewer Americans signed contracts to buy homes in August, the second straight month of declines.

The economy expanded at an annual rate of 1.3 percent in the April-June quarter, up from an estimate of 1 percent a month ago, the Commerce Department said. The improvement reflected modestly higher consumer spending and a bigger boost from trade.

Even so, the economy grew at an annual rate of just 0.9 percent in the first six months of the year. That's the weakest six-month performance since the recession ended more than two years ago.

Many Americans are spending less because they're paying off debt. That trend is likely to hold back the economy in the months ahead.

Michelle Fregoso, 32, and her husband recently put off buying a new car, and they canceled a gym membership. They're focused on paying off their credit cards.

All the talk of slow growth and a possible recession has made Fregoso, who lives and works outside Chicago, more cautious.

"Obviously the economy stinks," she said. "We just want to be careful about how we're spending our money."

Weak consumer spending, high unemployment and financial market turmoil could slow growth for the rest of this year.

Most economists don't expect another recession. But they also don't see growth accelerating much. Many foresee a rebound to between 2 percent and 2.5 percent growth in the current quarter.

Many economists expect similarly tepid growth in 2012 and 2013. The economy would need to grow consistently at 4 percent to 5 percent to generate enough hiring to lower unemployment significantly.

"Growth remains sluggish and insufficient to reduce the unemployment rate," Ryan Sweet, an economist at Moody's Analytics, said in a note to clients.

The unemployment rate was stuck at 9.1 percent in August for the second straight month. Employers didn't add any jobs in August — the weakest showing in nearly a year.

Economists expect little if any improvement in hiring for September. Sweet thinks employers will have added 50,000 jobs this month. More than twice as many jobs would be needed just to keep up with population growth.

Others are gloomier. Capital Economics predicts that the economy in September will have failed for a second straight month to create any jobs. The main problem, the firm says, is that businesses don't think their customer demand justifies additional workers.

Though growth has probably strengthened a bit in the July-September quarter, the economy suffered shocks that will restrain growth in the final quarter of this year, economists say.

In early August, for example, Congress fought to the final hours before raising the nation's borrowing limit. That delay, in part, led to a downgrade of long-term U.S. debt by Standard & Poor's. Stocks tumbled in response.

In addition, consumer confidence plunged last month to its lowest level since April 2009, when the economy was officially in recession.

And retail sales were flat in August, a sign that the turmoil caused consumers to pull back.

Businesses and investors are also worried that Europe won't be able to prevent Greece from defaulting and worsening the region's debt crisis. If Greece defaults, it could destabilize other indebted countries, such as Portugal, Ireland and Italy. It could also harm many of Europe's banks, which own Greek debt.

And if European banks hoard cash to make up for their losses and stop lending to their U.S. counterparts, that could restrict credit in the United States and slow the economy. A financial crisis in Europe would also reduce U.S. companies' exports and sales to the region.

Last week, applications for unemployment benefits dropped 37,000 to a seasonally adjusted 391,000. That was the fewest since April 2.

Some of the improvement was due to technical factors related to the seasonal adjustment of the data, a Labor Department spokesman said. The spokesman also said some states had reported higher applications in previous weeks due to Hurricane Irene.

As a result, the drop in applications for benefits "may not be as encouraging as it looks," said Paul Dales of Capital Economics. "Further falls will be needed before we can conclude a downward trend is underway."

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Throughout my childhood, I was raised in a town of suburbia, where I was fortunate to have a very large backyard to play in with friends. Thankfully, that was all my father's doing and his love for being outdoors. If I didn't find my dad barbecuing on the grill, I'd find him working on another landscaping project. He planted every vegetable and herb you can imagine in the garden. It was a great excuse to invite family, friends and neighbors over for our homegrown and homemade dinner. There were so many wonderful gatherings held and numerous jokes and stories told in our backyard.

Since then, I've instilled the tiny green thumb gene in me now that I live in a big city. My favorite is planting mint leaves in my kitchen because they are very mild for the living conditions they require and the smell reminds me of my childhood home. I use them in my tea, freshly squeezed juices and to garnish my cool spring and summer cocktails and snacks. Fresh-cut flowers are a must-have in my apartment and vital to my everyday work as an interior designer. Naturally, when the weather is warm and plants are in bloom, I host outside picnics or an afternoon soiree for my closest friends. There's simply nothing greater than revisiting my roots and sharing traditions with ones I love.


Atlantic Airways

Atlantic Airways (, Faroese: Atlantsflog) is the national airline of the Faroe Islands, operating domestic helicopter services and international passenger services as well as search and rescue responsibilities from its base at Vágar Airport, on the Faroese island of Vágar. Most of its pilots are members of the Faroese Pilot Association.

History
Regular air links to the Faroes had been in operation since 1963, between the islands and Denmark. Although the airport at Vágar had been constructed by the British Army during World War II, air traffic to the islands was practically non-existent between the departure of the British and the start of services to Copenhagen. Calls for the creation of a Faroese airline company began in the early 1980s. Passenger numbers were steadily increasing and Danish carrier Maersk Air enjoyed the monopoly as the sole airline to serve the Faroe Islands.

As a result, Atlantic Airways was established in 1987, initially between the Faroese government (51%) and Danish airline Cimber Air (49%), though the Faroese government would assume full ownership in 1989. Flights commenced between Vágar and Copenhagen on 28 March 1988 using a British Aerospace BAe 146.  A hangar was built at Vágar by the Faroese government in order to secure Atlantic Airways' home base in the Faroes, ensuring maintenance facilities were available on the islands.

The aim of the new airline company was to build up a Faroese aviation industry on a commercial basis and to ensure the Faroe Islands an air connection with the outside world. Flight crews and management were Faroese.

Though load factors were high and the new service was popular, Atlantic Airways had a turbulent beginning economically. The Faroe Islands suffered a severe economic depression in the early 1990s, and at its nadir in 1992, the Faroese government delivered 75 m DKK in aid to the ailing carrier. Atlantic Airways would not become profitable until 1995.

Flights were launched to Reykjavík in 1995 in co-operation with Air Iceland, and also to Narsarsuaq in Greenland in the summer months, in co-operation with Air Iceland. The latter half of the 1990s saw Billund in Denmark and Aberdeen in the UK added to Atlantic Airways' flight schedule.

The growing list of destinations and passenger numbers, together with the stabilisation of the airline's finances, saw a second BAe 146 added to the fleet in 2000. This new aircraft meant services to London (Stansted) in the UK and the Norwegian capital Oslo added to the network. Growth in tourism on the islands has also enabled flights to Aalborg, Stavanger, Stord and Edinburgh.  However, for the 2006 season services to Stord have been discontinued, and Edinburgh replaced by the Shetland Islands.  Atlantic Airways also entered the UK domestic market in 2006, becoming the only carrier to offer a direct service between Shetland and London, which it did on a twice weekly basis. The UK domestic operation ceased in 2008.

Atlantic Airways also operates a domestic service by helicopter, in many instances a vital connection to many of the islands, which otherwise can only be reached by sea. The helicopter has proved a vital tool on the islands since the 1960s, when helicopters from Danish coast guard vessels patrolling the Faroes undertook a variety of tasks, including ferrying equipment and supplies between the islands. The government hired a helicopter in 1978 for these tasks, but in the 1980s a commercial public helicopter service was launched linking each of the islands using two Bell 222 helicopters.

Initially, the helicopter service was a standalone company, SL Helicopters, but the decision to concentrate Faroese aviation into one firm led the helicopter department becoming part of Atlantic Airways in 1994.  The helicopters provide a round trip 'hopper' service to each of the islands, which is also ideal for tourists looking for aerial views.  The company is required to have at least one helicopter, operational and ready for search and rescue duties.

Over the last 5 years, Atlantic Airways has produced profits of between 8 and 13 million DKK.  The company has increased its turnover from 120 million in 1998 to 520 million DKK in 2006.  Atlantic Airways employed 177 people at January 2007.

Atlantic Airways was listed at the Iceland Stock Exchange on 10 December 2007.

The Faroese government has decided on a privatisation process and has sold off 33% of the company in the first bidding round. The first day of trading was 10 December 2007.

The government was planning to sell off 33% more in 2008, but this was cancelled due to the financial crisis.

The first Airbus A319 for Atlantic Airways, registered OY-RCG, entered service in March 2012, with a modified livery. The runway at Vágar required an extension to properly accommodate this aircraft.
The second and third Airbus 319s (OY-RCH and OY-RCI) entered service in May and October 2013 respectively. As the lease of these ran out by the end of 2016, only one was renewed while a brand new Airbus A320 was delivered.

On 3 June 2015, Jóhanna á Bergi became CEO of the company. She is the first woman to become CEO of a Nordic airline.

In December 2018, the airline submitted an application for commercial services to the United States.

Destinations

International services
As of December 2019, Atlantic Airways serves the following scheduled destinations:

Charter operations
Atlantic Airways also operates charters for Danish tour operators to destinations such as Italy, Croatia, Bulgaria, France, Scotland, Norway and the Czech Republic, out of Copenhagen Kastrup and Billund airports.

Domestic services
There is domestic helicopter service to the islands. The helicopters depart from Vágar Airport on Sunday, Monday (only in June, July August), Wednesday, and Friday.

The flights visit the capital Tórshavn and second largest town Klaksvík, the southern islands Skúvoy, Stóra Dímun, Suðuroy (Froðba), the northern islands Svínoy and Fugloy (Hattarvík and Kirkja), the western island Mykines, and the island Koltur.

Codeshare agreements

Atlantic Airways currently has codeshare agreements with Air France and KLM.

Fleet
As of August 2019, the Atlantic Airways fleet consists of the following aircraft:

Fixed-Wing Fleet

Helicopter Fleet

The AgustaWestland AW139 is the only primary helicopter used for flights to district villages. With a capacity to seat 15 passengers, the helicopter is used to shuttle passengers in the Faroe Islands.

Accidents and incidents
1989: an Atlantic Airways BAe 146–200 (registration OY-CRG) aircraft failed to stop at the end of the runway and was subsequently out of service for 3 weeks.
On 10 October 2006, Atlantic Airways Flight 670, a BAe 146–200, exactly the same aircraft as above, skidded off the runway at Stord Airport in Norway. Of the 12 passengers and 4 crew, 4 were killed and 12 survived with injuries. The aircraft had been chartered by Aker Kværner to fly personnel from Stavanger (Sola Airport) to Molde via Stord. The aircraft appears to have been unable to stop on the runway when its spoilers failed to extend during landing. The aircraft crossed the threshold and continued down a slope before coming to rest and catching fire.

References

External links

Official website

Category:Airlines of the Faroe Islands
Category:European Regions Airline Association
Category:Helicopter airlines
Category:Airlines established in 1987

Category:1987 establishments in Denmark


TR's Windows performance comparison

As if you needed another trilogyby Andy Brown  1:33 AM on November 8, 2001

Get past all that, however, and the first question that comes to mind (to us anyway) is "But is it any faster?" In the past, the tendency has been for newer Microsoft operating systems to run more slowly on older hardware, but offer performance benefits on well-equipped systems. Windows XP offers a new twist in that it's designed to bridge the gap between the 9x kernel and the NT kernel. How does Windows XP stack up from a performance standpoint, compared not only to Windows 2000, but to Windows ME?

Apart from InfoWorld's results, which show WinXP to be much slower than Win2K, not much research has been done one the performance characteristics of Microsoft's new operating system. Since Windows XP stands to replace both Windows 2000 and Windows ME, it seems appropriate to compare the new OS to its predecessors on a variety of tests; simply throwing a couple of Office tests at these OSes won't do them justice. Additionally, given the past importance of hardware on the results, testing on one platform would be inadequate. Therefore, we've compiled a wide array of synthetic and real world benchmarks, on both a high-end and low-end test platform, to determine the ultimate Windows performance king.

Is WinXP a dud? Is the 9x core really that dated? Is there a reason to upgrade from Windows 2000? Read on and find out.

The players Before we get into the performance benchmarks, it's worth taking a moment to consider the operating systems in question. We've chosen the most recent (pre-WinXP) versions of Microsoft's business and home operating systems to compare to the newly released WinXP.

Using Windows 2000 is a no-brainer here, but the choice of ME might ruffle a few feathers. Some might argue that Windows 98 or 98SE would be a better choice. However, Microsoft (at least their marketing department) claims that WinME is the pinnacle of the 9x kernel and the immediate predecessor to Windows XP. We decided to take MS at their word, which means ME is the best choice to represent the 9x kernel. We don't use 9x-based OSes for benchmarking much here at TR; we're NT snobs, so it's all 2000 or XP. Because XP forever banishes the 9x core from Microsoft's OS stable, it's only fair that we give it one last chance to go down in a blaze of glory.

Our testing methods As ever, we did our best to deliver clean benchmark numbers. Tests were run three times, and the results were averaged.

Our test systems were configured as follows:

The test systems' Windows desktops were set at 1024x768 in 32-bit color at a 75Hz screen refresh rate. Vertical refresh sync (vsync) was disabled for all tests.

For both WinME and WinXP, the System Restore utility was disabled. Otherwise, the OSes were left in their default configurations with no tweaking. Both XP and 2000 were installed on NTFS partitions; WinME was installed on a FAT32 partition due to its lack of NTFS support.


Del City police are investigating a shooting near SE 9th Street and Sunnylane.Police said the shooting happened around 5:45 a.m. Thursday at an apartment complex in a breezeway. According to police, an altercation turned into a shooting.Police said one person was hit in the head with gunfire, but it was minor and he was taken to the hospital in a private vehicle.One person is in custody, according to police. Both men may face charges.

DEL CITY, Okla. —

Del City police are investigating a shooting near SE 9th Street and Sunnylane.

Police said the shooting happened around 5:45 a.m. Thursday at an apartment complex in a breezeway. According to police, an altercation turned into a shooting.

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Police said one person was hit in the head with gunfire, but it was minor and he was taken to the hospital in a private vehicle.

One person is in custody, according to police. Both men may face charges.


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New Price Rollback for January 2009

Tuesday, January 06, 2009

Uyyy...Ang sweet! Hahaha!

Good news for everyone! The Department of Energy is expecting a major rollback in prices of diesel and gasoline this January. This has been the expected outcome since the prices of oil has not risen significantly in the last few months of 2008. Prices are still too high as to what is computed as fair in the 3 big oil companies.

Energy Secretary Angelo Reyes formally contradicted newbie local oil player Flying V that there would not be a rollback this month because the trend of oil prices is going up in the world market and they have already given the discounts as early as December of last year. They are also warning the public that the oil prices will continue to gain momentum and raise a few dollars more in the coming months. Reyes defended this stand stating that the prices of crude oil in the US was higher even in November which justifies the expected rollback for this month. If it's not given what's due, then an investigation will push through for these private companies he stated.


Office block fire in Glasgow brought under control Published duration 9 June 2018

image copyright R McGinley

A fire in Glasgow which sent smoke billowing across the city centre has been brought under control.

Four fire engines were sent to the scene at about 08:50 after the blaze broke out in a office block under renovation in Cadogan Street.

A spokeswoman for the Scottish Fire and Rescue Service said the blaze was now under control.

She said there were no casualties and no indication that nearby buildings were evacuated.

Police closed Cadogan Street at Blythswood Street while the blaze was dealt with.


So Hard to Say Goodbye: Blockchain.Info Goes Dot Com

One of the oldest, most respected sites in the cryptosphere, Blockchain.info (Info), is moving domains. For many ecosystem veterans, Info was where it all started. First wallets. First block exploration. First real interaction with cryptocurrency. Recently, the group announced its move and plans for the future. It’s also a change signaling maturation of the space.

Also read: Supremes Uphold Cell Privacy, Hope for Ross Ulbricht

Blockchain.Info Moving to Blockchain.com

“Later this month,” a notice on the Blockchain.info blog of read, “we’ll be consolidating all pages on blockchain.info under our one and only blockchain.com domain. We’ve been looking forward to this merger for quite some time, because it means you’ll only have one place to go for all of your crypto needs, instead of two. In the coming weeks, you’ll be able to access all of your .info favorites from blockchain.com.”

Info routinely ranks in the top 1,000 global websites, according to Alexa. The Luxembourg-based company took off Summer of 2011, and was widely known as a dependable block explorer. It grew to much more than that. Transaction data, charts, wallet, mined blocks information, developer resources, along with forum and media links. Their Android mobile app is also very popular.

The halcyon days in 2013-2014 saw Info become the most visited bitcoin-related website in the world, some 120 million views. It was the first to reach one million wallets. It was such a staple of the nascent community, when Apple nixed its iOS version, apeshit would be an understatement in terms of the reaction (people smashed their iPhones!). It was also during this time Info got its monetary sealegs, boasting tens of millions in venture capital. Street cred wasn’t dampened at all, as its wallet earlier embraced Tor.

Fast forward years later, and they’re “now one of the oldest, most established company in the industry and so much more than a bitcoin explorer,” they acknowledge. “We’re the world’s leading crypto wallet where 25 million users invest in and store Bitcoin (BTC), Ether (ETH), and Bitcoin Cash (BCH). We also allow users to analyze the top cryptocurrencies via our markets page and are continually expanding our widely used API services to make it even easier for developers to build on top of the block chain.”

Looking Forward

They continue to rake-in cash. During the 2017 run up, Info snapped up another $40 million in venture dough. It took a bold step that same year by partnering with Unocoin to bring greater crypto awareness to India. They’ve also become something of an exchange, operating in nearly half of US states as a way to buy and sell crypto.

The domain move keeps a solid team intact, including co-founder Nicolas Cary. Mr. Cary was an early business leader in the space, attempting to marry commerce and philanthropy. He has a particular passion for encouraging youth entrepreneurs, founding Skies the Limit project. They “use data provided from our entrepreneur and volunteer users – such as their skills or needs, location, and stage of business – to predict and recommend high-quality matches. Then, we monitor and support these matches over time to help our entrepreneurs develop skills, build businesses and create jobs for themselves and others in their communities.”

The company promises a seamless transition to its dot-com digs. “We’ve done a lot over the years,” they conclude, “but have a lot more to do in building the future of finance. As we move forward through 2018, we know that your needs are ever-changing, and we need to be prepared to offer you the end-to-end experience you’ve been waiting for.”

What are your thoughts on Blockchain.info’s move? Let us know in the comments.

Images via the Pixabay, Blockchain.info.

Verify and track bitcoin cash transactions on our BCH Block Explorer, the best of its kind anywhere in the world. Also, keep up with your holdings, BCH, and other coins, on our market charts at Satoshi Pulse, another original and free service from Bitcoin.com.


Kadawunu Poronduwa

Kadawunu Poronduwa (Sinhala: කඩවුනු පොරොන්දුව, "The Broken Promise") was the first film to be made in the Sinhala language; it is generally considered to have heralded the coming of Sinhala Cinema. The film was produced and filmed in India however, and was highly influenced by South Indian melodrama. It was first shown on January 21, 1947 at the Kingsley Cinema in Colombo, Sri Lanka.

A remake was released in 1982.

Plot

Ralahamy, a member of high status, dies leaving his family in debt after having squandered his fortune through extensive drinking and other vices. To get back into wealth, Ralahamy's wife Tackla pushes her daughter Ranjani to get married to a wealthy older man Victor with a child through an earlier marriage. In this process, Samson, Ranjani's boyfriend, who had tried extensively to get the family back into good graces going so far as to pay off their debts, is spurned. He then goes abroad to win a fortune.

When Samson returns he learns of Ranjani's engagement to Victor and tries to reach her through letter. His letters are hidden from her however, and rumours spread that Samson is now a cripple. Ultimately the truth is revealed.

Cast
Rukmani Devi as Ranjani: A high class girl who is pushed into a marriage with an older man and forced to reject her boyfriend.
Gemini Kantha as Jossie: village woman; love interest of Manappuwa
Rupa Devi as Tackla: Ranjani's mother
Miriam Jayamanne as Hilda
Eddie Jayamanne as Manappuwa: naive village simpleton; comic relief
B. A. W. Jayamanne as Samson: love interest of Ranjani; seeks to help her family achieve financial success but is spurned by the mother
Peter Peries as Victor: old wealthy man that Ranjani is forced into engagement with
Stanley Mallawarachchi as Hemapala
D. T. Perera as Jayasena
Asilyn Balasooriya as Sumana
J. B. Perera as Harmahana
Hugo Fernando as doctor
Suriya Rani as Aaya
Sina Pishpani as Narsi
Wida Soyza
S. S. Ponnisena

Production
Kadawunu Poronduwa was produced by S. M. Nayagam, a pioneer of Sinhala film industry and an Indian citizen. He had to ferry the entire cast to Madurai India for filming and production. started off first as a successful play for dramatist B. A. W. Jayamanne. In 1947 he filmed and processed the movie in South India.

Kadawunu Poronduwa produced a formula that Sinhala films would follow up through the 1960s; Jayamanne describes the formula as such:

Songs

"Sri Jaya Vijaya"            – Minerva Singing Group
"Prema Daya"               – Rukmani Devi
"Lapati Rupe Age"        – Eddie Jayamanne (original gramophone redord label was incorrectly printed as "Eddie jayanamme and Jemini Kantha" )
"Deva Swarmi"              – Rukmani Devi
"Sandyawe Sriya Ramya Lesa Pena" – Rukmani Devi and Hugo Fernando - for film  /  Rukmani Devi and Stanley Mallawarachchi - for gramophone record only
"Is Issara Welaa"           – Eddie Jayamanne and Jemini Kantha
"Mage Saka Bambarea" – Eddie Jayamanne and Jemini Kantha
"Thakkita Tharikita"      – Eddie Jayamanne and Jemini Kantha
"Jevithaye Saamey"      –  Rukmani Devi
"Yaami Indiya Desataa" – Rukmani Devi
"Sundari Rupa Rajini"   – Stanley Mallawarachchi and Peter Peries
"Papi Shayapi Do"        – Rukmani Devi and Hugo Fernando / Stanley Mallawarachchi

Songs of Kadawunu Poronduwa were issued by Parlophone gramophone records with the film release in 1947. They were the last records issued by Palophone label in Sri Lanka.

Please note that the last two songs listed above were not issued on gramophone records and now it is difficult to find them.

See also
List of Sri Lankan films

References

External links
Sri Lanka Cinema Database
National Film Corporation of Sri Lanka - Official Website

Category:1947 films
Category:Sri Lankan films
Category:1940s drama films
Category:Films set in British Ceylon
Category:Sri Lankan drama films
Category:Sri Lankan black-and-white films