*3.1. Modeled Ya*

Pixel-level Ya in 2010–2015 over the NCP was simulated using the modified PRYM– Maize. Results are shown in Figure 4. In each year, modeled prefecture-level yields had a root mean standard deviation (RMSD) value of 0.88 ± 0.14 t hm−2 and an R value of 0.49 ± 0.24 with the reference value. A pooled analysis for modeled yield vs. reference yield in 2010–2015 shows modeled yield by PRYM–Maize has an R (RMSD) of 0.45 (0.87 t hm−2). The performance of PRYM–Maize is improved when modeled and reference prefecture-level yields are averaged in time (Figure 5b). Uncertainties in modeled yield are significantly reduced, and the RMSD of mean annual modeled yield vs. the reference value is 0.66 t hm−2, which is less than that in any one year (Figure 4).

The average of R (RMSD) values for modeled yield vs. reference value in each year is 0.49 (0.86 t hm−2). The model achieves the best simulations in 2011 with an R value of 0.66. Generally, R values achieved by PRYM–Maize in this study are not high, and one important reason for this is that the prefecture-level maize yield values in 2010–2015 are in a narrow range (4–9 t hm−2) and show relatively small dynamics over space, as represented by both reference (standard deviation (STD) = 0.88 t hm−2 for reference yield) and modeled yield (Figures 4 and 5a). Therefore, these results demonstrate that PRYM–Maize outputs reasonable estimates for the Ya of summer maize over the NCP.


*3.4. Efficacy of Zinc for ADHD Treatment*

The study of Noorazar and colleagues used the next intervention [69]: (a) a dose of 0.5–1 mg/kg/day methylphenidate plus placebo in the control group; and (b) a dose of 0.5–1 mg/kg/day methylphenidate plus 10 mg zinc (10 cc zinc sulfate syrup). No differences between the groups were observed regarding the dose of methylphenidate. After 6 weeks of treatment, the authors found that the use of zinc was useful to decrease the inattention scores (*p* = 0.02), but no differences between the groups were found in the other measures for the hyperactivity and impulsivity scales. The lack of differences in the total ADHD score in this study suggested that augmentation with zinc could only partially improve ADHD severity levels. The authors of the study also noticed that the difference between the two groups regarding the gender ratio compromised the generalization capacity, and that the use of the Connors Parent's Questionnaire as the only measure for ADHD was a significant limitation [although it is a standardized tool, the inclusion of additional instruments and informants (such as teachers) could have provided different perspectives of the children's behaviors and impairments].

The study of Zamora and colleagues also valued the effect of zinc supplementation (10 mg/day) as an adjuvant therapy (complementary to methylphenidate, with a dose of 0.3 mg/kg/day) for ADHD in *n* = 40 pediatric children, and obtained an improvement in ADHD signs associated to the experimental group in the questionnaires answered by teachers (no differences emerged from the parents' reports) [70]. These authors also obtained decreased zinc levels during the intervention in both groups (control and experimental conditions), suggesting that the methylphenidate could contribute to a decrease in zinc concentration that can be counteracted with zinc supplementation.

In the research by Arnold et al. with *n* = 52 ADHD children treated with d-amphetamine (weight-standardized) and zinc complementation (15 mg/day or 30 mg/day) or d-amphetamine and a placebo, a similar improvement in ADHD was observed in all the conditions (more precisely, teachers' ratings showed medium effect sizes favoring zinc, but parents' reports showed an opposite trend favoring the placebo) [71]. Interestingly, this trial also observed that the group treated with 30 mg/day zinc obtained 37% lower plasma levels of conventional drugs. The authors of this trial concluded that rises in zinc levels in blood tests suggested that children with ADHD may have a zinc-wasting metabolism (defined as low levels of zinc related with potential deficits in absorption or losses in urine), and therefore the zinc administered in the morning acted only as an immediate-release stimulant (this was probably the reason of the teachers' reports favoring this dietary supplement) but was next immediately excreted by mid-afternoon (parents could not observe improvements on the children's behaviors). As a global conclusion, Arnold and colleagues indicated that their study did not support zinc supplementation as a complementary tool for ADHD treatments, but also suggested that before discarding zinc as a potential treatment, it would be desirable that future research explores the situation further with different zinc doses/preparations, samples with children characterized for low zinc levels, and measures focused on neuropsychological tests as primary outcomes.

The study carried out by Akhondzadeh et al. aimed to compare two groups of patients with ADHD (with or without zinc augmentation, with a dose of approximately 15 mg/day) and both conditions treated with methylphenidate (1 mg/kg/day), and the experimental group obtained more improvement according to parents' and teachers' ratings at 6 weeks of the intervention [72]. Trend analyses also showed that differences between the groups increased during the treatment: while the placebo and the zinc supplementation groups only showed small differences at week 2, moderate to high differences were found at 4 weeks and 6 weeks (this pattern was observed for the questionnaires answered by teachers and parents).

The study by Bilici and colleagues among a large sample of *n* = 400 children with ADHD observed that the group receiving the zinc supplement (approximate dose of 40 mg/day) compared with the control group (receiving placebo) obtained greater improvements in multiple measures (hyperactivity, impulsivity, and socialization symptoms) but results were similar for attention deficiency [73]. The greatest differences between the groups were observed at 12 weeks of the intervention, and were few during 1 to 4 weeks. Regarding the potential mechanisms explaining these results, the authors conclude that the zinc supplement could affect the conversion of dietary pyridoxine to its active form (pyrodoxal phosphate), implied in the process of conversion of tryptophan to serotonin. In this sense, zinc should contribute to the increase in serotonergic functions, contributing to a decrease in the characteristic of impulsivity as a symptom of ADHD. Alternatively, the authors also suggested the existence of a synergism of zinc in regulating dopamine and norepinephrine, which has been implied in ADHD treatments. The study by Bilici et al. also showed that pre/post differences in the ADHD measures were predicted by age and BMI (a positive association was found in the B-slopes in regression analyses as higher age, and the BMI as higher change). Low pre-treatment zinc and free fatty acid values were also associated with a smaller decrease in ADHD symptom levels before and after the treatments. This evidence was also useful to determine which children could benefit more from including zinc supplementations in the ADHD treatments.


*Article* **Liver Growth Factor "LGF" as a Therapeutic Agent for Alzheimer's Disease**

**Rafael Gonzalo-Gobernado 1,2,**†**, Juan Perucho 1,**†**, Manuela Vallejo-Muñoz 1,**†**, Maria José Casarejos 1, Diana Reimers 1, Adriano Jiménez-Escrig 1,3, Ana Gómez 1, Gonzalo M. Ulzurrun de Asanza 1 and Eulalia Bazán 1,\***

Received: 23 October 2020; Accepted: 29 November 2020; Published: 2 December 2020

**Abstract:** Alzheimer's disease (AD) is a progressive degenerative disorder and the most common cause of dementia in aging populations. Although the pathological hallmarks of AD are well defined, currently no effective therapy exists. Liver growth factor (LGF) is a hepatic albumin–bilirubin complex with activity as a tissue regenerating factor in several neurodegenerative disorders such as Parkinson's disease and Friedreich's ataxia. Our aim here was to analyze the potential therapeutic effect of LGF on the APPswe mouse model of AD. Twenty-month-old mice received intraperitoneal (i.p.) injections of 1.6 μg LGF or saline, twice a week during three weeks. Mice were sacrificed one week later, and the hippocampus and dorsal cortex were prepared for immunohistochemical and biochemical studies. LGF treatment reduced amyloid-β (Aβ) content, phospho-Tau/Tau ratio and the number of Aβ plaques with diameter larger than 25 μm. LGF administration also modulated protein ubiquitination and HSP70 protein levels, reduced glial reactivity and inflammation, and the expression of the pro-apoptotic protein Bax. Because the administration of this factor also restored cognitive damage in APPswe mice, we propose LGF as a novel therapeutic tool that may be useful for the treatment of AD.

**Keywords:** liver growth factor; Alzheimer's disease; inflammation; neuroprotection; microglia; Tg2576 transgenic mice; amyloid-beta