Modulation of plant root growth by nitrogen source-defined regulation of polar auxin transport.

Availability of the essential macronutrient nitrogen in soil plays a critical role in plant growth, development, and impacts agricultural productivity. Plants have evolved different strategies for sensing and responding to heterogeneous nitrogen distribution. Modulation of root system architecture, including primary root growth and branching, is among the most essential plant adaptions to ensure adequate nitrogen acquisition. However, the immediate molecular pathways coordinating the adjustment of root growth in response to distinct nitrogen sources, such as nitrate or ammonium, are poorly understood. Here, we show that growth as manifested by cell division and elongation is synchronized by coordinated auxin flux between two adjacent outer tissue layers of the root. This coordination is achieved by nitrate-dependent dephosphorylation of the PIN2 auxin efflux carrier at a previously uncharacterized phosphorylation site, leading to subsequent PIN2 lateralization and thereby regulating auxin flow between adjacent tissues. A dynamic computer model based on our experimental data successfully recapitulates experimental observations. Our study provides mechanistic insights broadening our understanding of root growth mechanisms in dynamic environments.

Strigolactones act downstream of gibberellins to regulate fiber cell elongation and cell wall thickness in cotton (Gossypium hirsutum).

Strigolactones (SLs) are a class of phytohormones that regulate plant shoot branching and adventitious root development. However, little is known regarding the role of SLs in controlling the behavior of the smallest unit of the organism, the single cell. Here, taking advantage of a classic single-cell model offered by the cotton (Gossypium hirsutum) fiber cell, we show that SLs, whose biosynthesis is fine-tuned by gibberellins (GAs), positively regulate cell elongation and cell wall thickness by promoting the biosynthesis of very long-chain fatty acids (VLCFAs) and cellulose, respectively. Furthermore, we identified two layers of transcription factors (TFs) involved in the hierarchical regulation of this GA-SL crosstalk. The top-layer TF GROWTH-REGULATING FACTOR 4 (GhGRF4) directly activates expression of the SL biosynthetic gene DWARF27 (D27) to increase SL accumulation in fiber cells and GAs induce GhGRF4 expression. SLs induce the expression of four second-layer TF genes (GhNAC100-2, GhBLH51, GhGT2, and GhB9SHZ1), which transmit SL signals downstream to two ketoacyl-CoA synthase genes (KCS) and three cellulose synthase (CesA) genes by directly activating their transcription. Finally, the KCS and CesA enzymes catalyze the biosynthesis of VLCFAs and cellulose, respectively, to regulate development of high-grade cotton fibers. In addition to providing a theoretical basis for cotton fiber improvement, our results shed light on SL signaling in plant development at the single-cell level.

Renin and renin blockade have no role in complement activity.

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.

Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 4 Report.

PURPOSE: To evaluate (1) the long-term efficacy of low-concentration atropine over 5 years, (2) the proportion of children requiring re-treatment and associated factors, and (3) the efficacy of pro re nata (PRN) re-treatment using 0.05% atropine from years 3 to 5. DESIGN: Randomized, double-masked extended trial. PARTICIPANTS: Children 4 to 12 years of age originally from the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: Children 4 to 12 years of age originally from the LAMP study were followed up for 5 years. During the third year, children in each group originally receiving 0.05%, 0.025%, and 0.01% atropine were randomized to continued treatment and treatment cessation. During years 4 and 5, all continued treatment subgroups were switched to 0.05% atropine for continued treatment, whereas all treatment cessation subgroups followed a PRN re-treatment protocol to resume 0.05% atropine for children with myopic progressions of 0.5 diopter (D) or more over 1 year. Generalized estimating equations were used to compare the changes in spherical equivalent (SE) progression and axial length (AL) elongation among groups. MAIN OUTCOMES MEASURES: (1) Changes in SE and AL in different groups over 5 years, (2) the proportion of children who needed re-treatment, and (3) changes in SE and AL in the continued treatment and PRN re-treatment groups from years 3 to 5. RESULTS: Two hundred seventy (82.8%) of 326 children (82.5%) from the third year completed 5 years of follow-up. Over 5 years, the cumulative mean SE progressions were -1.34 ± 1.40 D, -1.97 ± 1.03 D, and -2.34 ± 1.71 D for the continued treatment groups with initial 0.05%, 0.025%, and 0.01% atropine, respectively (P = 0.02). Similar trends were observed in AL elongation (P = 0.01). Among the PRN re-treatment group, 87.9% of children (94/107) needed re-treatment. The proportion of re-treatment across all studied concentrations was similar (P = 0.76). The SE progressions for continued treatment and PRN re-treatment groups from years 3 to 5 were -0.97 ± 0.82 D and -1.00 ± 0.74 D (P = 0.55) and the AL elongations were 0.51 ± 0.34 mm and 0.49 ± 0.32 mm (P = 0.84), respectively. CONCLUSIONS: Over 5 years, the continued 0.05% atropine treatment demonstrated good efficacy for myopia control. Most children needed to restart treatment after atropine cessation at year 3. Restarted treatment with 0.05% atropine achieved similar efficacy as continued treatment. Children should be considered for re-treatment if myopia progresses after treatment cessation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Safety Profile of Selective Serotonin Reuptake Inhibitors in Real-World Settings: A Pharmacovigilance Study Based on FDA Adverse Event Reporting System.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed agents to treat depression. Considering the growth in antidepressant prescription rates, SSRI-induced adverse events (AEs) need to be comprehensively clarified. OBJECTIVE: This study was to investigate safety profiles and potential AEs associated with SSRIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: A retrospective pharmacovigilance analysis was conducted using the FAERS database, with Open Vigil 2.1 used for data extraction. The study included cases from the marketing date of each SSRI (ie, citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, and sertraline) to April 30, 2023. We employed the reporting odds ratio and Bayesian confidence propagation neural network as analytical tools to assess the association between SSRIs and AEs. The Medical Dictionary for Regulatory Activities was used to standardize the definition of AEs. AE classification was achieved using system organ classes (SOCs). RESULTS: Overall, 427 655 AE reports were identified for the 6 SSRIs, primarily associated with 25 SOCs, including psychiatric, nervous system, congenital, familial, genetic, cardiac, and reproductive disorders. Notably, sertraline (n = 967) and fluvoxamine (n = 169) exhibited the highest and lowest signal frequencies, respectively. All SSRIs had relatively strong signals related to congenital, psychiatric, and nervous disorders. CONCLUSIONS AND RELEVANCE: Most of our findings are consistent with those reported previously, but some AEs were not previously identified. However, AEs attributed to SSRIs remain ambiguous, warranting further validation. Applying data-mining methods to the FAERS database can provide additional insights that can assist in appropriately utilizing SSRIs.

Effects of firsthand tobacco smoking on retinal vessel caliber: a systematic review and meta-analysis.

PURPOSE: To review the effects of firsthand tobacco smoking on central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) of firsthand tobacco smokers. METHODS: We performed a search on EMBASE and PubMed for studies up to 15th July 2022. Two independent reviewers selected studies with baseline data of CRAE and CRVE of current smokers, nonsmokers, and former smokers. Initial search identified 893 studies, of which 10 were included in the meta-analysis. Two independent reviewers extracted data from the included studies. The quality of studies was assessed by the Newcastle-Ottawa Scale. RESULTS: In this meta-analysis, 7431 nonsmokers, 2448 current smokers and 5786 former smokers, as well as 7404 nonsmokers, 2430 current smokers and 5763 former smokers were included in CRAE and CRVE analysis respectively. Nonsmokers had narrower CRVE (Weighted mean difference [WMD], -12.15; 95% CI, -17.33 - -6.96) and CRAE (WMD, -4.77; 95% CI, -7.96 - -1.57) than current smokers, and narrower CRVE (WMD, -3.08; 95% CI, -6.06 - -0.11) than former smokers. Current smokers had wider CRVE (WMD, 10.42; 95% CI, 7.80 - 13.04) and CRAE (WMD, 7.05; 95% CI, 6.65 - 7.46) than former smokers. Subgroup analysis and sensitivity analysis were performed. CONCLUSION: Firsthand tobacco smoking resulted in wider CRAE and CRVE in current and former smokers, particularly in CRVE, and such changes may not be reversible after smoking cessation. Therefore, retinal vessel caliber may reflect the effects of firsthand tobacco smoking and be used to estimate the risk of cardiovascular diseases.

Analysis of the Properties of 44 ABC Transporter Genes from Biocontrol Agent Trichoderma asperellum ACCC30536 and Their Responses to Pathogenic Alternaria alternata Toxin Stress.

ATP-binding cassette (ABC) transporters are involved in transporting multiple substrates, such as toxins, and may be important for the survival of Trichoderma when encountering biotic toxins. In this study, genome searching revealed that there are 44 ABC transporters encoded in the genome of Trichoderma asperellum. These ABC transporters were divided into six types based on three-dimensional (3D) structure prediction, of which four, represented by 39 ABCs, are involved in transport and the remaining two, represented by 5 ABCs, are involved in regulating translation. The characteristics of nucleotide-binding domain (NBD) are important in the identification of ABC proteins. Even though the 3D structures of the 79 NBDs in the 44 ABCs are similar, multiple sequence alignment showed they can be divided into three classes. In total, 794 motifs were found in the promoter regions of the 44 ABC genes, of which 541 were cis-regulators related to stress responses. To characterize how their ABCs respond when T. asperellum interact with fungi or plants, T. asperellum was cultivated in either minimal media (MM) control, C-hungry, N-hungry, or poplar medium (PdPap) to simulate normal conditions, competition with pathogens, interaction with pathogens, and interaction with plants, respectively. The results show that 17 of 39 transport ABCs are highly expressed in at least one condition, whereas four of the five translation-regulating ABCs are highly expressed in at least one condition. Of these 21 highly expressed ABCs, 6 were chosen for RT-qPCR expression under the toxin stress of phytopathogen Alternaria alternata, and the results show ABC01, ABC04, ABC05, and ABC31 were highly expressed and may be involved in pathogen interaction and detoxifying toxins from A. alternata.

Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy that can progress, when untreated, to end-stage renal disease. Most frequently, aHUS is caused by complement dysregulation due to pathogenic variants in genes that encode complement components and regulators. Among these genes, the factor H (FH) gene, CFH, presents with the highest frequency (15% to 20%) of variants and is associated with the poorest prognosis. Correct classification of CFH variants as pathogenic or benign is essential to clinical care but remains challenging owing to the dearth of functional studies. As a result, significant numbers of variants are reported as variants of uncertain significance. To address this knowledge gap, we expressed and functionally characterized 105 aHUS-associated FH variants. All FH variants were categorized as pathogenic or benign and, for each, we fully documented the nature of the pathogenicity. Twenty-six previously characterized FH variants were used as controls to validate and confirm the robustness of the functional assays used. Of the remaining 79 uncharacterized variants, only 29 (36.7%) alter FH expression or function in vitro and, therefore, are proposed to be pathogenic. We show that rarity in control databases is not informative for variant classification, and we identify important limitations in applying prediction algorithms to FH variants. Based on structural and functional data, we suggest ways to circumvent these difficulties and, thereby, improve variant classification. Our work highlights the need for functional assays to interpret FH variants accurately if clinical care of patients with aHUS is to be individualized and optimized.

Arabidopsis Flippases Cooperate with ARF GTPase Exchange Factors to Regulate the Trafficking and Polarity of PIN Auxin Transporters.

Cell polarity is a fundamental feature of all multicellular organisms. PIN auxin transporters are important cell polarity markers that play crucial roles in a plethora of developmental processes in plants. Here, to identify components involved in cell polarity establishment and maintenance in plants, we performed a forward genetic screening of PIN2:PIN1-HA;pin2 Arabidopsis (Arabidopsis thaliana) plants, which ectopically express predominantly basally localized PIN1 in root epidermal cells, leading to agravitropic root growth. We identified the regulator of PIN polarity 12 (repp12) mutation, which restored gravitropic root growth and caused a switch in PIN1-HA polarity from the basal to apical side of root epidermal cells. Next Generation Sequencing and complementation experiments established the causative mutation of repp12 as a single amino acid exchange in Aminophospholipid ATPase3 (ALA3), a phospholipid flippase predicted to function in vesicle formation. repp12 and ala3 T-DNA mutants show defects in many auxin-regulated processes, asymmetric auxin distribution, and PIN trafficking. Analysis of quintuple and sextuple mutants confirmed the crucial roles of ALA proteins in regulating plant development as well as PIN trafficking and polarity. Genetic and physical interaction studies revealed that ALA3 functions together with the ADP ribosylation factor GTPase exchange factors GNOM and BIG3 in regulating PIN polarity, trafficking, and auxin-mediated development.

Effect of Low-Concentration Atropine Eyedrops vs Placebo on Myopia Incidence in Children: The LAMP2 Randomized Clinical Trial.

Importance: Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed. Objective: To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% concentration for delaying the onset of myopia. Design, Setting, and Participants: This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022. Interventions: Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years. Main Outcomes and Measures: The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at least -0.50 D in either eye) and the percentage of participants with fast myopic shift (spherical equivalent myopic shift of at least 1.00 D). Results: Of the 474 randomized patients (mean age, 6.8 years; 50% female), 353 (74.5%) completed the trial. The 2-year cumulative incidence of myopia in the 0.05% atropine, 0.01% atropine, and placebo groups were 28.4% (33/116), 45.9% (56/122), and 53.0% (61/115), respectively, and the percentages of participants with fast myopic shift at 2 years were 25.0%, 45.1%, and 53.9%. Compared with the placebo group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 24.6% [95% CI, 12.0%-36.4%]) and percentage of patients with fast myopic shift (difference, 28.9% [95% CI, 16.5%-40.5%]). Compared with the 0.01% atropine group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 17.5% [95% CI, 5.2%-29.2%]) and percentage of patients with fast myopic shift (difference, 20.1% [95% CI, 8.0%-31.6%]). The 0.01% atropine and placebo groups were not significantly different in 2-year cumulative myopia incidence or percentage of patients with fast myopic shift. Photophobia was the most common adverse event and was reported by 12.9% of participants in the 0.05% atropine group, 18.9% in the 0.01% atropine group, and 12.2% in the placebo group in the second year. Conclusions and Relevance: Among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years. There was no significant difference between 0.01% atropine and placebo. Further research is needed to replicate the findings, to understand whether this represents a delay or prevention of myopia, and to assess longer-term safety. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-15006883.

Small signaling peptides mediate plant adaptions to abiotic environmental stress.

MAIN CONCLUSION: Peptide-receptor complexes activate distinct downstream regulatory networks to mediate plant adaptions to abiotic environmental stress. Plants are constantly exposed to various adverse environmental factors; thus they must adjust their growth accordingly. Plants recruit small secretory peptides to adapt to these detrimental environments. These small peptides, which are perceived by their corresponding receptors and/or co-receptors, act as local- or long-distance mobile signaling molecules to establish cell-to-cell regulatory networks, resulting in optimal cellular and physiological outputs. In this review, we highlight recent advances on the regulatory role of small peptides in plant abiotic responses and nutrients signaling.

Three-Year Clinical Trial of Low-Concentration Atropine for Myopia Progression (LAMP) Study: Continued Versus Washout: Phase 3 Report.

PURPOSE: (1) To compare the efficacy of continued and stopping treatment for 0.05%, 0.025%, and 0.01% atropine during the third year. (2) To evaluate the efficacy of continued treatment over 3 years. (3) To investigate the rebound phenomenon and its determinants after cessation of treatment. DESIGN: A randomized, double-masked extended trial. PARTICIPANTS: A total of 350 of 438 children aged 4 to 12 years originally recruited into the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: At the beginning of the third year, children in each group were randomized at a 1:1 ratio to continued treatment and washout subgroups. Cycloplegic spherical equivalent (SE) refraction and axial length (AL) were measured at 4-month intervals. MAIN OUTCOME MEASURES: Changes in SE and AL between groups. RESULTS: A total of 326 children completed 3 years of follow-up. During the third year, SE progression and AL elongation were faster in the washout subgroups than in the continued treatment groups across all concentrations: -0.68 ± 0.49 diopters (D) versus -0.28 ± 0.42 D (P < 0.001) and 0.33 ± 0.17 mm versus 0.17 ± 0.14 mm (P < 0.001) for the 0.05%; -0.57 ± 0.38 D versus -0.35 ± 0.37 D (P = 0.004) and 0.29 ± 0.14 mm versus 0.20 ± 0.15 mm (P = 0.001) for the 0.025%; -0.56 ± 0.40 D versus -0.38 ± 0.49 D (P = 0.04) and 0.29 ± 0.15 mm versus 0.24 ± 0.18 mm (P = 0.13) for the 0.01%. Over the 3-year period, SE progressions were -0.73 ± 1.04 D, -1.31 ± 0.92 D, and -1.60 ± 1.32 D (P = 0.001) for the 0.05%, 0.025%, and 0.01% groups in the continued treatment subgroups, respectively, and -1.15 ± 1.13 D, -1.47 ± 0.77 D, and -1.81 ± 1.10 D (P = 0.03), respectively, in the washout subgroup. The respective AL elongations were 0.50 ± 0.40 mm, 0.74 ± 0.41 mm, and 0.89 ± 0.53 mm (P < 0.001) for the continued treatment subgroups and 0.70 ± 0.47 mm, 0.82 ± 0.37 mm, and 0.98 ± 0.48 mm (P = 0.04) for the washout subgroup. The rebound SE progressions during washout were concentration dependent, but their differences were clinically small (P = 0.15). Older age and lower concentration were associated with smaller rebound effects in both SE progression (P < 0.001) and AL elongation (P < 0.001). CONCLUSIONS: During the third year, continued atropine treatment achieved a better effect across all concentrations compared with the washout regimen. 0.05% atropine remained the optimal concentration over 3 years in Chinese children. The differences in rebound effects were clinically small across all 3 studied atropine concentrations. Stopping treatment at an older age and lower concentration are associated with a smaller rebound.

Prototypes virus of hand, foot and mouth disease infections and severe cases in Gansu, China: a spatial and temporal analysis.

BACKGROUND: Little research has been conducted on the spatio-temporal relationship between the severe cases and the enteroviruses infections of hand, foot and mouth disease (HFMD). This study aimed to investigate epidemic features and spatial clusters of HFMD incidence rates and assess the relationship between Enterovirus 71 (EV71) and Coxsackievirus A16 (CoxA16) and severe cases of HMFD in Gansu province, China. METHODS: Weekly county-specific data on HFMD between 1st January and 31st December 2018 were collected from the China Infectious Disease Information System (CIDIS), including enterovirus type (EV71 and CoxA16), severe and non-severe cases in Gansu province, China. Temporal risk [frequency index (α), duration index (ß) and intensity index (γ)] and spatial cluster analysis were used to assess epidemic features and identify high-risk areas for HFMD. Time-series cross-correlation function and regression model were used to explore the relationship between the ratios of two types of viruses (i.e. EV71/Cox16) (EC) and severe cases index (i.e. severe cases/non-severe cases) (SI) of HFMD. RESULTS: Some counties in Dingxi City, Gansu were identified as a hot spot for the temporal risk indices. Time-series cross-correlation analysis showed that SI was significantly associated with EC (r = 0.417, P < 0.05) over a 4-week time lag. The regression analysis showed that SI was positively associated with EC (ß = 0.04, 95% confidence interval (CI) 0.02-0.06). CONCLUSION: The spatial patterns of HFMD incidence were associated with enteroviruses in Gansu. The research suggested that the EC could be considered a potential early warning sign for predicting severe cases of HFMD in Gansu province.

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.

Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

Amantadine, a promising therapeutic agent against viral encephalopathy and retinopathy.

Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is nervous necrosis virus (NNV), which mainly infects the early developmental stages of fish, limiting the effectiveness of vaccines. To counter this case, the anti-NNV potentials of nine drugs with broad-spectrum antiviral activity were explored using ribavirin as a positive drug. Toxicity of the selected drugs to SSN-1 cells and grouper was firstly evaluated to determine the safety concentrations. For screening in vitro, amantadine and oseltamivir phosphate can relieve the cytopathic effects and inhibit NNV replication with the 90% inhibitory concentrations (IC90 ) of 38.74 and 106.75 mg/L, respectively. Amantadine has a stronger anti-NNV activity than ribavirin at the with- and post-NNV infection stages, indicating that it is a potential therapeutic agent against VER by acting directly on NNV. Similarly, amantadine also has a strong anti-NNV activity in vivo with the IC90 of 27.91 mg/L at the 7 days post-infection, while that was 73.25 mg/L for ribavirin. Following exposure to amantadine (40 mg/L) and ribavirin (100 mg/L) for 7 days, the survival rates of NNV-infected grouper were increased to 44% and 39%, respectively. The maximum amantadine content (11.88 mg/Kg) in grouper brain was reached following exposure for 24 hr, and amantadine can be quickly excreted from fish, reducing the risk of drug residue. Results so far indicated that amantadine is a promising therapeutic agent against NNV in aquaculture, providing an effective strategy for VER control at the early developmental stages of fish.

The emotional adaptation aftereffect discriminates between individuals with high and low levels of depressive symptoms.

The adaptation aftereffect plays a critical role in human development and survival. Existing studies have found that, compared with general individuals, individuals with learning disability, autism and dyslexia show a smaller amount of non-affective-based cognitive adaptation aftereffect. Nevertheless, it is unclear whether individuals with depression or depression tendency show similar phenomenon in the adaptation aftereffect, and whether such depression tendency occurs in the non-affective-based cognitive or emotional adaptation aftereffect. To address this question, the present study conducted two experiments. Experiments 1A and 1B used the emotional facial expression adaptation paradigm to examine whether Chinese participants showed the emotional adaptation aftereffect and whether the emotional adaptation aftereffect was influenced by physical features of faces, respectively. Experiment 2 recruited two groups of participants, with high and low depression, respectively, to examine whether they showed differences in the emotional or cognitive adaptation aftereffect. Results showed that Chinese participants showed the typical emotional adaptation aftereffect, which was not influenced by physical features of faces. More importantly, compared to the low-depression group, the high-depression group showed a smaller emotional adaptation aftereffect, but the two groups showed a similar cognitive adaptation aftereffect. These results suggest that level of depressive symptoms is associated with the emotional adaptation aftereffect.

GhARF16-1 modulates leaf development by transcriptionally regulating the GhKNOX2-1 gene in cotton.

The leaf is a crucial organ evolved with remarkable morphological diversity to maximize plant photosynthesis. The leaf shape is a key trait that affects photosynthesis, flowering rates, disease resistance and yield. Although many genes regulating leaf development have been identified in the past years, the precise regulatory architecture underlying the generation of diverse leaf shapes remains to be elucidated. We used cotton as a reference model to probe the genetic framework underlying divergent leaf forms. Comparative transcriptome analysis revealed that the GhARF16-1 and GhKNOX2-1 genes might be potential regulators of leaf shape. We functionally characterized the auxin-responsive factor ARF16-1 acting upstream of GhKNOX2-1 to determine leaf morphology in cotton. The transcription of GhARF16-1 was significantly higher in lobed-leaved cotton than in smooth-leaved cotton. Furthermore, the overexpression of GhARF16-1 led to the up-regulation of GhKNOX2-1 and resulted in more and deeper serrations in cotton leaves, similar to the leaf shape of cotton plants overexpressing GhKNOX2-1. We found that GhARF16-1 specifically bound to the promoter of GhKNOX2-1 to induce its expression. The heterologous expression of GhARF16-1 and GhKNOX2-1 in Arabidopsis led to lobed and curly leaves, and a genetic analysis revealed that GhKNOX2-1 is epistatic to GhARF16-1 in Arabidopsis, suggesting that the GhARF16-1 and GhKNOX2-1 interaction paradigm also functions to regulate leaf shape in Arabidopsis. To our knowledge, our results uncover a novel mechanism by which auxin, through the key component ARF16-1 and its downstream-activated gene KNOX2-1, determines leaf morphology in eudicots.

Age Effect on Treatment Responses to 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

PURPOSE: To investigate the effect of age at treatment and other factors on treatment response to atropine in the Low-Concentration Atropine for Myopia Progression (LAMP) Study. DESIGN: Secondary analysis from a randomized trial. PARTICIPANTS: Three hundred fifty children aged 4 to 12 years who originally were assigned to receive 0.05%, 0.025%, or 0.01% atropine or placebo once daily, and who completed 2 years of the LAMP Study, were included. In the second year, the placebo group was switched to the 0.05% atropine group. METHODS: Potential predictive factors for change in spherical equivalent (SE) and axial length (AL) over 2 years were evaluated by generalized estimating equations in each treatment group. Evaluated factors included age at treatment, gender, baseline refraction, parental myopia, time outdoors, diopter hours of near work, and treatment compliance. Estimated mean values and 95% confidence intervals (CIs) of change in SE and AL over 2 years also were generated. MAIN OUTCOME MEASURES: Factors associated with SE change and AL change over 2 years were the primary outcome measures. Associated factors during the first year were secondary outcome measures. RESULTS: In 0.05%, 0.025%, and 0.01% atropine groups, younger age was the only factor associated with SE progression (coefficient of 0.14, 0.15, and 0.20, respectively) and AL elongation (coefficient of -0.10, -0.11, and -0.12, respectively) over 2 years; the younger the age, the poorer the response. At each year of age from 4 to 12 years across the treatment groups, higher-concentration atropine showed a better treatment response, following a concentration-dependent effect (Ptrend <0.05 for each age group). In addition, the mean SE progression in 6-year-old children receiving 0.05% atropine (-0.90 diopter [D]; 95% CI, -0.99 to -0.82) was similar to that of 8-year-old children receiving 0.025% atropine (-0.89 D; 95% CI, -0.94 to -0.83) and 10-year-old children receiving 0.01% atropine (-0.92 D; 95% CI, -0.99 to -0.85). All concentrations were well tolerated in all age groups. CONCLUSIONS: Younger age is associated with poor treatment response to low-concentration atropine at 0.05%, 0.025%, and 0.01%. Among concentrations studied, younger children required the highest 0.05% concentration to achieve similar reduction in myopic progression as older children receiving lower concentrations.

Using internet-based query and climate data to predict climate-sensitive infectious disease risks: a systematic review of epidemiological evidence.

The use of internet-based query data offers a novel approach to improve disease surveillance and provides timely disease information. This paper systematically reviewed the literature on infectious disease predictions using internet-based query data and climate factors, discussed the current research progress and challenges, and provided some recommendations for future studies. We searched the relevant articles in the PubMed, Scopus, and Web of Science databases between January 2000 and December 2019. We initially included studies that used internet-based query data to predict infectious disease epidemics, then we further filtered and appraised the studies that used both internet-based query data and climate factors. In total, 129 relevant papers were included in the review. The results showed that most studies used a simple descriptive approach (n=80; 62%) to detect epidemics of influenza (including influenza-like illness (ILI)) (n=88; 68%) and dengue (n=9; 7%). Most studies (n=61; 47%) purely used internet search metrics to predict the epidemics of infectious diseases, while only 3 out of the 129 papers included both climate variables and internet-based query data. Our research shows that including internet-based query data and climate variables could better predict climate-sensitive infectious disease epidemics; however, this method has not been widely used to date. Moreover, previous studies did not sufficiently consider the spatiotemporal uncertainty of infectious diseases. Our review suggests that further research should use both internet-based query and climate data to develop predictive models for climate-sensitive infectious diseases based on spatiotemporal models.

Mutation of complement factor B causing massive fluid-phase dysregulation of the alternative complement pathway can result in atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Its pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway of complement secondary to inherited and/or acquired factors. Here we evaluated two unrelated patients with atypical hemolytic uremic syndrome. The first, a five-year-old Caucasian female, presented at 10 months with schistocytes, thrombocytopenia and kidney injury. The second, a 55-year-old Caucasian female, presented at age 31 following caesarean section for preeclampsia. Complement biomarker testing was remarkable for undetectable levels of C3 in both. Circulating levels of C5 and properdin were also low consistent with over-activity of the alternative and terminal pathways of complement. Genetic testing identified a heterozygous novel variant in CFB (c.1101 C>A, p.Ser367Arg) in both patients. Functional studies found strong fluid-phase C3 cleavage when normal and proband sera were mixed. Cell-surface C3b deposition was strongly positive when patient serum was supplemented with C3. In vitro control of C3 convertase activity could be restored with increased concentrations of factor H. Thus, CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the alternative pathway in the fluid-phase and increased C3b deposition on cell surfaces. Our study highlights the complexities of complement-mediated diseases like atypical hemolytic uremic syndrome and illustrates the importance of functional studies at the variant level to gain insight into the disease phenotype.