Design of carbazole-based platinum complexes with steric hindrance for efficient organic light-emitting diodes.

The construction of platinum complexes with high steric hindrance is expected to suppress triple-triplet annihilation and π-π stacking to achieve high-performance organic light-emitting diodes (OLEDs) with low efficiency roll-off. Herein, two large steric hindrance platinum complexes (N-CzPhPtacac and N-CzCF3PhPtacac) were prepared by taking advantage of steric hindrance between the phenyl group on carbazole and the functional group (phenyl and trifluoromethyl substituted phenyl) at the 3-position of a pyridine moiety. Due to the similar electron cloud distribution and gap difference between the HOMO and LUMO, the two complexes showed similar orange-red emission peaks at 590 and 596 nm with high PL quantum yields of 90% and 92% and short excited state lifetimes of 2.77 and 3.08 µs in doped films, respectively. Consequently, OLEDs based on N-CzPhPtacac and N-CzCF3PhPtacac showed maximum external quantum efficiency (EQEmax) values of 15.4% and 18.9%, respectively. Importantly, benefitting from the more stretched spatial configuration from the -CF3 effect, the corresponding OLED exhibited a lower efficiency roll-off, with an EQE of 18.1% at 1000 cd m-2.

Frequency Dependent Changes of Regional Homogeneity in Children with Growth Hormone Deficiency.

Abnormal spontaneous neural activity in children with growth hormone deficiency (GHD) has been found in previous resting-state functional magnetic resonance imaging (rs-fMRI) studies. Nevertheless, the spontaneous neural activity of GHD in different frequency bands is still unclear. Here, we combined rs-fMRI and regional homogeneity (ReHo) methods to analyze the spontaneous neural activity of 26 GHD children and 15 healthy controls (HCs) with age- and sex-matching in four frequency bands: slow-5 (0.014-0.031 Hz), slow-4 (0.031-0.081 Hz), slow-3 (0.081-0.224 Hz), and slow-2 (0.224-0.25 Hz). In the slow-5 band, GHD children compared with HCs displayed higher ReHo in the left dorsolateral part of the superior frontal gyrus, triangular part of the inferior frontal gyrus, precentral gyrus and middle frontal gyrus, and right angular gyrus, while lower ReHo in the right precentral gyrus, and several medial orbitofrontal regions. In the slow-4 band, GHD children relative to HCs revealed increased ReHo in the right middle temporal gyrus, whereas reduced ReHo in the left superior parietal gyrus, right middle occipital gyrus, and bilateral medial parts of the superior frontal gyrus. In the slow-2 band, compared with HCs, GHD children showed increased ReHo in the right anterior cingulate gyrus, and several prefrontal regions, while decreased ReHo in the left middle occipital gyrus, and right fusiform gyrus and anterior cingulate gyrus. Our findings demonstrate that regional brain activity in GHD children exhibits extensive abnormalities, and these abnormalities are related to specific frequency bands, which may provide bases for understanding its pathophysiology significance.

Systematic profiling of subtelomeric silencing factors in budding yeast.

Subtelomeric gene silencing is the negative transcriptional regulation of genes located close to telomeres. This phenomenon occurs in a variety of eukaryotes with salient physiological implications, such as cell adherence, virulence, immune-system escape, and ageing. The process has been widely studied in the budding yeast Saccharomyces cerevisiae, where genes involved in this process have been identified mostly on a gene-by-gene basis. Here, we introduce a quantitative approach to study gene silencing, that couples the classical URA3 reporter with GFP monitoring, amenable to high-throughput flow cytometry analysis. This dual silencing reporter was integrated into several subtelomeric loci in the genome, where it showed a gradual range of silencing effects. By crossing strains with this dual reporter at the COS12 and YFR057W subtelomeric query loci with gene-deletion mutants, we carried out a large-scale forward screen for potential silencing factors. The approach was replicable and allowed accurate detection of expression changes. Results of our comprehensive screen suggest that the main players influencing subtelomeric silencing were previously known, but additional potential factors underlying chromatin conformation are involved. We validate and report the novel silencing factor LGE1, a protein with unknown molecular function required for histone H2B ubiquitination. Our strategy can be readily combined with other reporters and gene perturbation collections, making it a versatile tool to study gene silencing at a genome-wide scale.

Frequency specificity in the amplitude of low frequency oscillations in patients with white matter lesions.

Previous studies have reported that patients with white matter lesions (WMLs) have abnormal spontaneous brain activity in the resting state. However, the spontaneous neuronal activity of specific frequency bands in WMLs patients is unknown. Here, we included 16 WMLs patients and 13 gender and age-matched healthy controls (HCs) underwent resting-state magnetic resonance imaging (rs-fMRI) scan and studied the specificity of the amplitude of low-frequency fluctuations (ALFF) in WMLs patients in the slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), and typical (0.01-0.08 Hz) frequency bands. In addition, ALFF values of different frequency bands were extracted as classification features and support vector machines (SVM) were used to classify WMLs patients. In all three frequency bands, significant increases in ALFF values in WMLs patients were observed in the cerebellum. In the slow-5 band, the ALFF values of the left anterior cingulate and paracingulate gyri (ACG), and the right precentral gyrus, rolandic operculum and inferior temporal gyrus in WMLs patients were lower than those in HCs. In the slow-4 band, ALFF values were lower in WMLs patients than in HCs at the left ACG, the right median cingulate and paracingulate gyri, parahippocampal gyrus, caudate nucleus, and the bilateral lenticular nucleus, putamen. In the SVM classification model, the classification accuracy of slow-5, slow-4 and typical frequency bands is 75.86%, 86.21% and 72.41%, respectively. The results indicate that the ALFF abnormalities in WMLs patients have frequency specificity, and the ALFF abnormalities in the slow-4 frequency band may serve as imaging markers for WMLs.

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

Bisphenol A induces testicular oxidative stress in mice leading to ferroptosis.

Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability. By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research (ICR) mouse model, we found that a ferroptosis phenomenon may exist. Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days. Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde. Epididymal sperm was also collected for semen analysis, and testicular tissue was collected for ferritin content determination, electron microscope observation of mitochondrial morphology, immunohistochemistry, real-time quantitative polymerase chain reaction, and western blot analysis. Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage, iron accumulation, and mitochondrial damage in the testes of mice. In addition, bisphenol A was confirmed to affect the expression of the ferroptosis-related genes, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), cyclooxygenase 2 (COX2), and acyl-CoA synthetase 4 (ACSL4) in mouse testicular tissues. Accordingly, we speculate that bisphenol A induces oxidative stress, which leads to the ferroptosis of testicular cells. Overall, the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.

Bisphenol A induces testicular oxidative stress in mice leading to ferroptosis / 亚洲男科学杂志(英文版)

Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability. By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research (ICR) mouse model, we found that a ferroptosis phenomenon may exist. Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days. Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde. Epididymal sperm was also collected for semen analysis, and testicular tissue was collected for ferritin content determination, electron microscope observation of mitochondrial morphology, immunohistochemistry, real-time quantitative polymerase chain reaction, and western blot analysis. Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage, iron accumulation, and mitochondrial damage in the testes of mice. In addition, bisphenol A was confirmed to affect the expression of the ferroptosis-related genes, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), cyclooxygenase 2 (COX2), and acyl-CoA synthetase 4 (ACSL4) in mouse testicular tissues. Accordingly, we speculate that bisphenol A induces oxidative stress, which leads to the ferroptosis of testicular cells. Overall, the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.

Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulants and Their Use in Special Populations / 中山大学学报(医学科学版)

In the past few decades， heparin and warfarin have been the main anticoagulants used to treat and prevent venous thromboembolism. Recent studies at home and abroad have shown that non-vitamin K antagonist oral anticoagulants （NOACs） have similar or better efficacy and safety in the prevention and treatment of venous thromboembolism and non-valvular atrial fibrillation. NOACs do not require routine coagulation monitoring when used at a fixed dose. However， in special populations or specific scenarios such as emergency surgery， etc.， an overdose or underdose and abnormal metabolism of NOACs may reduce the drug efficacy and safety， so monitoring and evaluating the anticoagulant effect of NOACs is more conducive to the prognosis of patients.This paper briefly reviewed the common laboratory monitoring methods of NOACs and their use in special populations， aiming to explain different monitoring methods for different NOACs and the applicability of NOACs in special populations， and hoping to provide reference for clinical standard monitoring and use of NOACS.

Prevalence of depression, anxiety in China during the COVID-19 pandemic: an updated systematic review and meta-analysis.

Background: Mental health risks associated with the aftermath of the COVID-19 pandemic are often overlooked by the public. The aim of this study was to investigate the effects of the COVID-19 pandemic on depression and anxiety disorders in China. Methods: Studies were analyzed and extracted in accordance with the PRISMA 2020 flowchart. The studies were screened and extracted using electronic databases including PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov according to the predefined eligibility criteria. The Cochrane Review Manager software 5.3.1 was used for data analysis and the risk of bias assessment. Results: As of 2023, a total of 9,212,751 Chinese have been diagnosed with COVID-19 infection. A total of 913,036 participants in 44 studies were selected following the eligibility criteria, the statistical information of which was collected for meta-analysis. The pooled prevalence of depression and anxiety were 0.31 (95% CI: 0.28, 0.35; I2 = 100.0%, p < 0.001) and 0.29 (95% CI: 0.23, 0.36; I2 = 100.0%, p < 0.001), respectively. After performing a subgroup analysis, the prevalence of depression among women, healthcare workers, students, and adolescents was 0.31 (95% CI: 0.22, 0.41), 0.33 (95% CI: 0.26, 0.44), 0.32 (95% CI: 0.26, 0.39), and 0.37 (95% CI: 0.31, 0.44), respectively. Conclusion: The prevalence of depression and anxiety among the Chinese was overall high. Monitoring and surveillance of the mental health status of the population during crises such as sudden global pandemics are imperative. Systematic review registration: https://clinicaltrials.gov/, identifier [CRD42023402190].

Positive association between triglyceride glucose index and central systolic blood pressure among hypertensive adults.

BACKGROUND: While studies have suggested the association between triglyceride-glucose (TyG) index, a reliable surrogate for insulin resistance and hypertension data are limited to the correlation of TyG and central blood pressure. This study aims to test the hypothesis that a higher TyG index is associated with elevated central systolic blood pressure (cSBP). METHODS: A total of 9249 Chinese hypertensive adults from the H-type Hypertension and Stroke Prevention and Control Project were analyzed in this study. cSBP was measured noninvasively using an A-Pulse CASPro device. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Smoothing curve and multivariate linear regression models [beta coefficient (ß) with 95% CI] were applied to analyze the association between TyG index and cSBP. Subgroup analyses were conducted to explore potential modifications to such a correlation. RESULTS: The overall mean TyG index is 8.8 ± 0.7, and the total mean cSBP is 131.3 ± 12.8 mmHg. TyG index was observed to be independently and positively associated with cSBP among the total population (ß = 0.92, 95% CI: 0.53-1.31, P < 0.001), and participants who do not use antihypertensive drugs (ß = 1.03, 95% CI: 0.46-1.60, P < 0.001), which is in accordance with the result of the smoothing curve. The association between TyG index and cSBP appears robust in all tested subgroups. CONCLUSIONS: TyG index is positively and independently associated with cSBP among hypertensive adults. Our study result suggests that TyG index might serve as an effective marker for vascular function.

Individual and joint effects of borderline ankle-brachial index and high plasma total homocysteine on all-cause death in hypertensive adults.

BACKGROUND: The cardiovascular hazards of total homocysteine (tHcy) are long known. In addition, despite the acknowledgment on the importance of low ankle-brachial index (ABI) (< 0.9), borderline ABI (0.91-0.99) was once commonly overlooked. This study aims to explore the independent and joint effect of tHcy level and borderline ABI on all-cause death in hypertensive population. METHODS: This study included 10,538 participants from China H-type Hypertension Registry Study. ABI was described into two groups: normal ABI (1.00-1.40) and borderline ABI. tHcy level was also divided into two groups: < 15.02 and ≥ 15.02 µmo/L. Four groups were analyzed, using COX proportional hazard regression model, separately and pairwise to observe the independent and joint effect on all-cause death. RESULTS: A total of 126 (1.2%) deaths were observed in the 1.7 years follow-up time. Borderline ABI has a higher predicted risk of death than normal ABI (HR = 1.87, 95%CI: 1.17-3.00) after adjusting for potential covariates. Compare with tHcy level < 15.02 µmo/L (low tHcy), those with tHcy ≥ 15.02 µmo/L (high tHcy) had higher risk to event outcome (HR = 1.99, 95% CI: 1.30-3.05). According to the cumulative hazard curve, group with borderline ABI and high tHcy level has significantly higher altitude and larger increasing rate over follow-up period compare to other groups. Among those with borderline ABI, participants with high tHcy had higher death risk than those with low tHcy, nevertheless, no significant different between borderline and normal ABI among those with low tHcy levels. CONCLUSIONS: Borderline ABI and tHcy level both have independent predictive value on all-cause death. The combined group of borderline ABI and high tHcy has highest risk factor of outcomes, which suggested the mutual additive value of borderline ABI and tHcy. More attention should be given to the importance of borderline ABI in hypertensive population, especially with elevated tHcy level.

The complete mitochondrial genome of Zelkova schneideriana Hand-Mazz (Ulmaceae) and phylogenetic analysis.

Zelkova schneideriana Hand-Mazz is a second-class key protected wild plant in China. Here, the complete mitochondrial genome of Zelkova schneideriana Hand-Mazz was sequenced using Nanopore Sequel and Illumina NovaSeq platform. The mitochondrial genome was assembled into three circular-mapping molecules with the genome sizes of 154,640 bp, 192,388 bp and 146,907 bp, including 36 protein-coding genes, 19 tRNA genes, and 3 rRNA genes. Phylogenetic analysis indicated that Zelkova schneideriana Hand-Mazz is close with Hemiptelea davidii, a species in same Ulmaceae Mirb.

In Situ Microreaction Platform Based on Acoustic Droplet Manipulation for Ultra-High-Precision Multiplex Bioassay.

Liquid droplets rectors have been used in clinical diagnosis, high throughput screening and bioassay. However, it is challenging for droplet reactors to be used in practical applications due to the difficulty of uniformly mixing ultrasmall volumes of samples and the lack of rapid and high-precision detection protocols. Here, we have developed an acoustic droplet system for rapid and efficient biological detection and chemical screening. By employing acoustic wave devices, rapid and nondestructive uniform mixing of ∼nL-µL droplets can be achieved. By the acoustophoretic force, the perturbation of the droplets can quickly concentrate the sample and increase the detection limit by five times. Through the color reaction and the coordinated detection of photodiodes, we have developed a biomarker detection protocol with short reaction time and high accuracy. As a proof-of-concept application, we demonstrated that this system can detect ultrasmall or low-abundance samples faster and more accurately, highlighting its wide application in analytical chemistry, basic research, and clinical medicine.

Computational analysis of GAL pathway pinpoints mechanisms underlying natural variation.

Quantitative traits are measurable phenotypes that show continuous variation over a wide phenotypic range. Enormous effort has recently been put into determining the genetic influences on a variety of quantitative traits with mixed success. We identified a quantitative trait in a tractable model system, the GAL pathway in yeast, which controls the uptake and metabolism of the sugar galactose. GAL pathway activation depends both on galactose concentration and on the concentrations of competing, preferred sugars such as glucose. Natural yeast isolates show substantial variation in the behavior of the pathway. All studied yeast strains exhibit bimodal responses relative to external galactose concentration, i.e. a set of galactose concentrations existed at which both GAL-induced and GAL-repressed subpopulations were observed. However, these concentrations differed in different strains. We built a mechanistic model of the GAL pathway and identified parameters that are plausible candidates for capturing the phenotypic features of a set of strains including standard lab strains, natural variants, and mutants. In silico perturbation of these parameters identified variation in the intracellular galactose sensor, Gal3p, the negative feedback node within the GAL regulatory network, Gal80p, and the hexose transporters, HXT, as the main sources of the bimodal range variation. We were able to switch the phenotype of individual yeast strains in silico by tuning parameters related to these three elements. Determining the basis for these behavioral differences may give insight into how the GAL pathway processes information, and into the evolution of nutrient metabolism preferences in different strains. More generally, our method of identifying the key parameters that explain phenotypic variation in this system should be generally applicable to other quantitative traits.

The complete mitochondrial genome sequence of Fragaria orientalis (Rosaceae).

Fragaria orientalis Lozinsk. is valuable germplasm material for cross breeding in Fragaria. In this study, we assembled the complete mitochondrial genome of F. orientalis using a combination of Illumina data and Nanopore data. The mitochondrial genome was 275,143 bp in length, including 29 protein-coding genes, 20 tRNA genes, and three rRNA genes, with a total GC content 45.23%. Seven protein-coding genes contained introns, and three were trans-spliced. Phylogenetic analysis indicated that F. orientalis is making a sister clade to the Amygdaloideae species. The complete mitochondrial genome of F. orientalis reported in this study will improve our understanding of Fragaria evolution.

Apigenin suppresses proliferation, invasion, and epithelial-mesenchymal transition of cervical carcinoma cells by regulation of miR-152/BRD4 axis.

The present study aimed to investigate the role of apigenin and the molecular mechanism of miR-152-5p and bromodomain containing 4 (BRD4) in the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of cervical carcinoma cells. Quantitative real-time PCR was used to detect the transfection efficiency and the expression of miR-152-5p and BRD4. Western blotting was conducted to evaluate the protein level of BRD4, E-cadherin, N-cadherin, and MMP9. Luciferase reporter assay was performed to confirm whether miR-152-5p bound to BRD4. MTT and Transwell invasion assay were applied to determine the cell proliferation and invasion, respectively. MiR-152-5p was downregulated and BRD4 was upregulated in cervical carcinoma tissue. Besides, miR-152-5p could directly bind to BRD4 in Hela and CaSki cells. In addition, apigenin inhibited proliferation, invasion, and EMT of Hela and CaSki cells by regulating miR-152-5p/BRD4 axis. Apigenin suppresses proliferation, invasion, and induced EMT of cervical carcinoma cells by regulation of miR-152-5p/BRD4 axis.

Regional homogeneity abnormalities of resting state brain activities in children with growth hormone deficiency.

Growth hormone deficiency (GHD) is a common developmental disorder in children characterized by low levels of growth hormone secretion, short stature, and multiple cognitive and behavioral problems, including hyperactivity, anxiety, and depression. However, the pathophysiology of this disorder remains unclear. In order to investigate abnormalities of brain functioning in children with GHD, we preformed functional magnetic resonance imaging and regional homogeneity (ReHo) analysis in 26 children with GHD and 15 age- and sex-matched healthy controls (HCs) in a resting state. Compared with HCs, children with GHD exhibited increased ReHo in the left putamen and decreased ReHo in the right precentral gyrus, reflecting a dysfunction of inhibitory control. Decreased ReHo was also identified in the orbital parts of the bilateral superior frontal gyrus and the medial part of the left superior frontal gyrus, a finding that correlated with the inappropriate anxiety and depression that are observed in this patient population. Our results provide imaging evidence of potential pathophysiologic mechanisms for the cognitive and behavioral abnormalities of children with GHD.

Application of modern neuroimaging technology in the diagnosis and study of Alzheimer's disease.

Neurological abnormalities identified via neuroimaging are common in patients with Alzheimer's disease. However, it is not yet possible to easily detect these abnormalities using head computed tomography in the early stages of the disease. In this review, we evaluated the ways in which modern imaging techniques such as positron emission computed tomography, single photon emission tomography, magnetic resonance spectrum imaging, structural magnetic resonance imaging, magnetic resonance diffusion tensor imaging, magnetic resonance perfusion weighted imaging, magnetic resonance sensitive weighted imaging, and functional magnetic resonance imaging have revealed specific changes not only in brain structure, but also in brain function in Alzheimer's disease patients. The reviewed literature indicated that decreased fluorodeoxyglucose metabolism in the temporal and parietal lobes of Alzheimer's disease patients is frequently observed via positron emission computed tomography. Furthermore, patients with Alzheimer's disease often show a decreased N-acetylaspartic acid/creatine ratio and an increased myoinositol/creatine ratio revealed via magnetic resonance imaging. Atrophy of the entorhinal cortex, hippocampus, and posterior cingulate gyrus can be detected early using structural magnetic resonance imaging. Magnetic resonance sensitive weighted imaging can show small bleeds and abnormal iron metabolism. Task-related functional magnetic resonance imaging can display brain function activity through cerebral blood oxygenation. Resting functional magnetic resonance imaging can display the functional connection between brain neural networks. These are helpful for the differential diagnosis and experimental study of Alzheimer's disease, and are valuable for exploring the pathogenesis of Alzheimer's disease.

Abnormal amplitude of spontaneous low-frequency fluctuation in children with growth hormone deficiency: A resting-state functional magnetic resonance imaging study.

Growth hormone deficiency (GHD) is a developmental disorder caused by the partial or complete deficiency of growth hormone secreted by the pituitary gland, or its receptor. Patients with GHD are characterized by short stature, slow growth, and certain cognitive and behavioral abnormalities. Previous behavioral and neuroimaging studies indicate that GHD might affect the brain functional activity associated with cognitive and behavioral abilities. We thus investigated the spontaneous neural activity in children with GHD using amplitude of low-frequency fluctuation (ALFF) analysis. ALFF was calculated based on resting-state functional magnetic resonance imaging (rs-fMRI) data in 26 children with GHD and 15 age- and sex-matched healthy controls (HCs). Comparative analysis revealed that the ALFF of the right lingual gyrus and angular gyrus were significantly increased, while the ALFF of the right dorsolateral superior frontal gyrus, the left postcentral gyrus, superior parietal gyrus and middle temporal gyrus were significantly decreased in children with GHD relative to HCs. These findings support the presence of abnormal brain functional activity in children with GHD, which may account for the abnormal cognition and behavior, such as aggression, somatic complaints, attention deficits, and language withdrawal. This study provides imaging evidence for future studies on the pathophysiological mechanisms of abnormal behavior and cognition in children with GHD.

Computational study on ratio-sensing in yeast galactose utilization pathway.

Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration could expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit could tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications.