Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements.

Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

An encyclopedia of enhancer-gene regulatory interactions in the human genome.

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1-6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and largescale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 elementgene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancerpromoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Analysis of size-dependent optoelectronic properties of red AlGaInP micro-LEDs.

We have theoretically investigated the size-dependent optoelectronic properties of InGaP/AlGaInP-based red micro-LEDs through an electro-optical-thermal coupling model. The model considers thermal effects due to current crowding near the electrodes, non-thermal efficiency droop due to electron leakage, and etch defects on the LED sidewall. Sidewall defects reduce the carrier concentration at the light-emitting surface's edge and exacerbate the current crowding effect. In addition, p-side electron leakage at high current densities is the leading cause of the efficiency droop of AlGaInP LEDs. In contrast, the effect of temperature on the overall efficiency degradation of LEDs is even more significant.

Case report: Recurrent pontine stroke and leukoencephalopathy in a patient with de novo mutation in COL4A1.

This report presents a case of pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) in a 35 year-old male patient. The patient exhibited a consistent history of recurrent ischemic strokes, concentrated primarily in the pons region, accompanied by concurrent manifestations of leukoencephalopathy and microbleeds. Genetic evaluation revealed a heterozygous missense mutation consistent with c.3431C>G, p. Thr1144Arg substitution within exon 40 of the COL4A1 gene. This mutation was also identified in the patient's mother, affirming an autosomal dominant inheritance model. Our findings serve as testament to the potential role of mutation in the exon 40 of COL4A1 in the pathogenesis and progression of PADMAL, contributing to ongoing efforts aimed at better understanding the genetic basis of this debilitating disorder.

10 Hz repetitive transcranial magnetic stimulation (rTMS) may improve cognitive function: An exploratory study of schizophrenia patients with auditory hallucinations.

Objectives: Cognitive impairment in schizophrenia patients with auditory hallucinations is more prominent compared to those without. Our study aimed to investigate the cognitive improvement effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) in schizophrenia with auditory hallucinations. Methods: A total of 60 schizophrenic patients with auditory hallucinations in this study were randomly assigned to sham or active group. Both groups received 10 Hz or sham rTMS targeted in left DLPFC for 20 sessions. The Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucination Rating Scale (AHRS), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Udvalg for Kliniske Under-sogelser (UKU) side effect scale were used to measure psychiatric symptoms, auditory hallucinations, cognition, and side reaction, respectively. Results: Our results indicated that the active group experienced greater improvements in RBANS-total score (P = 0.043) and immediate memory subscale score (P = 0.001). Additionally, the PANSS-total score, negative and positive subscale score were obviously lower in the active group compared to the sham group (all P < 0.050). Furthermore, our study found that the improvement of RBANS-total score was positively associated with the decline of positive factor score, and the improvement of language score in RBANS was positively associated with the reduction in PANSS-total scale, negative and positive subscale score in the real stimulation group (all P < 0.050). Conclusion: Our results demonstrated that a four-week intervention of 10 Hz rTMS over the left DLPFC can improve cognition (particularly immediate memory) among schizophrenia patients with auditory hallucinations. Future studies with larger sample size are needful to verify our preliminary findings.

Microfluidic static droplet generated quantum dot arrays as color conversion layers for full-color micro-LED displays.

This paper presents an easy and intact process based on microfluidics static droplet array (SDA) technology to fabricate quantum dot (QD) arrays for full-color micro-LED displays. A minimal sub-pixel size of 20 µm was achieved, and the fluorescence-converted red and green arrays provide good light uniformity of 98.58% and 98.72%, respectively.

Mammalian evolution of human cis-regulatory elements and transcription factor binding sites.

Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.

Evolutionary constraint and innovation across hundreds of placental mammals.

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

Toward a comprehensive catalog of regulatory elements.

Regulatory elements are the genomic regions that interact with transcription factors to control cell-type-specific gene expression in different cellular environments. A precise and complete catalog of functional elements encoded by the human genome is key to understanding mammalian gene regulation. Here, we review the current state of regulatory element annotation. We first provide an overview of assays for characterizing functional elements, including genome, epigenome, transcriptome, three-dimensional chromatin interaction, and functional validation assays. We then discuss computational methods for defining regulatory elements, including peak-calling and other statistical modeling methods. Finally, we introduce several high-quality lists of regulatory element annotations and suggest potential future directions.

Investigating the debrominations of a subset of brominated flame retardants by biogenic reactive sulfur species.

Brominated flame retardants (BFRs) are persistent organic pollutants. Many bacteria are able to debrominate BFRs, but the underlying mechanism is unclear. Herein, we discovered that reactive sulfur species (RSS), which have strong reductive activity and are commonly present in bacteria, might be one of the reasons leading to such ability. Experiments performed with RSS (H2S and HSSH) and BFRs indicated that RSS can debrominate BFRs via two different mechanisms simultaneously: the substitutive debromination that generates thiol-BFRs and the reductive debromination that generates hydrogenated BFRs. Debromination reactions rapidly happened under neutral pH and ambient temperature, and the debromination degree was around 30% - 55% in one hour. Two Pseudomonas strains, Pseudomonas sp. C27 and Pseudomonas putida B6-2 both produced extracellular RSS and showed debromination activity. C27 debrominated HBCD, TBECH, and TBP by 5.4%, 17.7%, and 15.9% in two days. Whereas, B6-2 debrominated the three BFRs by 0.4%, 0.6%, and 0.3% in two days. The two bacteria produced different amounts and species of RSS, which were likely responsible for the contrasted degrees of the debromination. Our finding unveiled a novel, non-enzymatic debromination mechanism that many bacteria may possess. RSS producing bacteria have potentials to contribute to bioremediation of BFRs-polluted environments.

Recent Advances in Biotechnologies for the Treatment of Environmental Pollutants Based on Reactive Sulfur Species.

The definition of reactive sulfur species (RSS) is inspired by the reactivity and variable chemical valence of sulfur. Sulfur is an essential element for life and is a part of global geochemical cycles. Wastewater treatment bioreactors can be divided into two major categories: sulfur reduction and sulfur oxidation. We review the origins of the definition of RSS and related biotechnological processes in environmental management. Sulfate reduction, sulfide oxidation, and sulfur-based redox reactions are key to driving the coupled global carbon, nitrogen, and sulfur co-cycles. This shows the coupling of the sulfur cycle with the carbon and nitrogen cycles and provides insights into the global material-chemical cycle. We also review the biological classification and RSS metabolic mechanisms of functional microorganisms involved in the biological processes, such as sulfate-reducing and sulfur-oxidizing bacteria. Developments in molecular biology and genomic technologies have allowed us to obtain detailed information on these bacteria. The importance of RSS in environmental technologies requires further consideration.

Altered mitochondrial lymphocyte in overweight schizophrenia patients treated with atypical antipsychotics and its association with cognitive function.

Objective: Increasing evidence indicated that schizophrenia and obesity are associated with altered mitochondrial and immune function. In this study, we investigated the levels of CRP (C-reactive protein) and mitochondrial lymphocytes in chronically treated schizophrenia patients with atypical antipsychotic medications and further explored the relationship between mitochondrial lymphocyte and weight gain as well as cognitive function in these patients. Methods: We evaluated the mitochondrial lymphocyte count of 97 patients (53 overweight, 44 non-overweight) and 100 healthy controls using mitochondrial fluorescence staining and flow cytometry (NovoCyte, Agilent Technologies, US). The serum CRP was measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA). Clinical symptoms and cognitive function of the patients were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results: The results showed that mitochondrial lymphocyte counts of CD3+ T, CD3+CD4+ T, and CD3+CD8+ T cells in schizophrenia patients were higher than in the control group (p < 0.05). Additionally, overweight patients had significantly higher mitochondrial lymphocyte counts of CD3+ T and CD3+CD4+ T cells compared to schizophrenia patients with normal weight. Stratified analysis by gender revealed that there was a statistically significant difference in CD3+CD4+ mitochondrial lymphocyte count in male patients (p = 0.014) and a marginal trend toward significance in female patients (p = 0.058). Furthermore, the mitochondrial lymphocyte counts of CD3+ T and CD3+CD4+ T cells, as well as CRP levels, were positively correlated with BMI in schizophrenia patients, but the mitochondrial lymphocyte counts of CD3+CD4+ T cells were negatively correlated with the language scale in the RBANS. Conclusion: Our study results provide evidence for the association between altered mitochondrial T lymphocyte and weight gain as well as cognitive impairment in schizophrenia patients treated with atypical antipsychotic medications.

The mixed/mixotrophic nitrogen removal for the effective and sustainable treatment of wastewater: From treatment process to microbial mechanism.

Biological nitrogen removal (BNR) is one of the most important environmental concerns in the field of wastewater treatment. The conventional BNR process based on heterotrophic nitrogen removal (HeNR) is suffering from several limitations, including external carbon source dependence, excessive sludge production, and greenhouse gas emissions. Through the mediation of autotrophic nitrogen removal (AuNR), mixed/mixotrophic nitrogen removal (MixNR) offers a viable solution to the optimization of the BNR process. Here, the recent advance and characteristics of MixNR process guided by sulfur-driven autotrophic denitrification (SDAD) and anammox are summarized in this review. Additionally, we discuss the functional microorganisms in different MixNR systems, shedding light on metabolic mechanisms and microbial interactions. The significance of MixNR for carbon reduction in the BNR process has also been noted. The knowledge gaps and the future research directions that may facilitate the practical application of the MixNR process are highlighted. Overall, the prospect of the MixNR process is attractive, and this review will provide guidance for the future implementation of MixNR process as well as deciphering the microbially metabolic mechanisms.

A novel intra- and extracellular distribution pattern of elemental sulfur in Pseudomonas sp. C27-driven denitrifying sulfide removal process.

Pseudomonas sp. C27 can achieve the conversion of toxic sulfide to economical elemental sulfur (S0) with various electron acceptors. In this study the distribution pattern of S0 produced by C27 in denitrifying sulfide removal (DSR) process was explored. The SEM observation identified that the particle size of the biogenic S0 was at micron level. Strikingly, a novel distribution pattern of S0 was revealed that the produced S0 was not directly secreted extracellularly, but be stored temporarily in the cell interior. Pyrolysis at 65 °C for 20 min were recommended prior to S0 recovery, which could maximize the separation of extracellular polymeric substances (EPS) from C27. Furthermore, the effects of N/S molar ratio, initial sulfide concentration, and micro-oxygen condition were investigated to improve the production of S0 by C27. The highest S0 production was obtained at S/N of 3 and anaerobic condition seemed to favor the S0 production by C27. This study would provide a theoretical support for highly efficient sulfide removal as well as S0 recovery in sulfide-laden wastewater treatment.

Cryptic Sulfur and Oxygen Cycling Potentially Reduces N2O-Driven Greenhouse Warming: Underlying Revision Need of the Nitrogen Cycle.

Increasing global deoxygenation has widely formed oxygen-limited biotopes, altering the metabolic pathways of numerous microbes and causing a large greenhouse effect of nitrous oxide (N2O). Although there are many sources of N2O, denitrification is the sole sink that removes N2O from the biosphere, and the low-level oxygen in waters has been classically thought to be the key factor regulating N2O emissions from incomplete denitrification. However, through microcosm incubations with sandy sediment, we demonstrate here for the first time that the stress from oxygenated environments does not suppress, but rather boosts the complete denitrification process when the sulfur cycle is actively ongoing. This study highlights the potential of reducing N2O-driven greenhouse warming and fills a gap in pre-cognitions on the nitrogen cycle, which may impact our current understanding of greenhouse gas sinks. Combining molecular techniques and kinetic verification, we reveal that dominant inhibitions in oxygen-limited environments can interestingly undergo triple detoxification by cryptic sulfur and oxygen cycling, which may extensively occur in nature but have been long neglected by researchers. Furthermore, reviewing the present data and observations from natural and artificial ecosystems leads to the necessary revision needs of the global nitrogen cycle.

Flexible Quantum-Dot Color-Conversion Layer Based on Microfluidics for Full-Color Micro-LEDs.

In this article, red and green perovskite quantum dots are incorporated into the pixels of a flexible color-conversion layer assembly using microfluidics. The flexible color-conversion layer is then integrated with a blue micro-LED to realize a full-color display with a pixel pitch of 200 µm. Perovskite quantum dots feature a high quantum yield, a tunable wavelength, and high stability. The flexible color-conversion layer using perovskite quantum dots shows good luminous and display performance under different bending conditions; is easy to manufacture, economical, and applicable; and has important potential applications in the development of flexible micro-displays.

Integration of high-resolution promoter profiling assays reveals novel, cell type-specific transcription start sites across 115 human cell and tissue types.

Accurate transcription start site (TSS) annotations are essential for understanding transcriptional regulation and its role in human disease. Gene collections such as GENCODE contain annotations for tens of thousands of TSSs, but not all of these annotations are experimentally validated nor do they contain information on cell type-specific usage. Therefore, we sought to generate a collection of experimentally validated TSSs by integrating RNA Annotation and Mapping of Promoters for the Analysis of Gene Expression (RAMPAGE) data from 115 cell and tissue types, which resulted in a collection of approximately 50 thousand representative RAMPAGE peaks. These peaks are primarily proximal to GENCODE-annotated TSSs and are concordant with other transcription assays. Because RAMPAGE uses paired-end reads, we were then able to connect peaks to transcripts by analyzing the genomic positions of the 3' ends of read mates. Using this paired-end information, we classified the vast majority (37 thousand) of our RAMPAGE peaks as verified TSSs, updating TSS annotations for 20% of GENCODE genes. We also found that these updated TSS annotations are supported by epigenomic and other transcriptomic data sets. To show the utility of this RAMPAGE rPeak collection, we intersected it with the NHGRI/EBI genome-wide association study (GWAS) catalog and identified new candidate GWAS genes. Overall, our work shows the importance of integrating experimental data to further refine TSS annotations and provides a valuable resource for the biological community.

Childhood Trauma and Insomnia Increase Suicidal Ideation in Schizophrenia Patients: A Cross-Sectional Study.

Objectives: This study aimed to investigate the effect of childhood trauma, especially its specific dimensions, and clinical risk factors for suicidal ideation in patients with schizophrenia. Methods: A total of 83 inpatients with schizophrenia were enrolled and divided into two groups: with suicidal ideation (n = 33) and without suicidal ideation (n = 50). All participants were administered the Childhood Trauma Questionnaire-Short Form, the Insomnia Severity Index, the Beck Scale for Suicide Ideation, the Modified Overt Aggression Scales, the auditory hallucination rating scale, the Hamilton Rating Scale of Depression and the Positive and Negative Syndrome Scale. Results: In our sample, 39.8% of the subjects had suicidal ideation, and 60.6% of them had suffered from childhood trauma. Patients with suicidal ideation had a higher Insomnia Severity Index score, Physical neglect score, the Childhood Trauma Questionnaire-Short Form total score (all P < 0.05) compared to those without. The logistic regression analysis revealed that physical neglect in Childhood Trauma Questionnaire was significantly associated with suicidal ideation (OR = 5.46, P < 0.05, 95% CI = 0.007-0.483). Further stepwise multiple linear regression identified that insomnia (ß = 0.272, P = 0.011) and physical neglect (ß = 0.257, P = 0.017) were strong risk factors for the severity of suicidal ideation in patients with schizophrenia. Mediation analysis showed that insomnia played a complete mediating role between physical neglect and suicidal ideation. Conclusion: Our results indicate that childhood maltreatment of physical neglect is a strong independent risk factor for suicidal ideation in schizophrenia. The risk is probably aggravated by the poor quality of sleep. Early screening and psychosocial treatment are recommended for psychotic individuals with a trauma history.

Low vitamin D levels and the long-term functional outcome of stroke up to 5 years.

BACKGROUND AND PURPOSE: Previous studies have established that vitamin D was associated with stroke. The purpose of this study was to investigate the relationship between vitamin D and 5-year outcome of patients with stroke including acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) stroke. METHODS: Serum 25-hydroxyvitamin D levels were prospectively analyzed in patients admitted to the First Affiliated Hospital of Wenzhou Medical University from 2013 to 2015. Modified Rankin scale (mRS) was used to evaluate their 5-year functional outcome, and univariate and multivariate logistic regressions were applied to evaluate the effects of vitamin D on stroke outcome. RESULTS: In total, 668 patients diagnosed with stroke were recruited, and 420 completed the 5-year follow-up. Ninety-five patients experienced poor outcome in the 5 years since stroke onset. Vitamin D levels in patients with poor outcome showed significant differences compared to good outcome patients (p < .001). In multivariable logistic regression analysis, after adjusting the potential confounders, the 5-year functional outcome was significantly associated with vitamin D levels. Stroke patients with vitamin D levels less than 38.4 nmol/L had a higher risk for poor outcome compared with those with vitamin D level over 71.4 nmol/L at 5-year (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.42-9.45, p = .007), which was consistent with AIS patients (OR = 6.36, 95% CI = 1.89-21.44, p = .003). CONCLUSION: Vitamin D level less than 38.4 nmol/L at admission is a potential risk biomarker for poor functional outcome at 5-year prognosis in AIS patients, which might provide new ideas for the prognostic assessment of stroke.

Corrigendum: Age-Dependent Association Between Elevated Homocysteine and Cognitive Impairment in a Post-stroke Population: A Prospective Study.

[This corrects the article DOI: 10.3389/fnut.2021.691837.].