bluuebunny/crossref_metadata_2025 huggingface dataset:
Resting state aperiodic slope predicts Research Domain Criteria Social Processes in young typically developing adults
Authors: Ford Talitha C. , Hill Aron T. , Parrella Nina-Francesca , Kirkovski Melissa , Donaldson Peter , Enticott Peter G.
Published: September 2023

Background

The aperiodic exponent has been utilised to demonstrate differences in brain excitation-inhibition (E/I) in ageing, cognition, and neuro- and psycho-pathology. Furthermore, E/I imbalance has been associated with social communication difficulties in clinical and non-clinical cohorts. No work to date, however, has explored the association between aperiodic activity and social communication difficulties.

Methods

A total of 40 typically developing young adults aged 18-24 (24 female; age mean=21.6, SD=1.9) each underwent 5 minutes each of eyes open and eyes closed resting state EEG using a 64-channel HydroCel Geodesic Sensor Net. Participants also completed Research Domain Criteria Social Processes measures: Social Responsiveness Scale (SRS), Reading the Mind in the Eyes task (RME), and Penn Emotional Recognition Task (ER-40).

Results

Sex differences in aperiodic exponent and offset were observed, with steeper exponent and greater offset observed in males, suggestive of greater inhibitory tone (ps<.05). Whole-brain aperiodic activity was not associated with SRS, RME, or ER-40. There was some support for increased SRS scores and steeper exponent in right social brain (suggestive of greater excitatory tone), however, this was not significant (p=.068).

Conclusions

These preliminary data show promise for supporting the notion that brain E/I is associated with social communication and processing difficulties, however, larger samples are needed to validate these findings.
Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs
Authors: Yi Guoqiang , Liu Lei , Yao Yilong , Liu Yuwen , Li Jiang , Yang Yalan , Fang Lingzhao , Mo Delin , Zhang Longchao , Liu Yonggang , Niu Yongchao , Wang Liyuan , Qu Xiaolu , Pan Zhangyuan , Wang Lei , Chen Muya , Fan Xinhao , Chen Yun , Zhang Yongsheng , Li Xingzheng , Wang Zhen , Tang Yijie , Huang Hetian , Yuan Pengxiang , Liao Yuying , Li Xinjian , Yin Zongjun , Liu Di , Zhang Dongjie , Zhou Quanyong , Wu Wangjun , Jiang Jicai , Gao Yahui , Liu George E. , Wang Lixian , Chen Yaosheng , Groenen Martien A M , Tang Zhonglin
Published: September 2023

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-qualityde novoassembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes likeGHSRandBDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.
MMD-DTA: A multi-modal deep learning framework for drug-target binding affinity and binding region prediction
Authors: Liu Liwei , Zhang Qi , Wei Yuxiao , Zhang Shengli , Liao Bo
Published: September 2023

Abstract

The prediction of drug-target affinity (DTA) plays an important role in the development of drugs and the discovery of potential drug targets. In recent years, computer-assisted DTA prediction has become an important method in this field. In this work, we propose a multi-modal deep learning framework for drug-target binding affinity and binding region prediction, namely MMD-DTA. The model can predict DTA while unsupervised learning of drug-target binding regions. The experimental results show that MMD-DTA performs better than the existing models on the main evaluation metrics. In addition, external validation results show that MMD-DTA improves the generalization ability of the model by integrating sequence information and structural information of drugs and targets, and the model trained on the benchmark dataset can be well generalized to independent virtual screening tasks. Visualization of drug-target binding region prediction shows the powerful interpretability of MMD-DTA, which has important implications for exploring the functional regions of drug molecules acting on proteins.
Atazanavir/ritonavir increased tizoxanide exposure from oral nitazoxanide through pharmacokinetic interaction in healthy volunteers
Authors: Akinloye Abdulafeez , Oyedeji Timothy , Eniayewu Oluwasegun , Adeagbo Babatunde , Bolaji Oluseye , Rannard Steve , Owen Andrew , Olagunju Adeniyi
Published: September 2023

Aims

Nitazoxanide is a broad-spectrum antiviral with potential application in a number of viral infections. Its use is limited by gastrointestinal side effects associated with increasing dose. In this study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir.

Method

This was a crossover drug-drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alone in period 1 and in combination with 300/100 mg atazanavir/ritonavir in period 2 after a washout period of 21 days. On both days, blood samples for intensive pharmacokinetic analyses were collected before and at 0.25, 0.5, 1, 2, 4, 6, and 12 h after dose. To explore the utility of dried blood spots (DBS) as alternative to plasma for tizoxanide quantification, 50 µL of blood from some participants was spotted on DBS cards. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between periods 1 and 2. The correlation between tizoxanide concentration in plasma and DBS was also evaluated.

Results

Co-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure. The geometric mean ratios (90% CI) of tizoxanide AUC0-12h, Cmaxand C12hwere 1.872 (1.870 – 1.875), 2.029 (1.99 – 2.07) and 3.14 (2.268 – 4.352) respectively, were all outside the 0.8 – 1.25 interval, implying clinically significant interaction. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma concentrations, with a strong correlation (R = 0.89, P < 0.001). Similarly, DBS- derived plasma concentration and plasma concentrations displayed very strong correlation with linearity (R = 0.95, P<0.001).

Conclusion

Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers.
Genetic Variants in Carbohydrate Digestive Enzyme and Transport Genes Associated with Risk of Irritable Bowel Syndrome
Authors: Hong Hyejeong , Schulze Katharina V. , Copeland Ian E. , Atyam Manasa , Kamp Kendra , Hanchard Neil A. , Belmont John , Ringel-Kulka Tamar , Heitkemper Margaret , Shulman Robert J.
Published: September 2023

Irritable Bowel Syndrome (IBS) is characterized by abdominal pain and alterations in bowel pattern, such as constipation (IBS-C), diarrhea (IBS-D), or mixed (IBS-M). Since malabsorption of ingested carbohydrates (CHO) can cause abdominal symptoms that closely mimic those of IBS, identifying genetic mutations in CHO digestive enzymes associated with IBS symptoms is critical to ascertain IBS pathophysiology. Through candidate gene association studies, we identify several common variants inTREH,SI, SLC5A1andSLC2A5that are associated with IBS symptoms. By investigating rare recessive Mendelian or oligogenic inheritance patterns, we identify case-exclusive rare deleterious variation in known disease genes (SI, LCT, ALDOB,andSLC5A1)as well as candidate disease genes (MGAMandSLC5A2),providing potential evidence of monogenic or oligogenic inheritance in a subset of IBS cases. Finally, our data highlight that moderate to severe IBS-associated gastrointestinal symptoms are often observed in IBS cases carrying one or more of deleterious rare variants.
A novel framework for assessing causal effect of microbiome on health: long-term antibiotic usage as an instrument
Authors: Taba Nele , Fischer Krista ,   Estonian Biobank research team, Org Elin , Aasmets Oliver
Published: September 2023

Assessing causality is undoubtedly one of the key questions in microbiome studies for the upcoming years. Since randomised trials in human subjects are often unethical or difficult to pursue, analytical methods to derive causal effects from observational data deserve attention. As simple covariate adjustment is not likely to account for all potential confounders, the idea of instrumental variable (IV) analysis is worth exploiting. Here we propose a novel framework of antibiotic instrumental variable regression (AB-IVR) for estimating the causal relationships between microbiome and various diseases. We rely on the recent studies showing that antibiotic treatment has a cumulative long-term effect on the microbiome, resulting in individuals with higher antibiotic usage to have a more perturbed microbiome. We apply the AB-IVR method on the Estonian Biobank data and show that the microbiome has a causal role in numerous diseases including migraine, depression and irritable bowel syndrome. We show with a plethora of sensitivity analyses that the identified causal effects are robust, and propose ways for further methodological developments.
Converting between the International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite (EPIC) Urinary Subscales: Modeling and External Validation
Authors: Windisch Paul , Becker Ivo , Tang Hongjian , Schröder Christina , Buchali André , Aebersold Daniel M. , Zwahlen Daniel R. , Förster Robert , Shelan Mohamed
Published: September 2023

Background

The 50-item Expanded Prostate Cancer Index Composite (EPIC) and the International Prostate Symptom Score (IPSS) are two widely used options to assess prostate-related quality of life (QoL), but there is no method to convert between the two. We, therefore, developed and externally validated models for this purpose.

Methods

347 consecutive patients who had previously received radiotherapy and surgery for prostate cancer at two institutions in Switzerland and Germany were contacted via mail and instructed to complete both questionnaires. The Swiss cohort was used to train and internally validate different machine learning models using 4-fold cross-validation. The German cohort was used for external validation.

Results

Converting between the EPIC Urinary Irritative/Obstructive subscale and the IPSS using linear regressions resulted in mean absolute errors (MAEs) of 3.88 and 6.12 below the respective previously published minimal important differences (MIDs) of 5.2 and 10 points. Converting between the EPIC Urinary Summary and the IPSS was less accurate with MAEs of 5.13 and 10.45, similar to the MIDs. More complex model architectures did not result in improved performance.

Conclusions

Linear regressions can be used to convert between the IPSS and the EPIC Urinary subscales. While the equations obtained in this study can be used to compare results across clinical trials, they should not be used to inform clinical decision-making in individual patients.
Patient Insights into the Diagnosis of Smell and Taste Disorders in the United States
Authors: Naimi Bita R. , Hunter Stephanie R. , Boateng Katie , Rawson Nancy E. , Garvey Emily , Dalton Pamela H. , Trachtman Jenifer , Murphy Claire , Joseph Paule V. , Schrandt Suz , Silberman Pamela , Duffy Alexander , Nyquist Gurston G.
Published: September 2023

OBJECTIVES

Diagnosis of smell/taste dysfunction is necessary for appropriate medical care. This study examines factors affecting testing and diagnosis of smell/taste disorders.

METHODS

The onlineUSA Smell and Taste Patient Surveywas made available to US patients with smell/taste disorders between April 6-20, 2022. 4,728 respondents were included.

RESULTS

1,791 (38%) patients reported a documented diagnosis. Patients most often saw family practitioners (34%), otolaryngologists (20%), and Taste/Smell clinics (6%) for smell/taste dysfunction. 64% of patients who went to Taste/Smell clinics received smell testing, followed by 39% of patients who saw otolaryngologists, and 31% of patients who saw family practitioners. Factors associated with increased odds of diagnosis included age (25-39 years (OR 2.97, 95% CI [2.25, 3.95]), 40-60 (OR 3.3, 95% CI [2.56, 4.52]), and >60 (OR 4.25, 95% CI [3.21, 5.67]) vs. 18-24 years), male gender (OR 1.26, 95% CI [1.07, 1.48]), insurance status (private (OR 1.61, 95% CI [1.15, 2.30]) or public (OR 2.03, 95% CI [1.42, 2.95]) vs. uninsured), perception of their family practitioner to be knowledgeable (OR 2.12, 95% CI [1.16, 3.90]), otolaryngologic evaluation (OR 6.17, 95% CI [5.16, 7.38]), and psychophysical smell testing (OR 1.77, 95% CI [1.42, 2.22]).

CONCLUSION

Psychophysical testing, otolaryngologic evaluation, patient assessment of family practitioner knowledge level, insurance, age, and gender are significant factors in obtaining smell/taste dysfunction diagnosis. This study identifies barriers to diagnosis including lack of insurance or access to specialist evaluation and highlights the importance of educating family practitioners in diagnosis and management of patients with smell/taste disorders.
Development and validation of a deep-learning model to predict 10-year ASCVD risk from retinal images using the UK Biobank and EyePACS 10K datasets
Authors: Vaghefi Ehsan , Squirrell David , Yang Song , An Songyang , Xie Li , Durbin Mary K. , Hou Huiyuan , Marshall John , Shreibati Jacqueline , McConnell Michael V , Budoff Matthew
Published: September 2023

Background

Atherosclerotic Cardiovascular Disease (ASCVD) is a leading cause of death globally, and early detection of high-risk individuals is essential for initiating timely interventions. The authors aimed to develop and validate a deep learning (DL) model to predict an individual’s elevated 10-year ASCVD risk score based on retinal images and limited demographic data.

Methods

The study used 89,894 retinal fundus images from 44,176 UK Biobank participants (96% non-Hispanic White, 5% diabetic) to train and test the DL model. The DL model was developed using retinal images plus age, race/ethnicity, and sex at birth to predict an individual’s 10-year ASCVD risk score using the Pooled Cohort Equation (PCE) as the ground truth. This model was then tested on the US EyePACS 10K dataset (5.8% Non-Hispanic white 99.9% diabetic), composed of 18,900 images from 8,969 diabetic individuals. Elevated ASCVD risk was defined as a PCE score of ≥7.5%.

Results

In the UK Biobank internal validation dataset, the DL model achieved area under the receiver operating characteristic curve (AUROC) of 0.89, sensitivity 84%, and specificity 90%, for detecting individuals with elevated ASCVD risk scores. In the EyePACS 10K and with the addition of a regression-derived diabetes modifier, it achieved sensitivity 94%, specificity 72%, mean error −0.2%, and mean absolute error 3.1%.

Conclusion

This study demonstrates that DL models using retinal images can provide an additional approach to estimating ASCVD risk, and the value of applying DL models to different external datasets and opportunities about ASCVD risk assessment in patients living with diabetes.
The brain time estimation system is dynamically assembled by non-temporal perceptual states
Authors: Han Wenhao , Feng Tingting , Han Yifei , Sun Yawen , Jiang Yi , Zhang Tao
Published: September 2023

To investigate how neural integration of visual signals distorts human time perception, we developed a novel apparent motion paradigm. We found that the higher the frequency of visual events defined by spatial location, the longer the perception duration. At the same visual event frequency, perceptual duration was shorter when motion perception was evoked. We propose that the non-temporal perceptual states dynamically determine which core brain region (read-out system) and which group of activated neurons (timing units) assemble into a time estimation system. Timing units have activation delays in integrating input signals, which results in shorter perceptual time since perceptual duration depends only on the outputs of timing units. The read-out system consumes operating time to accumulate each timing unit, this results in a longer perception time the more timing units are accumulated in the same physical duration. Subsequently, experiments further validated two predictions of our perceptual assembly model.
Differential and lasting gene expression changes in circulating CD8 T cells in chronic HCV infection with cirrhosis and related insights on the role of Hedgehog signaling
Authors: Li Jiafeng , Vranjkovic Agatha , Read Daniel , Delaney Sean P , Stanford William L , Cooper Curtis L , Crawley Angela M
Published: September 2023

The impact of chronic hepatic infection on antigen non-specific immune cells in circulation is not well understood and may influence long term health. We reported lasting global hyperfunction of circulating CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. RNA sequencing of blood CD8 T cells from treatment-naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. Principal component analyses determined robust differences in over 350 genes expressed by CD8 T cells from HCV-infected individuals with minimal or advanced fibrosis and data suggests this remains relatively stable after viral clearance. Gene ontology analyses identified disaggregated gene expression related to cellular metabolism, including upregulated phospholipase, phosphatidyl-choline/inositol activity and second-messenger-mediated signaling, while genes in pathways associated with nuclear processes, RNA transport and cytoskeletal dynamics were reduced. Gene Set Enrichment Analysis identified decreased expression of genes regulated by the cMyc and E2f transcription factors in cirrhotics, compared to the minimal fibrosis group, as well as reduced expression of genes linked to oxidative phosphorylation, mTOR signaling, and more. Upregulated gene sets in cirrhotics included IFN-α, -γ, TGF-β response genes, apoptosis and apical surface pathways, among others. The hedgehog (Hh) signaling pathway was the top featured gene set upregulated in cirrhotics. Inhibition of Hh signaling with cyclopamine ablated CD8 T cell IFN-γ production, suggesting its involvement in hyperfunction. This is the first analysis of bulk CD8 T cell gene expression profiles in HCV infection in the context of liver fibrosis severity, and suggests cirrhosis significantly reprograms the CD8 T cell pool. The novel finding of increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
Genetic diversity of the Atacama Desert shrubHuidobria chilensisin the context of geography and climate
Authors: Bechir Ferchichi K. , Böhnert T. , Ritter B. , Harpke D. , Stoll A. , Morales P. , Fiedler S. , Mu F. , Bechteler J. , Münker C. , Koch M.A. , Wiehe T. , Quandt D.
Published: September 2023

Survival in hyperarid deserts is a major challenge for plant life, requiring the development of evolutionary strategies. The Atacama Desert presents harsh conditions such as limited rainfall, crusted soils, high soil salinity, high altitude, and intense solar radiation. These conditions, together with paleoclimatic variability since the past millions of years, have influenced the genetic structure and connectivity of plant populations, resulting in a diverse flora with high endemism. However, the diversification of most lineages appears to be relatively recent, in contrast to proposed age of the Atacama Desert and the onset, evolution and expansion of hyperarid conditions since the Late Oligocene and Early Miocene. A prominent exception is the Atacama paleoendemicHuidobria chilensis(Loasaceae), which is thought to be adapted to such conditions since the Eocene. Still, the environmental limits and thresholds for life in the Atacama remain poorly understood. To investigate the genetic structure in relation to the history of the Atacama Desert, we studied 186 individuals from 11 populations using genotyping-by-sequencing (GBS). Genome-wide single nucleotide polymorphisms (SNPs) were analyzed for population structure and genetic diversity. We identified three genetic clusters corresponding to geographic regions: the coastal region south of Tocopilla, the Coastal Cordillera around Chañaral, and the Copiapó watershed in the south. These clusters as well as genetic diversity were analyzed alongside rainfall, altitude, and landscape data. Although the genetic data generally supports isolation by distance as a major factor for genetic variation between populations, the study also reveals the influence of the topography on the distribution ofH. chilensisand highlights the role of hydrologically connected watersheds and rivers in plant migration and colonization. This shapes the species’ evolutionary trajectory and genetic diversity. Understanding these patterns provides insights into the adaptation and survival strategies of plants in extreme desert environments such as the Atacama.
Developmental effect of RASopathy mutations on neuronal network activity on a chip
Authors: Weiss Eva-Maria , Guhathakurta Debarpan , Petrušková Aneta , Hundrup Verena , Zenker Martin , Fejtová Anna
Published: September 2023

RASopathies are a group of genetic disorders caused by mutations in genes encoding components and regulators of the RAS/MAPK signaling pathway, resulting in overactivation of signaling. RASopathy patients exhibit distinctive facial features, cardiopathies, growth and skeletal abnormalities, and varying degrees of developmental delay, neurocognitive impairment, intellectual disabilities, and attention deficits. At present, it is unclear how RASopathy mutations cause neurocognitive impairment and what their neuron-specific cellular and network phenotypes are. Such knowledge would be crucial for the development of specific therapies, which are still lacking for the treatment of the neurocognitive and behavioral symptoms in RASopathies. Here, we investigated the effect of RASopathy mutations on the establishment and functional maturation of neuronal networks. We isolated cortical neurons from RASopathy mouse models and cultured them for several weeks in multiwell plates with implanted multielectrode arrays. The arrays were used for longitudinal recordings of spontaneous activity in developing networks as well as for recordings of evoked responses in mature neurons. To facilitate the analysis of large and complex data sets resulting from long-term multielectrode recordings, we developed MATLAB-based tools for data processing, analysis and statistical evaluation. Longitudinal analysis of spontaneous network activity revealed a convergent developmental phenotype in neurons carrying the gain-of-function RASopathy mutationsPtpn11D61YandKrasV14l. The phenotype was more pronounced at early time points and faded out over time, suggesting compensatory effects during network maturation. Nevertheless, persistent differences in excitatory/inhibitory balance and network excitability were observed in mature networks. This study improves the understanding of the complex relationship between genetic mutations and clinical manifestations in RASopathies by adding insights into functional network processes as an additional piece of the puzzle.
Coordinated Human-Exoskeleton Locomotion Emerges from Regulating Virtual Energy
Authors: Nasiri Rezvan , Dinovitzer Hannah , Arami Arash
Published: September 2023

Lower-limb exoskeletons showed great potential for the gait rehabilitation of individuals with motor impairments; however, maintaining human-exoskeleton coordination is still a challenge. Human-exoskeleton coordination problem, referred to as any mismatch or asynchrony between the user’s intended trajectories and exoskeleton desired trajectories, results in sub-optimal gait performance, particularly for the individuals with residual motor ability. Here, we investigate the virtual energy regulator (VER)’s ability to generate coordinated locomotion in lower limb exoskeleton in a study on nine individuals. A comprehensive analysis of metrics obtained at three different speeds demonstrates the emergence of natural and coordinated locomotion as a result of a shared control between human and exoskeleton maintained with the VER. We also introduce a metric to measure the user’s contribution to gait and demonstrated that the resultant locomotion limit cycle is a linear combination of human-intended limit cycle and the VER’s limit cycle. This results may have implications about how central nervous system controls our locomotion.
Dopamine and schizophrenia from bench to bedside: Discovery of a striatal co-expression risk gene set that predicts in vivo measures of striatal function
Authors: Sportelli Leonardo , Eisenberg Daniel P. , Passiatore Roberta , D’Ambrosio Enrico , Antonucci Linda A. , Chen Qiang , Czarapata Jasmine , Goldman Aaron L. , Gregory Michael , Griffiths Kira , Hyde Thomas M. , Kleinman Joel E. , Pardiñas Antonio F. , Parihar Madhur , Popolizio Teresa , Rampino Antonio , Shin Joo Heon , Veronese Mattia , Ulrich William S. , Zink Caroline F. , Bertolino Alessandro , Howes Oliver D. , Berman Karen F. , Weinberger Daniel R. , Pergola Giulio
Published: September 2023

Schizophrenia (SCZ) is characterized by a polygenic risk architecture implicating diverse molecular pathways important for synaptic function. However, how polygenic risk funnels through these pathways to translate into syndromic illness is unanswered. To evaluate biologically meaningful pathways of risk, we used tensor decomposition to characterize gene co-expression in post-mortem brain (of neurotypicals: N=154; patients with SCZ: N=84; and GTEX samples N=120) from caudate nucleus (CN), hippocampus (HP), and dorsolateral prefrontal cortex (DLPFC). We identified a CN-predominant gene set showing dopaminergic selectivity that was enriched for genes associated with clinical state and for genes associated with SCZ risk. Parsing polygenic risk score for SCZ based on this specific gene set (parsed-PRS), we found that greater pathway-specific SCZ risk predicted greaterin vivostriatal dopamine synthesis capacity measured by [18F]-FDOPA PET in three independent cohorts of neurotypicals and patients (total N=235) and greater fMRI striatal activation during reward anticipation in two additional independent neurotypical cohorts (total N=141). These results reveal a ‘bench to bedside’ translation of dopamine-linked genetic risk variation in drivingin vivostriatal neurochemical and hemodynamic phenotypes that have long been implicated in the pathophysiology of SCZ.
A muscle hypertrophy-derived myokine reprograms the stromal vascular fractions differentiation towards thermogenic adipocytes in subcutaneous adipose tissue
Authors: Yao Xiangping , Mai Xudong , Tian Ye , Liu Yifan , Jin Guanghui , Li Ze , Chen Shujie , Dai Xiaoshuang , Jin Xuejie , Huang Liujing , Han Mulan , Fan Zijing , Xiao Lanling , Pan Guihua , Pan Xiaohan , Lin Ziying , Li Xiangmin , Sun Jia , Ou Jingxing , Chen Hong , Xie Liwei
Published: September 2023

Skeletal muscle plays a significant role in both local and systemic energy metabolism; however, the cross-talk between skeletal muscle and adipose tissue remains largely unexplored. In this study, we identify the HIF2α-Bambi-Thbs4 axis as a critical driver of muscle hypertrophy and metabolic improvement. Deletion ofBambiinduces muscle hypertrophy and oxidative switching, thereby enhancing local and systemic metabolism under conditions of rodent chow and high-fat diets (HFD). Other than the metabolic regulation of skeletal muscle hypertrophy, we hypothesize that a portion of this improvement may be attributed to the metabolic reprogramming of the stromal vascular fraction (SVFs) of iWAT, promoting the development of beige adipocytes. Leveraging multi-omics approaches, we establish Thbs4 as a newly identified, muscle hypertrophy-derived myokine that serves as an essential regulator of this metabolic reprogramming. Thbs4 is upregulated in skeletal muscle during hypertrophy and aerobic exercise, localizes to the iWAT membrane, and facilitates the transformation of white adipocytes into beige adipocytes under conditions such as cold exposure, muscle hypertrophy, or aerobic exercise. Moreover, overexpression of Thbs4 elevates its plasma levels and leads to the transformation of white to beige adipocytes, therefore offering long-term protection against HFD-induced metabolic disorders. Conversely,Thbs4knockout (Thbs4-KO) disrupts the metabolic reprogramming of SVFs and exacerbates metabolic syndromes induced by an HFD, mirroring the observed decline in Thbs4 levels in aged mice. Therefore, our findings underscore Thbs4’s potential as both a long-term metabolic protective factor and a therapeutic target for the treatment of metabolic disorders.

Graphical Abstract

Highlights

Bambi, a direct target gene of HIF2α in skeletal muscle, when deleted, triggers muscle hypertrophy and the transformation of white into beige adipocytes, improving systemic energy metabolism.

The metabolic reprogramming of stromal vascular fractions (SVFs) contributes to the observed improvements in energy metabolism and adipocyte hyperplasia.

Thbs4, a novel myokine produced in skeletal muscle during hypertrophy and aerobic exercise, plays a key role in the transformation of white into beige adipocytes.

Overexpression of Thbs4 provides enduring protection against high-fat diet (HFD)-induced metabolic disorders, demonstrating its potential as a therapeutic target.

Thbs4deletion abrogates the beneficial metabolic reprogramming of SVFs and exacerbates HFD-induced metabolic syndromes, further underlining its crucial role in metabolic regulation.
Viable mutants of essential genes inPhyscomitrium patensas tools for studying primary metabolic processes
Authors: Haslam Tegan M. , Herrfurth Cornelia , Feussner Ivo
Published: September 2023

Sphingolipids are essential components of plant cells, which have been notoriously difficult to study in part due to pleiotropic or lethal knock-out mutant phenotypes. By relying on alternative end-joining of double stranded breaks, we successfully used CRISPR/Cas9 mutagenesis to generate a population of diverse, viable mutant alleles of genes required for sphingolipid assembly in totipotent protoplasts of the mossPhyscomitrium patens. We targeted theINOSITOL PHOSPHORYLCERAMIDE SYNTHASE(IPCS) gene family, which catalyzes the committed step in the synthesis of glycosyl inositol phosphorylceramides (GIPCs), the most abundant class of sphingolipids found in plants. We isolated knock-out single mutants and knock-down higher-order mutants showing a spectrum of deficiencies in GIPC content. Remarkably, we also identified two mutant alleles accumulating inositol phosphorylceramides, the direct products of IPCS activity, and provide our best explanation for this unexpected phenotype. Our approach is broadly applicable for studying essential genes and gene families, and for obtaining unusual lesions within a gene of interest.
Systems-wide analysis of the ROK-family regulatory generokL6and its role in the control of glucosamine toxicity inStreptomyces coelicolor
Authors: Li Chao , Urem Mia , Du Chao , Zhang Le , van Wezel Gilles P.
Published: September 2023

Streptomycetes are saprophytic bacteria that grow on complex polysaccharides, such as cellulose, starch, chitin and chitosan. For the monomeric building blocks glucose, maltose andN-acetylglucosamine (GlcNAc), the metabolic pathways are well documented, but that of glucosamine (GlcN) is largely unknown.Streptomyces nagBmutants, which lack glucosamine-6-phosphate deaminase activity, fail to grow in the presence of high concentrations of GlcN. Here we report that mutations in the gene for the ROK-family transcriptional regulator RokL6 relieve the toxicity of GlcN innagBmutants, as a result of elevated expression of the Major Facilitator Superfamily (MFS) exporter SCO1448. Systems- wide analysis using RNA sequencing, ChIP-Seq, EMSAs, 5’RACE, bioinformatics and genetics revealed that RokL6 is an autoregulator that represses transcription of sco1448 by binding to overlapping promoters in therokL6-sco1448 intergenic region. RokL6-independent expression of sco1448 fully relieved toxicity of GlcN tonagBmutants. Taken together, our data show a novel system of RokL6 as a regulator that controls the expression of the MFS transporter SCO1448, which in turn protects cells against GlcN toxicity, most likely by exporting toxic metabolites out of the cell.

IMPORTANCE

Central metabolism plays a key role in the control of growth and antibiotic production in streptomycetes. Specifically, aminosugars act as signaling molecules that affect development and antibiotic production, via metabolic interference with the global repressor DasR. While aminosugar metabolism directly connects to other major metabolic routes such as glycolysis and cell wall synthesis, several important aspects of their metabolism are yet unresolved. Accumulation ofN-acetylglucosamine 6-phosphate (GlcNAc-6P) or glucosamine 6-phosphate (GlcN-6P) is lethal to many bacteria, a yet unresolved phenomenon referred to as “aminosugar sensitivity”. We made use of this concept by selecting for suppressors in genes related to GlcN toxicity innagBmutants, which showed that the gene pair ofrok-family regulatory generokL6and MFS transporter gene sco1448 forms a cryptic rescue mechanism. Inactivation ofrokL6resulted in the expression of sco1448, which then prevents toxicity of amino sugar-derived metabolites inStreptomyces. The systems biology of RokL6 and its transcriptional control of sco1448 sheds new light on aminosugar metabolism in streptomycetes and on the response of bacteria to aminosugar toxicity.
HOCl-producing Electrochemical Bandages for TreatingPseudomonas aeruginosa-Infected Murine Wounds
Authors: Fleming Derek , Bozyel Ibrahim , Ozdemir Dilara , Otero Judith Alvarez , Karau Melissa J. , Islam Anoy Md Monzurul , Koscianski Christina , Schuetz Audrey N. , Greenwood-Quaintance Kerryl E. , Mandrekar Jayawant N. , Beyenal Haluk , Patel Robin
Published: September 2023

A novel electrochemical bandage (e-bandage) delivering low-level hypochlorous acid (HOCl) was evaluated againstPseudomonas aeruginosamurine wound biofilms. 5 mm skin wounds were created on the dorsum of Swiss-Webster mice and infected with 106colony forming units (CFU) ofP. aeruginosa. Biofilms were formed over two days, after which e-bandages were placed on the wound beds and covered with Tegaderm™. Mice were administered Tegaderm-only (control), non-polarized e-bandage (no HOCl production), or polarized e-bandage (using an HOCl-producing potentiostat), with or without concurrently administered systemic amikacin. Purulence and wound areas were measured before and after treatment. After 48 hours, animals were sacrificed, and wounds were harvested for bacterial quantification. Forty-eight hours of polarized e-bandage treatment resulted in mean biofilm reductions of 1.4 log10CFUs/g (9.0 vs 7.6 log10; p = 0.0107)vsnon-polarized controls, and 2.2 log10CFU/g (9.8 vs 7.6 log10; p = 0.004)vsTegaderm only controls. Systemic amikacin improved CFU reduction in Tegaderm-only (p = 0.0045) and non-polarized control groups (p = 0.0312), but not in the polarized group (p = 0.3876). Compared to the Tegaderm only group, there was more purulence reduction in the polarized group (p = 0.009), but not in the non-polarized group (p = 0.064). Wound closure was not impeded or improved by either polarized or non-polarized e-bandage treatment. Concurrent amikacin did not impact wound closure or purulence. In conclusion, an HOCl-producing e-bandage reducedP. aeruginosain wound biofilms with no impairment in wound healing, representing a promising antibiotic-free approach for addressing wound infections.
Selectivity to acoustic features of human speech in the auditory cortex of the mouse
Authors: Mohn Jennifer L. , Baese-Berk Melissa M. , Jaramillo Santiago
Published: September 2023

A better understanding of the neural mechanisms of speech processing can have a major impact in the development of strategies for language learning and in addressing disorders that affect speech comprehension. Technical limitations in research with human subjects hinder a comprehensive ex-ploration of these processes, making animal models essential for advancing the characterization of how neural circuits make speech perception possible. Here, we investigated the mouse as a model organism for studying speech processing and explored whether distinct regions of the mouse auditory cortex are sensitive to specific acoustic features of speech. We found that mice can learn to categorize frequency-shifted human speech sounds based on differences in formant transitions (FT) and voice onset time (VOT). Moreover, neurons across various auditory cortical regions were selective to these speech features, with a higher proportion of speech-selective neurons in the dorso-posterior region. Last, many of these neurons displayed mixed-selectivity for both features, an attribute that was most common in dorsal regions of the auditory cortex. Our results demonstrate that the mouse serves as a valuable model for studying the detailed mechanisms of speech feature encoding and neural plasticity during speech-sound learning.
Cold-induced skin darkening does not protect amphibian larvae from UV-associated DNA damage
Authors: Hird Coen , Flanagan Emer , Franklin Craig E. , Cramp Rebecca L.
Published: September 2023

Many amphibian declines are correlated with increasing levels of ultraviolet radiation (UVR). While disease is often implicated in declines, environmental factors such as temperature and UVR play an important role in disease epidemiology.

The mutagenic effects of UVR exposure on amphibians are worse at low temperatures. Amphibians from cold environments may be more susceptible to increasing UVR. However, larvae of some species demonstrate cold acclimation, reducing UV-induced DNA damage at low temperatures. Understanding of the mechanisms underpinning this response is lacking.

We rearedLimnodynastes peroniilarvae in cool (15°C) or warm (25°C) waters before acutely exposing them to 1.5 h of high intensity (80 μW cm-2) UVBR. We measured the colour of larvae and mRNA levels of a DNA repair enzyme. We reared larvae at 25°C in black or white containers to elicit a skin colour response, and then measured DNA damage levels in the skin and remaining carcass following UVBR exposure.

Cold acclimated larvae were darker and displayed lower levels of DNA damage than warm-acclimated larvae. There was no difference in CPD-photolyase mRNA levels between cold- and warm-acclimated larvae. Skin darkening in larvae did not reduce larval accumulation of DNA damage following UVR exposure.

Our results showed that skin darkening alone does not explain cold-induced reductions in UV-associated DNA damage inL. peroniilarvae. Beneficial cold-acclimation is more likely underpinned by increased CPD-photolyase abundance and/or increased photolyase activity at low temperatures.

Research Highlights

L. peroniiilarvae darken when exposed to cold temperatures

Darker larvae were not protected from the effects of UV on DNA damage

Cold acclimation of larvae when exposed to UV is likely driven by DNA repair enzymes not melanin
Beadex, theDrosophilaLIM only protein, is required for the growth of the larval neuromuscular junction and sensorimotor activities
Authors: Chitre Kripa , Kairamkonda Subhash , Dwivedi Manish Kumar , Yadav Saumitra , Kumar Vimlesh , Sikdar Sujit K. , Nongthomba Upendra
Published: September 2023

The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioural studies have identified many molecular players and investigated their roles in various neuromuscular processes. In this paper, we show that Beadex (Bx), theDrosophilaLIM only (LMO) protein, is required for motor activities and neuromuscular growth ofDrosophila.Bx7, a null allele, adult flies are flightless, with reduced walking and jumping activities. The larvae ofBx7, and the RNAi-mediated neuronal-specific knockdown ofBxshow drastically reduced crawling behaviour, a diminished synaptic span of the neuromuscular junctions and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria, that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show thatHighwire(Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulatesBx, as the latter’s deficiency was able to rescue the phenotype of theHiwnull mutant,HiwDN. Thus, our data indicates that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.
Hospital-Acquired Acute Kidney Injury in Non-critical Medical Patients in a Developing Country Tertiary Hospital: Incidence and Predictors
Authors: Mekonnen Nahom Dessalegn , Leulseged Tigist Workneh , Hassen Buure Ayderuss , Yemaneberhan Kidus Haile , Berhe Helen Surafeal , Mera Nebiat Adane , Beyene Anteneh Abera , Getachew Lidiya Zenebe , Habtezgi Birukti Gebreyohannes , Abriha Feven Negasi
Published: September 2023

Background

Acute kidney injury (AKI) is a frequent complication in critical patients leading to worse prognosis. Although the consequences of AKI are worse among critical patients, AKI is also associated with less favorable outcomes in non-critical patients. Hence, understanding the magnitude of the problem in these patients is crucial, yet there is a scarcity of evidence in non-critical settings, especially in resource limited countries. Hence, the study aimed at determining the incidence and predictors of hospital acquired acute kidney injury (HAAKI) in non-critical medical patients who were admitted at a large tertiary hospital in Ethiopia.

Methods

A retrospective chart review study was conducted among 232 hospitalized non-critical medical patients admitted to St. Paul’s Hospital Millennium Medical College between January 2020 and January 2022. Data was characterized using frequency and median with interquartile range. To identify predictors of HAAKI, a log binomial regression model was fitted at a p value of ≤ 0.05. The magnitude of association was measured using adjusted relative risk (ARR) with its 95% CI.

Results

During the median follow-up duration of 11 days (IQR, 6-19 days), the incidence of HAAKI was estimated to be 6.0 per 100 person-day observation (95% CI= 5.5 to 7.2). Significant predictors of HAAKI were found to be having type 2 diabetes mellitus (ARR=2.36, 95% CI= 1.03, 5.39, p-value=0.042), and taking vancomycin (ARR=3.04, 95% CI= 1.38, 6.72, p-value=0.006) and proton pump inhibitors (ARR=3.80, 95% CI = 1.34,10.82, p-value=0.012).

Conclusions

HAAKI is a common complication in hospitalized non-critical medical patients, and is associated with a common medical condition and commonly prescribed medications. Therefore, it is important to remain vigilant in the prevention and timely identification of these cases and to establish a system of rational prescribing habits.
Statistical analysis of three data sources for Covid-19 monitoring in Rhineland-Palatinate, Germany
Authors: Pilz Maximilian , Küfer Karl-Heinz , Mohring Jan , Münch Johanna , Wlazło Jarosław , Leithäuser Neele
Published: September 2023

In Rhineland-Palatinate, Germany, a system of three data sources has been established to track the Covid-19 pandemic. These sources are the number of Covid-19-related hospitalizations, the Covid-19 genecopies in wastewater, and the prevalence derived from a cohort study. This paper presents an extensive comparison of these parameters. It is investigated whether wastewater data and a cohort study can be valid surrogate parameters for the number of hospitalizations and thus serve as predictors for coming Covid-19 waves. We observe that this is possible in general for the cohort study prevalence, while the wastewater data suffer from a too large variability to make quantitative predictions by a purely data-driven approach. However, the wastewater data as well as the cohort study prevalence are able to detect hospitalizations waves in a qualitative manner. Furthermore, a detailed comparison of different normalization techniques of wastewater data is provided.
A monoclonal antibody collection forC. difficiletyping
Authors: Hunault Lise , England Patrick , Barbut Frédéric , Iannascoli Bruno , Godon Ophélie , Déjardin François , Thomas Christophe , Dupuy Bruno , Guo Chunguang , Macdonald Lynn , Gorochov Guy , Sterlin Delphine , Bruhns Pierre
Published: September 2023

Clostridioides difficileis the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in adults. VariousC. difficilestrains circulate currently, associated with different outcomes and antibiotic resistance profiles. However, most studies still focus on the reference strain 630 that does not circulate anymore, partly due to the lack of immunological tools to study current clinically importantC. difficilePCR ribotypes. Herein, we immunized mice expressing human variable antibody genes with the Low Molecular Weight (LMW) subunit of the surface layer protein SlpA from variousC. difficilestrains. Monoclonal antibodies purified from hybridomas bound LMW with high-affinity and whole bacteria from currentC. difficileribotypes with different cross-specificities. This first collection of anti-C. difficilemAbs represent valuable tools for basic and clinical research.