bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: September 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed.. Using the g:Profiler, the function and pathway enrichment analysis of DEGs were performed. Then, a protein–protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst database was used to construct the targeted microRNAs (miRNAs) and transcription factors (TFs) of the hub genes. Finally receiver operating characteristic (ROC) curve analysis was used to validates the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8 and EFHC2 were selected. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.
Biomedical researchers’ perspectives on the reproducibility of research: a cross-sectional international survey
Authors: Cobey Kelly D. , Ebrahimzadeh Sanam , Page Matthew J. , Thibault Robert T. , Nguyen Phi-Yen , Abu-Dalfa Farah , Moher David
Published: September 2023

We conducted an international cross-sectional survey of biomedical researchers’ perspectives on the reproducibility of research. This study builds on a widely cited 2016 survey on reproducibility, and provides a biomedical-specific and contemporary perspective on reproducibility. To sample the community, we randomly selected 400 journals indexed in MEDLINE, from which we extracted the author names and e-mails from all articles published between October 1, 2020 and October 1, 2021. We invited participants to complete an anonymous online survey which collected basic demographic information, perceptions about a reproducibility crisis, perceived causes of irreproducibility of research results, experience conducting replication studies, and knowledge of funding and training for research on reproducibility. A total of 1924 participants accessed our survey, of which 1630 provided useable responses (response rate 7% of 23,234). Key findings include that 72% of participants agreed there was a reproducibility crisis in biomedicine, with 27% of participants indicating the crisis was ‘significant’. The leading perceived cause of irreproducibility was a ‘pressure to publish’ with 62% of participants indicating it ‘always’ or ‘very often’ contributes. About half of the participants (54%) had run a replication of their own previously published study while slightly more (57%) had run a replication of another researcher’s study. Just 16% of participants indicated their institution had established procedures to enhance the reproducibility of biomedical research; and 67% felt their institution valued new research over replication studies. Participants also reported few opportunities to obtain funding to attempt to reproduce a study and 83% perceived it would be harder to do so than to get funding to do a novel study. Our results may be used to guide training and interventions to improve research reproducibility and to monitor rates of reproducibility over time. The findings are also relevant to policy makers and academic leadership looking to create incentives and research cultures that support reproducibility and value research quality.
PubNavigator as an undergraduate teaching tool
Authors: Marroquín-Flores Rosario A. , Campbell Maverick A. , Grimes Stephanie , Limeri Lisa B.
Published: September 2023

The ability to use data and evidence as the basis for scientific reasoning is a critical skill that undergraduate students must learn to successfully transition into science careers. There is a need for pedagogical tools that promote the development of science process skills and reduce barriers to implementation in the classroom. PubNavigator (www.pubnavigator.com) is a science communication platform that shares the findings of primary literature using accessible language and features biographical information about the authors. This research assesses the utility of PubNavigator as an undergraduate teaching resource. We analyzed responses to an assignment prompting discussion of PubNavigator articles in an asynchronous online discussion forum in an introductory biology course. We conducted thematic analysis guided by the evidence-based reasoning framework to identify evidence of science reasoning and interactive enagement. We found evidence that the PubNavigator assignment elicited engagement in scientific reasoning. Students who demonstrated higher levels of engagement with the assignment also demonstrated higher levels of science reasoning in their discussion of the articles. Our findings support PubNavigator as an undergraduate teaching tool that can be used to promote science reasoning and engagement in introductory biology. We provide recommendations for implementation to instructors interested in integrating PubNavigator activities into their courses.
Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data
Authors: Zhu James , Wang Yunguan , Chang Woo Yong , Malewska Alicia , Napolitano Fabiana , Gahan Jeffrey C. , Unni Nisha , Zhao Min , Yuan Rongqing , Wu Fangjiang , Yue Lauren , Guo Lei , Zhao Zhuo , Chen Danny Z. , Hannan Raquibul , Zhang Siyuan , Xiao Guanghua , Mu Ping , Hanker Ariella B. , Strand Douglas , Arteaga Carlos L. , Desai Neil , Wang Xinlei , Xie Yang , Wang Tao
Published: September 2023

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacia’s power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate inPDL1/PD1signaling in tumors. We demonstrated that a CD8+T cell/PDL1effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between γδ T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.
#ActuallyAutistic Twitter dataset for precision diagnosis of Autism Spectrum Disorder (ASD)
Authors: Jaiswal Aditi , Washington Peter
Published: September 2023

The increasing usage of social media platforms has given rise to an unprecedented surge in user- generated content with millions of users sharing their thoughts, experiences, and health-related information. Because of this social media has turned out to be a useful means to study and understand public health. Twitter is one such platform that has proven to be a valuable source of such information for both public and health officials. We present a novel dataset consisting of 6,515,470 tweets collected from users self identifying with autism using “#ActuallyAutistic” and a control group. The dataset also has supporting information such as posting dates, follower count, geographical location, and interaction metrics. We illustrate the utility of the dataset through common Natural Language Processing (NLP) applications such as sentiment analysis, tweet and user classification, and topic modeling. The textual differences in social media communications can help researchers and clinicians to conduct symptomatology studies, in natural settings, by establishing effective biomarkers to distinguish an autistic individual from their typical peers. For better accessibility, reusability and new research insights, we have released the dataset publicly.
Screening of Thalassemia Carriers, Hemoglobin Variants, and Comparison of Hematological Parameters between Children of Bangladesh and Forcibly Displaced Myanmar Nationals
Authors: Mahtarin Rumana , Azad Kasrina , Hossain Mohabbat , Aktar Mukta Mst. Sharmin , Habib Mohammad Tanbir , Siddik Abu Bakar , Sultana Nishat , Kawser Zannat , Kulsum Umme , Sultana Nusrat , Noor Farjana Akther , Mahdi Ahmad Zubair , Asaduzzaman Muhammad , Habib Md. Ahashan , Chowdhury Emran Kabir , Qadri Firdausi , Begum Mst. Noorjahan , Nurun Nabi A.H.M.
Published: September 2023

Thalassemia is a hereditary blood disorder with different severity spectrums. This study aimed to assess thalassemia screening rates between children of Bangladesh and selected camps of Forcibly Displaced Myanmar Nationals (FDMN) in Cox’s Bazar in Bangladesh and compare the hematological parameters among the screening groups. Complete blood count (CBC) analysis and hemoglobin electrophoresis for each participant were performed by collecting venous blood. Statistical analysis was employed for the comparison of parameters in blood. The thalassemia carrier and other hemoglobin variant rate in Bangladeshi children in selected areas have been found to be 20.7% and in FDMN children, the rate is 8.2%. Hematological differences are visualized among children of two nations. Intra-and interpopulation variances are highlighted in principal component analysis where higher variance (94.87%) in Bangladeshi children than FDMN children (80.68%). Receiver operating characteristics (ROC) and area under the curve (AUC) analyses revealed, RBC (0.761, 0.902, and 0.791) and RDW-CV are better model (0.819, 0.925, and 0.858) among the classifier of blood parameters. Pearson correlation shows distinguished covariation or association among the parameters. The outcome of the study highlights the discrepancies in levels of carriers in regions in Bangladesh and suggests further screening as well as population based molecular research to ensure better treatment strategies.
Targeted malaria elimination interventions reducePlasmodium falciparuminfections up to 3 kilometers away
Authors: Benjamin-Chung Jade , Li Haodong , Nguyen Anna , Heitmann Gabriella Barratt , Bennett Adam , Ntuku Henry , Prach Lisa M. , Tambo Munyaradzi , Wu Lindsey , Drakeley Chris , Gosling Roly , Mumbengegwi Davis , Kleinschmidt Immo , Smith Jennifer L. , Hubbard Alan , van der Laan Mark , Hsiang Michelle S.
Published: September 2023

Malaria elimination interventions in low-transmission settings aim to extinguish hot spots and prevent transmission to nearby areas. In malaria elimination settings, the World Health Organization recommends reactive, focal interventions targeted to the area near malaria cases shortly after they are detected. A key question is whether these interventions reduce transmission to nearby uninfected or asymptomatic individuals who did not receive interventions. Here, we measured direct effects (among intervention recipients) and spillover effects (among non-recipients) of reactive, focal interventions delivered within 500m of confirmed malaria index cases in a cluster-randomized trial in Namibia. The trial delivered malaria chemoprevention (artemether lumefantrine) and vector control (indoor residual spraying with Actellic) separately and in combination using a factorial design. We compared incidence, infection prevalence, and seroprevalence between study arms among intervention recipients (direct effects) and non-recipients (spillover effects) up to 3 km away from index cases. We calculated incremental cost-effectiveness ratios accounting for spillover effects. The combined chemoprevention and vector control intervention produced direct effects and spillover effects. In the primary analysis among non-recipients within 1 km from index cases, the combined intervention reduced malaria incidence by 43% (95% CI 20%, 59%). In secondary analyses among non-recipients 500m-3 km from interventions, the combined intervention reduced infection by 79% (6%, 95%) and seroprevalence 34% (20%, 45%). Accounting for spillover effects increased the cost-effectiveness of the combined intervention by 37%. Our findings provide the first evidence that targeting hot spots with combined chemoprevention and vector control interventions can indirectly benefit non-recipients up to 3 km away.

Significance Statement

In settings where malaria transmission is declining and approaching elimination, new malaria cases are clustered in space and time. Prior studies have found that targeting prophylactic antimalarial drugs and vector control in the area around newly detected malaria cases reduced community-wide malaria. Here, we found that when antimalarials and vector control were delivered as a combined strategy in the area near recent cases, malaria incidence was reduced up to 3 kilometers away among individuals who did not receive interventions. Accounting for these benefits to non-recipients increased cost-effectiveness of the intervention. Overall, our findings suggest that combined, targeted malaria interventions can reduce local transmission and support their use for malaria elimination.
USP48/USP31 Is a Nuclear Deubiquitinase that Potently Regulates Synapse Remodeling
Authors: Ma Qi , Ruan Hongyu , Dai Huihui , Yao Wei-Dong
Published: September 2023

Deubiquitinases present locally at synapses regulate synaptic development, function, and plasticity. It remains largely unknown, however, whether deubiquitinases localized outside of the synapse control synapse remodeling. Here we identify ubiquitin specific protease 48 (USP48; formerly USP31) as a nuclear deubiquitinase mediating robust synapse removal. USP48 is expressed primarily during the first postnatal week in the rodent brain and is virtually restricted to nuclei, mediated by a conserved, 13-amino acid nuclear localization signal. When exogenously expressed, USP48, in a deubiquitinase and nuclear localization-dependent manner, induces striking filopodia elaboration, marked spine loss, and significantly reduced synaptic protein clustering in vitro, and erases ∼70% of functional synapses in vivo. USP48 interacts with the transcription factor NF-κB, deubiquitinates NF-κB subunit p65 and promotes its stability and activation, and up-regulates NF-κB target genes known to inhibit synaptogenesis. Depleting NF-κB prevents USP48-dependent spine pruning. These findings identify a novel nucleus-enriched deubiquitinase that plays critical roles in synapse remodeling.
Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2
Authors: Connor Ruth I. , Sakharkar Mrunal , Rappazzo C. Garrett , Kaku Chengzi I. , Curtis Nicholas C. , Shin Seungmin , Wieland-Alter Wendy F. , Weiner Joshua A. , Ackerman Margaret E. , Walker Laura M. , Lee Jiwon , Wright Peter F.
Published: September 2023

Characterization of functional antibody responses to the N-terminal domain (NTD) of the SARS-CoV-2 spike (S) protein has included identification of both potent neutralizing activity and putative enhancement of infection. Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by NTD-binding monoclonal antibodies (mAbs) has been observedin vitro, but the functional significance of these antibodiesin vivois not clear. Here we studied 1,213 S-binding mAbs derived from longitudinal sampling of B-cells collected from eight COVID-19 convalescent patients and identified 72 (5.9%) mAbs that enhanced infection in a VSV-SARS-CoV-2-S-Wuhan pseudovirus (PV) assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least five months post-infection. Enhancement of PV infection by NTD-binding mAbs was not observed using intestinal (Caco-2) and respiratory (Calu-3) epithelial cells as infection targets and was diminished or lost against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire from two of the convalescent subjects identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum (i.e., functionally secreted antibody). Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins. Taken together, these findings suggest functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display diverse attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.
Immunogenicity and Efficacy of TNX-1800, A Live Virus Recombinant Poxvirus Vaccine Candidate, Against SARS-CoV-2 Challenge in Nonhuman Primates
Authors: Awasthi Mayanka , Macaluso Anthony , Myscofski Dawn , Prigge Jon , Koide Fusataka , Noyce Ryan S , Fogarty Siobhan , Stillwell Helen , Goebel Scott J , Daugherty Bruce , Nasar Farooq , Bavari Sina , Lederman Seth
Published: September 2023

TNX-1800 is a synthetically derived live chimeric Horsepox Virus (rcHPXV) vaccine expressing Wuhan SARS-CoV-2 spike (S) protein. The primary objective of this study was to evaluate the immunogenicity and efficacy of TNX-1800 in two nonhuman primate species challenged with USA-WA1/2020 SARS-CoV-2. TNX-1800 vaccination was well tolerated, as indicated by the lack of serious adverse events or significant changes in clinical parameters. A single dose of TNX-1800 generated robust humoral responses in African Green Monkeys and Cynomolgus Macaques, as measured by the total binding anti-SARS-CoV-2 S IgG and neutralizing antibody titers against the USA-WA1/2020 strain. In Cynomolgus Macaques, a single dose of TNX-1800 induced a strong interferon-gamma (IFN-γ) mediated T cell response, promoting both pathogen clearance in the upper and lower airways and generation of systemic neutralizing antibody response against WA strain SARS-CoV-2. Future studies will assess the efficacy of TNX-1800 against newly emerging variants and demonstrate its safety in humans.
Exportin 1 is required for the reproduction and maize mosaic virus accumulation in its insect vectorPeregrinus maidis
Authors: Xavier Cesar A. D. , Tyson Clara , Kerner Leo M. , Whitfield Anna E.
Published: September 2023

Exportin 1 (XPO1) is the major karyopherin-β nuclear receptor mediating the nuclear export of hundreds of proteins and some classes of RNA and regulates several critical processes in the cell, including but not limited to, cell-cycle progression, transcription, translation, oncogenesis and longevity. Viruses have co-opted XPO1 to promote nucleocytoplasmic transport of viral proteins and RNA. Maize mosaic virus (MMV) is anAlphanucleorhabdovirustransmitted in a circulative propagative manner by the corn planthopper,Peregrinus maidis. MMV replicates in the nucleus of plant and insect hosts, and it remains unknown whether MMV co-optsP. maidis XPO1(PmXPO1) to complete its life cycle. Because XPO1 plays multiple regulatory roles in cell functions and virus infection, we hypothesized that RNAi-mediated silencing ofXPO1would simultaneously and negatively affect MMV accumulation and insect physiology. AlthoughPmXPO1expression was not modulated during MMV infection,PmXPO1knockdown negatively affected MMV accumulation inP. maidisat 12 and 15 days after microinjection. Likewise,PmXPO1knockdown negatively affectedP. maidissurvival and reproduction.PmXPO1exhibited tissue specific expression patterns with higher expression in the ovaries compared to the guts of adult females. Survival rate was significantly lower forPmXPO1knockdown females, compared to controls, but no effect was observed for males. Adult females withPmXPO1knockdown were heavier and had a larger abdomen compared to controls at 4, 8 and 12 days after dsRNA microinjection. Consistent with an increase in weight, glyceride content specifically and significantly increased inPmXPO1knockdown female planthoppers. Ovary development was significantly inhibited, and mature eggs were not observed in adult females withPmXPO1knockdown. Consistent with a major role ofPmXPO1 in ovary function and egg production, oviposition and egg hatch in plants was dramatically reduced in dsRNAPmXPO1treated insects compared with control. Altogether, these results suggest thatPmXPO1is a positive regulator ofP. maidisreproduction and that it plays a proviral role in the insect vector supporting MMV infection.
Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice
Authors: Murali Megha , Alabi Nikolay , Chelikani Prasanth K. , MacDonald Justin A.
Published: September 2023

Smoothelin-like 1 (SMTNL1) is expressed in smooth and skeletal muscle tissues as well as a variety of steroid hormone-sensitive tissues. SMTNL1 can play a sex-dependent regulatory role in skeletal muscle metabolism in mice. Previous studies have documented appreciable changes in muscle morphology and metabolic function of young male mice with genetic deletion ofSmtnl1. SMTNL1 can also impact the energy metabolism and insulin sensitivity of female mice during pregnancy. Therefore, we investigated the metabolic outcome of global SMTNL1 knockout (KO) in male and female mice with advancing age using a comprehensive lab animal monitoring system (CLAMS). With ageing, body weight gain was markedly higher with a concomitant increase in whole body adiposity as well as specific white adipose depots in the absence of SMTNL1. Moreover, this genotypic difference in whole body adiposity was greater in the female cohort. The deletion of SMTNL1 was also associated with delayed satiety in mice fed a high fat diet, which was more pronounced in the female mice. A significant genotypic difference was also revealed for the metabolic energy balance in 12 month old animals of both sexes. The KO animals were metabolically less efficient and displayed a preference for carbohydrate catabolism. However, reduced glucose tolerance was observed only in the female group with the deletion of SMTNL1. Taken together, the current findings establish a novel role for SMTNL1 in modulating adiposity and energy metabolism with ageing in a sex dimorphic way.
A role for the ATP-dependent DNA ligase Lig E ofNeisseria gonorrhoeaein biofilm formation
Authors: Pan Jolyn , Hicks Joanna , Williamson Adele
Published: September 2023

The ATP-dependent DNA ligase Lig E is present as an accessory DNA ligase in numerous proteobacterial genomes, including many disease-causing species. Here we have constructed a genomic Lig E knock-out in the obligate human pathogenNeisseria gonorrhoeaeand characterised its growth and infection characteristics. This demonstrates thatN. gonorrhoeaeLig E is a non-essential gene and its deletion does not cause defects in replication or survival of DNA-damaging stressors. Knock-out strains were partially defective in biofilm formation on an artificial surface as well as adhesion to epithelial cells which coupled with the predicted extracellular/ periplasmic location of Lig E indicates a role in extracellular DNA joining. In addition toin vivocharacterisation, we have recombinantly expressed and assayedN. gonorrhoeaeLig E and determined the crystal structure of the enzyme-adenylate engaged with DNA substrate in an open non-catalytic conformation, providing insight into the binding dynamics of these minimal DNA ligases.
Serotonin predictively encodes value
Authors: Harkin Emerson F. , Grossman Cooper D. , Cohen Jeremiah Y. , Béïque Jean-Claude , Naud Richard
Published: September 2023

Thein vivoresponses of dorsal raphe nucleus (DRN) serotonin neurons to emotionally-salient stimuli are a puzzle. Existing theories centred on reward, surprise, or uncertainty individually account for some aspects of serotonergic activity but not others. Here we find a unifying perspective in a biologically-constrained predictive code for cumulative future reward, a quantity called state value in reinforcement learning. Through simulations of trace conditioning experiments common in the serotonin literature, we show that our theory, called value prediction, intuitively explains phasic activation by both rewards and punishments, preference for surprising rewards but absence of a corresponding preference for punishments, and contextual modulation of tonic firing—observations that currently form the basis of many and varied serotonergic theories. Next, we re-analyzed data from a recent experiment and found serotonin neurons with activity patterns that are a surprisingly close match: our theory predicts the marginal effect of reward history on population activity with a precision ≪0.1 Hz neuron−1. Finally, we directly compared against quantitative formulations of existing ideas and found that our theory best explains both within-trial activity dynamics and trial-to-trial modulations, offering performance usually several times better than the closest alternative. Overall, our results show that previous models are not wrong, but incomplete, and that reward, surprise, salience, and uncertainty are simply different faces of a predictively-encoded value signal. By unifying previous theories, our work represents an important step towards understanding the potentially heterogeneous computational roles of serotonin in learning, behaviour, and beyond.
Quantifying Harmony between Direct and Indirect Pathways in The Basal Ganglia; Healthy and Parkinsonian States
Authors: Kim Sang-Yoon , Lim Woochang
Published: September 2023

The basal ganglia (BG) show a variety of functions for motor and cognition. There are two competitive pathways in the BG; direct pathway (DP) which facilitates movement and indirect pathway (IP) which suppresses movement. It is well known that diverse functions of the BG may be made through "balance" between DP and IP. But, to the best of our knowledge, so far no quantitative analysis for such balance was done. In this paper, as a first time, we introduce the competition degreeCdbetween DP and IP. Then, by employingCd, we quantify their competitive harmony (i.e., competition and cooperative interplay), which could lead to improving our understanding of the traditional "balance" so clearly and quantitatively. We first consider the case of normal dopamine (DA) level of φ*=0.3. In the case of phasic cortical input (10 Hz), a healthy state withCd*=2.82 (i.e., DP is 2.82 times stronger than IP) appears. In this case, normal movement occurs via harmony between DP and IP. Next, we consider the case of decreased DA level, φ=φ*(=0.3)xDA(1>xDA≥0). With decreasingxDAfrom 1, the competition degreeCdbetween DP and IP decreases monotonically fromCd*, which results in appearance of a pathological Parkinsonian state with reducedCd. In this Parkinsonian state, strength of IP is much increased than that in the case of normal healthy state, leading to disharmony between DP and IP. Due to such break-up of harmony between DP and IP, impaired movement occurs. Finally, we also study treatment of the pathological Parkinsonian state via recovery of harmony between DP and IP.
Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelial cells
Authors: Zhao Caiqi , Wang Wei , Bai Yan , Amonkar Gaurang , Mou Hongmei , Olejnik Judith , Hume Adam J , Mühlberger Elke , Fang Yinshan , Que Jianwen , Fearns Rachel , Ai Xingbin , Lerou Paul H.
Published: September 2023

Respiratory syncytial virus (RSV) can cause severe disease especially in infants; however, mechanisms of age-associated disease severity remain elusive. Here, employing human bronchial epithelium models generated from tracheal aspirate-derived basal stem cells of neonates and adults, we investigated whether age regulates RSV-epithelium interaction to determine disease severity. We show that following RSV infection, only neonatal epithelium model exhibited cytopathy and mucus hyperplasia, and neonatal epithelium had more robust viral spread and inflammatory responses than adult epithelium. Mechanistically, RSV-infected neonatal ciliated cells displayed age-related impairment of STAT3 activation, rendering susceptibility to apoptosis, which facilitated viral spread. In contrast, SARS-CoV-2 infection of ciliated cells had no effect on STAT3 activation and was not affected by age. Taken together, our findings identify an age-related and RSV-specific interaction with neonatal bronchial epithelium that critically contributes to severity of infection, and STAT3 activation offers a potential strategy to battle severe RSV disease in infants.
Causal evidence of coherent theta rhythms in the modulation of multiregional brain communication
Authors: Ferraro Gino Del , Qiao Shaoyu , Sedillo J. Isaac , Pesaran Bijan
Published: September 2023

Neuromodulatory interventions seek to treat neuropsychiatric disorders by manipulating multiregional communication across the mesolimbic mood network. Modulations of multiregional communication are rarely measured directly and are often inferred from correlated neural activity such as neural coherence. Whether and how neural coherence reflects dynamic multiregional communication remains unclear. To address this limitation, we performed a causal-correlation analysis of theta-frequency (4-10 Hz) rhythms and mesolimbic multiregional communication. Selectively stimulating sender sites while recording from receiver sites revealed a mechanism of dynamic multiregional communication involving theta-coherent neural dynamics across a network of sender-receiver-modulator sites. Modulator site activity was highly theta-coherent with the receiver site activity, less theta-coherent with sender site activity, site specific and not shared by neighboring sites in the same region. These results reveal fundamental mechanisms of dynamic multiregional communication and support the use of theta-coherence as a target for neuromodulatory interventions in the mesolimbic mood network.
The CASwitch: a synthetic biology solution for high-performance inducible gene expression systems in biotechnology
Authors: De Carluccio Giuliano , Fusco Virginia , di Bernardo Diego
Published: September 2023

Inducible gene expression systems can be used to control the expression of a gene of interest by means of a small-molecule. One of the most common designs involves engineering a small-molecule responsive transcription factor (TF) and its cognate promoter, which often results in a compromise between minimal uninduced background expression (leakiness) and maximal induced expression. Here, we focussed on an alternative strategy using quantitative synthetic biology to mitigate leakiness while maintaining high expression, without modifying neither the TF nor the promoter. Through mathematical modelling and experimental validations, we designed the CASwitch, a mammalian synthetic gene circuit based on combining two well-known network motifs: the Coherent Feed-Forward Loop (CFFL) and the Mutual Inhibition (MI). The CASwitch combines the CRISPR-Cas endoribonuclease CasRx with the state-of-the-art Tet-On3G inducible gene system to achieve high performances. To demonstrate the potentialities of the CASwitch, we applied it to three different scenarios: enhancing a whole-cell biosensor, controlling expression of a toxic gene and inducible production of Adeno-Associated Virus (AAV) vectors.
Loss of cilia after neurulation impacts brain development and neuronal activity in larval zebrafish
Authors: D’Gama Percival P. , Jeong Inyoung , Nygård Andreas Moe , Trinh Anh-Tuan , Yaksi Emre , Jurisch-Yaksi Nathalie
Published: September 2023

Cilia are slender, hair-like structures extending from cell surfaces and playing essential roles in diverse physiological processes. Within the nervous system, primary cilia contribute to signaling and sensory perception, while motile cilia facilitate cerebrospinal fluid flow. Here, we investigated the impact of ciliary loss on neural circuit development using a zebrafish line displaying ciliogenesis defects. We found that cilia loss after neurulation affects neurogenesis and brain morphology, and lead to altered gene expression profiles. Using whole brain calcium imaging, we measured reduced light-evoked and spontaneous neuronal activity in all brain regions. By shedding light on the intricate role of cilia in neural circuit formation and function in the zebrafish, our work highlights their evolutionary conserved role in the brain and set the stage for future analysis of ciliopathy models.
The RNA-binding domain of hnRNP U extends beyond the RGG/RG motifs
Authors: Kletzien Otto A. , Wuttke Deborah S. , Batey Robert T.
Published: September 2023

Heterogeneous nuclear ribonucleoprotein U (hnRNP U) is a ubiquitously expressed protein that regulates chromatin architecture through its interactions with numerous DNA, protein, and RNA partners. The RNA-binding domain (RBD) of hnRNP U was previously mapped to an RGG/RG element within its disordered C-terminal region, but little is understood about its binding mode and potential for selective RNA recognition. Analysis of publicly available hnRNP U enhanced UV crosslinking and immunoprecipitation (eCLIP) data identified high-confidence binding sites within human RNAs. We synthesized a set of diverse RNAs encompassing eleven of these identified crosslink sites for biochemical characterization using a combination of fluorescence anisotropy and electrophoretic mobility shift assays. Thesein vitrobinding experiments with a rationally designed set of RNAs and hnRNP U domains revealed that the RGG/RG element is a small part of a more expansive RBD that encompasses most of the disordered C-terminal region. This RBD contains a second, previously experimentally uncharacterized RGG/RG element with RNA-binding properties comparable to the canonical RGG/RG element. These RGG/RG elements serve redundant functions, with neither serving as the primary RBD. While in isolation each RGG/RG element has modest affinity for RNA, together they significantly enhance the association of hnRNP U with RNA, enabling binding of most of the designed RNA set with low to mid-nanomolar binding affinities. Identification and characterization of the complete hnRNP U RBD highlights the perils of a reductionist approach to defining biochemical activities in this system and paves the way for a detailed investigation of its RNA-binding specificity.
An RGB based deep neural network for high fidelity Fusarium head blight phenotyping in wheat
Authors: Cooper Julian , Du Chuan , Beaver Zach , Zheng Ming , Page Rae , Wodarek Joseph R. , Matny Oadi , Szinyei Tamas , Quiñones Alejandra , Anderson James A. , Smith Kevin P. , Yang Ce , Steffenson Brian J. , Hirsch Cory D.
Published: September 2023

Fusarium head blight (FHB) in wheat is an economically important disease, which can cause yield losses exceeding 50% and the causal pathogen that infects spikes produces harmful mycotoxins. Breeding for host resistance remains the most effective disease control method; but time, labor, and human subjectivity during disease scoring limits selection advancements. In this study we describe an innovative, high-throughput phenotyping rover for capturing in-field RGB images and a deep neural network pipeline for wheat spike detection and FHB disease quantification. The image analysis pipeline successfully detects wheat spikes from images under variable field conditions, segments spikes and diseased tissue in the spikes, and quantifies disease severity as the region of intersection between spike and disease masks. Model inferences on an individual spike and plot basis were compared to human visual disease scoring in the field and on imagery for model evaluation. The precision and throughput of the model surpassed traditional field rating methods. The accuracy of FHB severity assessments of the model was equivalent to human disease annotations of images, however individual spike disease assessment was influenced by field location. The model was able to quantify FHB in images taken with different camera orientations in an unseen year, which demonstrates strong generalizability. This innovative pipeline represents a breakthrough in FHB phenotyping, offering precise and efficient assessment of FHB on both individual spikes and plot aggregates. The model is robust to different conditions and the potential to standardize disease evaluation methods across the community make it a valuable tool for studying and managing this economically significant fungal disease.
The Shiga toxin (Stx)-Phage Encoded Ribosomal RNA Methyltransferase Regulates Stx-producingEscherichia coli(STEC) Virulence by Blocking Stx-Mediated Inactivation of Bacterial Ribosomes
Authors: Gong Chen , Koudelka Gerald B.
Published: September 2023

Shiga toxin (Stx) produced and released after induction of Stx-encoding prophage resident within Shiga toxin producingE. coli(STEC) causes life-threatening illness. We previously identified that a two-subunit Stx prophage-encoded 16S rRNA methyltransferase, M.ECPA8_3172P-PNB-2, which is both uniquely encoded by and commonly found in Stx2- encoding bacteriophage, regulates both prophage spontaneous induction and STEC virulence. We found here that sequential deletion of these two subunits leads to concomitant, progressive reduction in both prophage spontaneous induction and STEC virulence. This observation indicates that these outcomes are linked. The translation activity of extracts made from a ΔM.ECPA8_3172PΔPNB-2 Stx prophage-containing strain was lower that of extracts made from either the methyltransferase replete STEC strain or from a strain that did not contain a Stx-encoding prophage. We found that the ΔM.ECPA8_3172PΔPNB-2 STEC strain contained significantly fewer ribosomes that did the methyltransferase replete STEC strain. These observations suggested that the M.ECPA8_3172P-PNB-2 methyltransferase may block Stx-mediated ribosome inactivation. Consistent with this idea, we found that translation extracts made from STEC expressing M.ECPA8_3172P-PNB-2 are more resistant to Stx- mediated inactivation than are those made from ΔM.ECPA8_3172PΔPNB-2 STEC. These findings indicate the M.ECPA8_3172P-PNB-2 methylation of 16S rRNA protects the ribosome from Stx-mediated inactivation, thereby allowing more phage and more Stx to be spontaneously produced. Direct 16S rRNA sequencing identified 4 putative M.ECPA8_3172P-PNB-2 methylation sites, all of which map onto the RNA polymerase contacting surface of the 30S ribosome subunit in the expressome, suggesting the M.ECPA8_3172P-PNB-2 may protect the ribosome from inactivation by stabilizing this complex.
Mitochondrial outer membrane integrity regulates a ubiquitin-dependent NF-κB inflammatory response
Authors: Vringer Esmee , Riley Joel S , Black Annabel , Cloix Catherine , Lilla Sergio , Walczak Henning , Gyrd-Hansen Mads , Huang Danny T , Zanivan Sara , Tait Stephen WG
Published: September 2023

Mitochondria are often essential for apoptosis through mitochondrial outer membrane permeabilization (MOMP). This central event enables cytochromecrelease leading to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory, for instance, by enabling mitochondrial DNA-dependent activation of cGAS-STING signalling. Alongside having emerging functions in health and disease, MOMP associated inflammation can also elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell counteracts this remains poorly defined. We find that upon MOMP, mitochondria are ubiquitylated in a promiscuous manner targeting proteins localised to both inner and outer mitochondrial membranes. Mitochondrial ubiquitylation serves to recruit the essential adaptor molecule, NEMO, leading to activation of pro-inflammatory NF-κB signalling. We find that disruption of mitochondrial outer membrane integrity through different means leads to engagement of a similar pro-inflammatory signalling platform. Thus, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling. This event may be important for the various pathophysiological functions of MOMP-associated inflammation.
3D electron diffraction analysis of a novel, mechanochemically synthesized supramolecular organic framework based on tetrakis-4-(4-pyridyl)phenylmethane
Authors: Marchetti Danilo , Pedrini Alessandro , Massera Chiara , Faye Diouf Moussa Diame , Jandl Christian , Steinfeld Gunther , Gemmi Mauro
Published: September 2023

Tetrakis-4-(4-pyridyl)phenylmethane (TPPM) is a tetrahedral rigid molecule that crystallizes forming a dynamically responsive supramolecular organic framework (SOF). When exposed to different stimuli, this supramolecular network can reversibly switch from an empty to a filled solvated solid phase. This article describes a novel expanded form of a TPPM-based SOF that has been mechanochemically synthesized and whose crystal structure has been determined by 3D electron diffraction analysis using a novel electron diffractometer.
From liquid to crystal via mechanochemical grinding: unique host–guest (HOF) cocrystal
Authors: Som Shubham , Hasija Avantika , Chopra Deepak
Published: September 2023

Mechanochemical synthesis via grinding of trimesic acid (TA, C9H6O6) and 4-chlorophenyl diphenyl phosphate (4CDP, C18H14ClO4P) (liquid at room temperature) in a 1:1 ratio resulted in the formation of an inclusion type of cocrystal. The crystallization of this phase via slow evaporation at low temperature (276–277 K) from methanol resulted in a rare `stairstep morphology' during the process of crystal growth. This morphology was not observed after crystallization of the compound from other solvents like toluene, dichloromethane, acetone, hexane and isooctane, and hence this was characteristically observed in methanol only. The characterization from single-crystal X-ray diffraction revealed the formation of a cocrystal with five molecules of TA and two molecules of 4CDP in the asymmetric unit. The trimesic acid molecules form hydrogen-bonded dimers resulting in hexagonal rings, and these rings are stacked through π–π intermolecular interactions to make a hexagonal honeycomb-like structure. The phosphate molecules, 4CDP, were found to be trapped as guests in these hexagonal channels. The similarity in the packing of trimesic acid is compared in the cocrystal and the free acid quantitatively via
Xpac analysis, which establishes the relationship of a `2D supramolecular construct' between them. This signifies a unique type of arrangement in which the voids created by the trimesic acid moiety do not undergo distortion by the inclusion of the guest molecules. The quantitative analysis of the intermolecular interactions using Hirshfeld surfaces and fingerprint plots deciphers the role of both strong O—H...O hydrogen bonds and weak intermolecular interactions in the crystal packing.
Pressure-induced metallization in the absence of a structural transition in the layered transition-metal dichalcogenide ZrSe2
Authors: Xiao Lingping , Yi Xiaojie
Published: September 2023

First-principles calculations were carried out on the ZrSe2 compound, which has been of interest owing to its technologically important physical properties. The structural, electronic and optical properties of this compound were investigated under pressure through the plane wave pseudopotential approach within the framework of density functional theory. A comparison between the computed crystal structure parameters and the corresponding experimental counterparts shows a very good agreement between them. Fitting the pressure–volume data using the third-order Birch–Murnaghan equation of state yielded a bulk modulus B
0 = 38.17 GPa and a pressure derivative of bulk modulus B'0 = 8.2 for hexagonal ZrSe2. The relationship between the band structure and pressure is revealed. We calculated the total density of state (TDOS) under different pressures and partial density of state (PDOS) from 0 to 10 GPa. According to our calculations, metallization of hexagonal ZrSe2 is predicted to occur at around 10 GPa and pressure-induced band-gap engineering reveals the transformation of the indirect to direct band gap with increasing pressure. Furthermore, optical properties, such as the complex dielectric function, refractive index and reflectivity spectra of this compound, were studied for incident electromagnetic waves in an energy range up to 45 eV. The contributions to various transition peaks in the optical spectra are analyzed and discussed with the help of the energy-dependent imaginary part of the dielectric function.
Two new bismuth salts with succinic acid: synthesis, structural, spectroscopic and thermal characterization
Authors: Timakova Evgeniya V. , Afonina Liubov I. , Drebushchak Tatiana N. , Zakharov Boris A.
Published: September 2023

Two novel bismuth succinate hydrates, namely, poly[[diaqua(μ3-butane-1,4-dicarboxylato)hemi(μ-butane-1,4-dicarboxylato)bismuth] monohydrate], {[Bi(C4H4O4)1.5(H2O)2]·H2O}n(1), and poly[[μ-aqua-aqua(μ3-butane-1,4-dicarboxylato)(μ-butane-1,4-dicarboxylato)-μ-oxido-dibismuth] monohydrate], {[Bi2(C4H4O4)2O(H2O)2]·H2O}n(2), have been synthesized. Their crystal structures were determined by single-crystal X-ray diffraction and the compounds were characterized by IR and Raman spectroscopy, powder X-ray diffraction and thermal analysis. The crystal structure analysis revealed that the compounds are coordination polymers, with1having a two-dimensional layered structure and2displaying a three-dimensional (3D) framework. Fully deprotonated succinate anions (C4H4O42−) in two different conformations (transandgauche) are included in their composition. The Bi3+cations are surrounded by O atoms from the carboxylate groups of succinate anions and aqua ligands. BiO9coordination polyhedra in1are connected in pairs by edges. These pairs are bound together by bridging succinate ligands to form layers. Bismuth coordination polyhedra of two different types (BiO9and BiO7) in2are connected by edges to form infinite ribbons. Ribbons of polyhedra with bridging succinate ligands form a 3D polymeric structure.