bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell evaluation of endocardial HAND2 gene regulatory networks reveals critical HAND2 dependent pathways impacting cardiac morphogenesis
Authors: George Rajani M , Firulli Beth A , Podicheti Ram , Rusch Douglas B , Mannion Brandon J , Pennacchio Len A , Osterwalder Marco , Firulli Anthony B 
Published: October 2022

AbstractThe transcription factor HAND2 plays critical roles during cardiogenesis. Hand2 endocardial deletion (H2CKO) results in tricuspid atresia or double inlet left ventricle with accompanying intraventricular septum defects, hypo-trabeculated ventricles, and an increased density of coronary lumens. To understand the regulatory mechanisms of these phenotypes, single cell transcriptome analysis of E11.5 H2CKO hearts was performed revealing a number of disrupted endocardial regulatory pathways. Utilizing HAND2 DNA occupancy data, we identify several HAND2-dependent enhancers, including two endothelial enhancers for the sheer-stress master regulator, KLF2. A 1.8kb enhancer located 50kb upstream of the Klf2 transcriptional start site imparts specific endothelial/endocardial expression within the vasculature and endocardium. This enhancer is HAND2-dependent for ventricular endocardium expression but HAND2-independent for Klf2 vascular and valve expression. Deletion of this Klf2 enhancer reveals reduced Klf2 expression within ventricular endocardium. These data reveal that HAND2 functions within endocardial gene regulatory networks including sheer stress response.
Harmonic memory signals in the human cerebral cortex induced by sematic relatedness of words
Authors: Noguchi Yasuki 
Published: October 2022

AbstractWhen we memorize multiple words simultaneously, semantic relatedness among those words assists memory. For example, the information of “apple”, “banana” and “orange” will be connected via a common concept of “fruits” and become easy to retain and recall. Neural mechanisms underlying this semantic integration in verbal working memory remain unclear. Here I used electroencephalography (EEG) and investigated neural signals when healthy human participants memorized five nouns semantically related (Sem trial) or not (NonSem trial). The regularity of oscillatory signals (8 – 30 Hz) during the retention period was found to be lower in NonSem than Sem trials, indicating that memorizing words unrelated to each other induced a non-harmonic (irregular) waveform in the temporal cortex. These results suggest that (i) semantic features of a word are retained as a set of neural oscillations at specific frequencies and (ii) memorizing words sharing a common semantic feature produces harmonic brain responses through a resonance or integration (sharing) of the oscillatory signals.
Perspectives and use of telemedicine by doctors in India: A cross-sectional study
Authors: Nagaraja Vikranth H. , Dastidar Biswanath Ghosh , Suri Shailesh , Jani Anant R. 
Published: October 2022

AbstractObjectivesIndia has committed to formulating a roadmap for realising a resilient health system, with digital health being an important element of this. Following the successful implementation of a free telemedicine service, eSanjeevani, India published the Telemedicine Practice Guidelines in 2020 to further scale telemedicine use in India. The main objective of the current study was to understand the perspective and use of telemedicine by medical doctors in India after the release of its telemedicine policy.MethodsData were acquired through an anonymous, cross-sectional, internet-based survey of medical doctors (n = 444) at a pan-India level. Replies were subjected to statistical analysis.ResultsTelemedicine was used for various non-mutually exclusive reasons, with the top two reasons being live audio or video consultations (60.4%) and online payments (19.1%) and smartphones were the most frequently used device type (60.6%). The telemedicine benefit that the greatest proportion of respondents (93%) recognised was its potential to reduce COVID-19 infection risk for healthcare professionals. Interestingly, nearly 45% of respondents felt that limited and fragmented insurance coverage was an important limitation to the practice of telemedicine in India and 49% believed reduced patient fees for teleconsultations could help incentivise telemedicine use.ConclusionsThis study helps to appraise the use of telemedicine in India after the publication of telemedicine guidelines in 2020. Furthermore, the findings can inform the development of telemedicine platforms, policies and incentives to improve the design and implementation of effective telemedicine in India.Public Interest SummaryIndia has committed to formulating a roadmap for realising a resilient health system, with digital health being an important element of this. In 2020, India published its Telemedicine Practice Guidelines to scale telemedicine use in India. The main objective of the current study was to survey medical doctors in India to understand their perspectives on and use of telemedicine after the release of India’s telemedicine policy. Our findings revealed that the top two reasons doctors used telemedicine were for live audio or video consultations and online payments. Interestingly, a large proportion of respondents felt that limited and fragmented insurance coverage was an important limitation to the practice of telemedicine in India. This study helps to appraise the use of telemedicine in India after the publication of its telemedicine guidelines and can inform the development of telemedicine platforms, policies and incentives to improve the design and implementation of telemedicine in India.
Effectiveness of mRNA-1273 against infection and COVID-19 hospitalization with SARS-CoV-2 Omicron subvariants: BA.1, BA.2, BA.2.12.1, BA.4, and BA.5
Authors: Tseng Hung Fu , Ackerson Bradley K. , Bruxvoort Katia J. , Sy Lina S. , Tubert Julia E. , Lee Gina S. , Ku Jennifer H. , Florea Ana , Luo Yi , Qiu Sijia , Choi Soon Kyu , Takhar Harpreet S. , Aragones Michael , Paila Yamuna D. , Chavers Scott , Talarico Carla A. , Qian Lei 
Published: October 2022

AbstractStudies have reported reduced natural SARS-CoV-2 infection- and vaccine-induced neutralization against Omicron BA.4/BA.5 compared with earlier Omicron subvariants. We conducted a test-negative case–control study evaluating mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with Omicron subvariants. The study included 30,809 SARS-CoV-2 positive and 92,427 SARS-CoV-2 negative individuals aged ≥18 years tested during 1/1/2022-6/30/2022. While 3-dose VE against BA.1 infection was high and waned slowly, VE against BA.2, BA.2.12.1, BA.4, and BA.5 infection was initially moderate to high (61.0%-90.6% 14-30 days post third dose) and waned rapidly. The 4-dose VE against infection with BA.2, BA.2.12.1, and BA.4 ranged between 64.3%-75.7%, and was low (30.8%) against BA.5 14-30 days post fourth dose, disappearing beyond 90 days for all subvariants. The 3-dose VE against hospitalization for BA.1, BA.2, and BA.4/BA.5 was 97.5%, 82.0%, and 72.4%, respectively; 4-dose VE against hospitalization for BA.4/BA.5 was 88.5%. Evaluation of the updated bivalent booster is warranted.
Functionally distinct promoter classes initiate transcription via different mechanisms reflected in focused versus dispersed initiation patterns
Authors: Serebreni Leonid , Pleyer Lisa-Marie , Haberle Vanja , Hendy Oliver , Vlasova Anna , Loubiere Vincent , Nemčko Filip , Bergauer Katharina , Roitinger Elisabeth , Mechtler Karl , Stark Alexander 
Published: October 2022

AbstractRecruitment of RNA polymerase II (Pol II) to promoter regions is essential for transcription. Despite conflicting evidence, the Pol II Pre-Initiation Complex (PIC) is often thought to be of uniform composition and assemble at all promoters via an identical mechanism. Here, we show usingDrosophila melanogasterS2 cells as a model that promoter classes with distinct functions and initiation patterns function via PICs that display different compositions and dependencies: developmental promoter DNA readily associates with the canonical Pol II PIC, whereas housekeeping promoter DNA does not and instead recruit different factors such as DREF. Consistently, TBP and DREF are required by distinct sets of promoters, and TBP and its paralog TRF2 function at different promoter types, partly exclusively and partly redundantly. In contrast, TFIIA is required for transcription from all promoters, and we identify factors that can recruit and/or stabilize TFIIA at housekeeping promoters and activate transcription. We show that promoter activation by these factors is sufficient to induce the dispersed transcription initiation patterns characteristic of housekeeping promoters. Thus, different promoter classes direct distinct mechanisms of transcription initiation, which relate to different focused versus dispersed initiation patterns.
Dual states of Bmi1-expressing intestinal stem cells drive epithelial development and tissue regeneration
Authors: Smith Nicholas R. , Sengupta Sidharth K. , Conley Patrick , Giske Nicole R. , Klocke Christopher , Walker Brett , McPhail Noelle , Swain John R. , Yoo Yeon Jung , Anderson Ashley , Davies Paige S. , Sanati Nasim , Nguyen Theresa N. , Torkenczy Kristof , Adey Andrew C. , Fischer Jared M. , Wu Guanming , Wong Melissa H. 
Published: October 2022

SummaryIntestinal development, response to injury and disease states rely upon balanced stem cell proliferation. Historically, two subtypes of intestinal epithelial stem cells (ISCs)—slow-cycling/label-retaining, and actively-cycling/canonical Wnt-dependent—coordinate to drive proliferation and regulate epithelial renewal during adult tissue homeostasis and injury response. Recent studies focused on Bmi1-expressing cells revealed that differentiated Bmi1+ enteroendocrine cells could dedifferentiate towards a canonical Wnt-dependent stem cell state, calling into question the dogma that a dual stem cell axis regulates epithelial proliferation. Herein, we identify stem cell function in a Bmi1+ cell population in early murine intestinal development prior to the establishment of canonical Wnt-dependent, Lgr5-expressing ISCs. In-depth analyses of developmental Bmi1+ ISCs using lineage-tracing and single cell RNA-sequencing reveal their distinct identity and capacity to differentiate into Lgr5+ ISCs and other differentiated lineages. Further, during in utero development, the Bmi1+ ISCs initially exists in a highly proliferative state then transitions to a slow-cycling state, with the emergence of actively-cycling Lgr5+ ISCs. In adult tissue, Bmi1+ ISCs are a distinct population that re-express developmental gene and protein profiles, and a non-canonical Wnt signaling signature in response to injury and in human colorectal tumors. Further, developmental Bmi1+ ISCs are distinct from Lgr5+ ISCs and the previously identified differentiated Bmi1+ progenitor cells. Re-evaluation of an under-appreciated Bmi1+ ISC population with fundamental importance in intestinal development re-establishes the importance of the dynamic interplay between discrete ISC populations that are regulated by opposing Wnt signaling pathways. This finding opens opportunities and targetable pathways to augment regeneration or inhibit tumorigenesis.
Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape
Authors: Marzi Roberta , Bassi Jessica , Silacci-Fregni Chiara , Bartha Istvan , Muoio Francesco , Culap Katja , Sprugasci Nicole , Lombardo Gloria , Saliba Christian , Cameroni Elisabetta , Cassotta Antonino , Low Jun Siong , Walls Alexandra C. , McCallum Matthew , Tortorici M. Alejandra , Bowen John E. , Dellota Exequiel A. , Dillen Josh R. , Czudnochowski Nadine , Pertusini Laura , Terrot Tatiana , Lepori Valentino , Tarkowski Maciej , Riva Agostino , Biggiogero Maira , Pellanda Alessandra Franzetti , Garzoni Christian , Ferrari Paolo , Ceschi Alessandro , Giannini Olivier , Havenar-Daughton Colin , Telenti Amalio , Arvin Ann , Virgin Herbert W. , Sallusto Federica , Veesler David , Lanzavecchia Antonio , Corti Davide , Piccoli Luca 
Published: October 2022

SUMMARYMemory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month timeframe. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both pre- and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.
Accelerated signal propagation speed in human neocortical dendrites
Authors: Oláh Gáspár , Lákovics Rajmund , Shapira Sapir , Leibner Yoni , Szűcs Attila , Csajbók Éva Adrienn , Barzó Pál , Molnár Gábor , Segev Idan , Tamás Gábor 
Published: October 2022

AbstractHuman-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Dual somato-dendritic and somato-axonal patch recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Accurate biophysical models of human and rat L2/3 PCs, combined with pharmacological manipulations of membrane properties, have shown that various factors enhance EPSP propagation in humans; the key factor is the large conductance load imposed by the large basal dendritic tree in humans, the key factor responsible for the accelerated signal propagation in human cortical dendrites. Larger dendritic diameter in humans as well as differences in cable and ion channel properties, also contribute to the enhancement of signal propagation in human L2/3 dendrites.
Novel and simple simulation method to design and development of antisense template
Authors: Deo Devendra Vilas , Shaikh Nawaj 
Published: October 2022

AbstractAntisense technology is emerging as potential therapeutics against lethal infections. Basically, Antisense-mRNA complex inhibits the protein translation of pathogens and thus it is used for treatment. Based on previous online tools and literatures and difficulties for designing antisense template, finding high conserved regions from large number of long sequences, by taking all those factors in consideration, we proposed new innovative offline target simulation methods i.e. Deletion of unwanted region from viral sequence alignment (DURVA) and Most frequent region (MFR) for designing and developing antisense template from large number of long sequence or genomic data. Based on current pandemic crisis and long genomic sequence of SARS-CoV-2, we chose coronavirus for simulation. Initially, we hypothesized that DURVA-MFR would find stable region from large annotated sequencing data. As per Chan et.al. guidelines for antisense designing and development, we designed couple of algorithms and python scripts to process the data of approximately 30kbp sequence length and 1Gb file size in short turnaround time. The steps involved were as: 1) Simplifying whole genome sequence in single line; 2) Deletion of unwanted region from Virus sequence alignment(DURVA); 3)Most frequent antisense target region(MFR) and 4)Designing and development of antisense template. This simulation method is identifying most frequent regions between 20-30bp long, GC count≥10. Our study concluded that targets were highly identical with large population and similar with high number of remaining sequences. In addition, designed antisense sequences were stable and each sequence is having tighter binding with targets. After studying each parameter, here we suggested that our proposed method would be helpful for finding best antisense against all present and upcoming lethal infection.The initial design of this logic was published in Indian Patent Office Journal No.08/2021withApplication number202121005964A.Simple summaryThe antisense development is state of the art for modern therapeutics. There are number of online soft-wares and open sources for designing of antisense template. But all other tools did not consider frequency as major factor for designing antisense. Also; all sources excepting our simulation approach does not process large file or long sequences. Therefore; we designed an offline innovative simulation method which deletes the unwanted region from sequences and stores the data which are fulfilled antisense criteria. Further; the calculation of frequency from these short listed target regions; the most frequent region is desire antisense target and further antisense template will be designed according to Watson-Crick model. This article explained all information about how our new approach is best for designing antisense template against SARS-CoV-2 and many lethal infectious viruses etc.
Global transmission of Salmonella enterica serovars associated with historical pork trade via Euramerica centralized sourcing
Authors: Wu Yilei , Zhong Lin , Li Shengkai , Li Heng 
Published: October 2022

AbstractPast decades have witnessed swine as the common sources of Salmonella enterica infections. Nevertheless, how Salmonella enterica entered food supply chains and caused foodborne outbreaks remains to be excluded. By analysis of 718 publicly Salmonella enterica isolates, we demonstrated that Euramerica act as the centralized sourcing for the global spread of Salmonella enterica which origins at the pinnacle of pork production. Specifically, the lineage of Salmonella Choleraesuis lend geographic support for their dispersal from Euramerica centralized origins. We used the generalized linear model to quantify the relative contributions of potential explanatory variables to the global transmission of Salmonella enterica. The global pork trade may act as the key driver for the geographic dispersal of Salmonella enterica over the world. In addition, the application of antimicrobials over the past 80 years may also exert a large impact on the evolution of Salmonella enterica genomics. Taken together, our findings provided the global lineage evolution of Salmonella enterica. Further investigation and potential intervention are needed to identify the global spread of Salmonella enterica over the world.
Use of Transient Transfection for cGMP Manufacturing of eOD-GT8 60mer, a Self-Assembling Nanoparticle Germline-Targeting HIV-1 Vaccine Candidate
Authors: Sharma Vaneet K. , Tsvetnitsky Vadim , Menis Sergey , Brower Evan T. , Sayeed Eddy , Ackland Jim , Lombardo Angela , Hassell Thomas , Schief William R. 
Published: October 2022

AbstractWe describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1 vaccine candidate germline-targeting priming immunogen. Production was carried out by transient expression in the human embryonic kidney 293 (HEK293) cell line followed by a combination of purification techniques. A large scale cGMP (200 L) production run yielded 354 mg of the purified eOD-GT8 60mer drug product material, which was formulated at 1 mg/mL in 10% sucrose in phosphate-buffered saline (PBS) at pH 7.2. The clinical trial material was comprehensively characterized for purity, antigenicity, glycan composition, amino acid sequence, aggregation, and by several safety-related tests during cGMP lot release. A comparison of purified products produced at 1 L scale and 200 L cGMP scale demonstrated consistency and robustness of the transient transfection upstream process and the downstream purification strategies. The cGMP clinical trial material is being tested in a phase 1 clinical trial (NCT03547245) and is currently stored at −80°C and on a stability testing program as per regulatory guidelines. The methods described here illustrate the utility of transient transfection for cGMP production of complex products such as glycosylated self-assembling nanoparticles.
DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+T cells of neonatal mice withE. colipneumonia
Authors: Michki Nigel S. , Ndeh Roland , Helmin Kathryn A. , Singer Benjamin D. , McGrath-Morrow Sharon A. 
Published: October 2022

AbstractIntroductionBacterial pulmonary infections are a major cause of morbidity and mortality in neonates, with less severity in older children. Previous studies demonstrated that the DNA of CD4+T cells in the mouse lung, whose primary responsibility is to coordinate the immune response foreign pathogens, is differentially methylated in neonates compared with juveniles. Nevertheless, the effect of this differential DNA methylation on CD4+T cell gene expression and response to infection remains unclear.MethodsWe treatedE. coli-infected neonatal (4-day-old) and juvenile (13-day-old) mice with decitabine (DAC), a DNA methyltransferase inhibitor with broad-spectrum DNA demethylating activity, and performed simultaneous genome-wide DNA methylation and transcriptional profiling on lung CD4+T cells.ResultsJuvenile and neonatal mice experienced differential demethylation in response to DAC treatment, with larger methylation differences observed in neonates. By cross-filtering differentially expressed genes between juveniles and neonates with those sites that were demethylated in neonates, we found that interferon-responsive genes such asIfit1are the most down-regulated methylation-sensitive genes in neonatal mice. DAC treatment shifted neonatal lung CD4+T cells toward a gene expression program similar to that of juveniles.ConclusionFollowing lung infection withE. coli, lung CD4+T cells in neonatal mice exhibit epigenetic repression of important host defense pathways, which are activated by inhibition of DNA methyltransferase activity to resemble a more mature profile.
Expansion Segment ES30L enriched in birds and mammals can potentially regulate protein synthesis
Authors: Hariharan Nivedita , Ghosh Sumana , Nallan Aditi N. , Ramesh Arati , Agashe Deepa , Palakodeti Dasaradhi 
Published: October 2022

ABSTRACTRibosomes, the molecular machines that are central to protein synthesis, have gradually been gaining prominence for their regulatory role in translation. Eukaryotic cytosolic ribosomes are typically larger than bacterial ones, partly due to multi-nucleotide insertions at specific conserved positions in the ribosomal RNAs (rRNAs). Such insertions called expansion segments (ESs) are present primarily on the ribosomal surface, with their role in translation and its regulation remaining under-explored. One such ES in the ribosomal large subunit (LSU) is ES30L, which is present only in mammals and birds among eukaryotes. In this study, we show that ES30L possesses complementarity to many protein-coding transcripts in humans and that the complementarity is enriched around the start codon, hinting at a possible role in translation regulation. Further, our in silico analysis analyses and pull-down assays indicate that ES30L may bind to secondary structures in the 5’ UTR of several transcripts and RNA binding proteins (RBPs) that are essential for translation. Thus, we have identified a potential regulatory role for ES30L in translation.