bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cingulate cortex facilitates auditory perception under challenging listening conditions
Authors: Anbuhl Kelsey L. , Diez Castro Marielisa , Lee Nikki A. , Lee Vivian S. , Sanes Dan H. 
Published: November 2023

AbstractWe often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults, and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggest that the cingulate cortex is engaged under difficult listening conditions, and may exert top-down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either ‘Easy’ or ‘Hard’ blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1, and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.Significance StatementSensory perception often occurs under challenging conditions, such a noisy background or dim environment, yet stimulus sensitivity can remain unaffected. One hypothesis is that cognitive resources are recruited to the task, thereby facilitating perceptual performance. Here, we identify a top-down cortical circuit, from cingulate to auditory cortex in the gerbils, that supports auditory perceptual performance under challenging listening conditions. This pathway is a plausible circuit that supports effortful listening, and may be degraded by hearing loss.
LMD: Cluster-Independent Multiscale Marker Identification in Single-cell RNA-seq Data
Authors: Li Ruiqi , Qu Rihao , Parisi Fabio , Strino Francesco , Lam Hainan , Stanley Jay S. , Cheng Xiuyuan , Myung Peggy , Kluger Yuval 
Published: November 2023

AbstractIdentifying accurate cell markers in single-cell RNA-seq data is crucial for understanding cellular diversity and function. Localized Marker Detector (LMD) is a novel tool to identify “localized genes” - genes exclusively expressed in groups of highly similar cells - thereby characterizing cellular diversity in a multi-resolution and fine-grained manner. LMD constructs a cell-cell affinity graph, diffuses the gene expression value across the cell graph, and assigns a score to each gene based on its diffusion dynamics. LMD’s candidate markers can be grouped into functional gene modules, which accurately reflect cell types, subtypes, and other sources of variation such as cell cycle status.We apply LMD to mouse bone marrow and hair follicle dermal condensate datasets, where LMD facilitates cross-sample comparisons, identifying shared and sample-specific gene signatures and novel cell populations without requiring batch effect correction or integration methods. Furthermore, we assessed the performance of LMD across nine single-cell RNA sequencing datasets, compared it with six other methods aimed at achieving similar objectives, and found that LMD outperforms the other methods evaluated.
UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis
Authors: Barajas Juan M. , Umeda Masayuki , Contreras Lisett , Khanlari Mahsa , Westover Tamara , Walsh Michael P. , Xiong Emily , Yang Chenchen , Otero Brittney , Arribas-Layton Marc , Abdelhamed Sherif , Song Guangchun , Ma Xiaotu , Thomas Melvin E. , Ma Jing , Klco Jeffery M. 
Published: November 2023

AbstractRecent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features ofUBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 ofUBTF. We demonstrate thatUBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm thatUBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition ofFLT3orWT1mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 ofUBTFthat phenocopy exon 13 duplications, expanding the spectrum ofUBTFalterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS withUBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.Key PointsLargest cohort of pediatricUBTF-TD in myeloid neoplasms reported to date.Use of single-cell DNA+protein sequencing technology in 3UBTF-TD samples reveals a clonal evaluation pattern characterized by sequential acquisition ofWT1andFLT3mutations and a more stem cell-like protein expression pattern.Pediatric MDS and AML patients withUBTF-TD alterations dysplastic features with an increase erythroid precursors.Tandem duplications in exon 9 ofUBTFrepresent a rare but functionally equivalent subgroup ofUBTF-TD myeloid neoplasms.Impact StatementUBTFtandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatricUBTF-TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.
A TWO PARAMETER CLOSED FORM SOLUTION TO KERMACK AND MCKENDRICK’S INTEGRO-DIFFERENTIAL EQUATIONS
Authors: Duclos Ted , Reichert Tom 
Published: November 2023

AbstractA closed form solution of the full Kermack and McKendrick (K&M) integro-differential equations (Kermack and McKendrick 1927), called the KMES, is presented and verified. Intuitively, the KMES states that the total case count in an epidemic is the integral of the product of the probability rate of transmission and the number of infectious contacts from the epidemic start to the current point in time.This solution was derived by pursuing the logical consequences of a construct that combines network concepts with the recognition that the infectiousness of an individual depends on their exposure to susceptible persons. The KMES has two parameters: the probability rate of disease transmission, and the basic reproduction number. The proof of the solution uses the weighted averages of K&M’s rate parameters, and a restatement of the proper integral limits in their recovery function.Practical analytical expressions, including novel expressions for the effective reproduction number, time to peak in new infections, and the final size flow directly from the solution. Notably, the latter two expressions project phenomena antithetical to currently accepted epidemic concepts. Using early COVID-19 pandemic data from six different countries to estimate the model parameters, the KMES accurately projects case data from the COVID-19 pandemic in the following 60-day period with R2values > 0.78. In addition, the projection of a typical individual’s contagiousness, derived from the KMES, closely approximates the time course of viral shedding as measured in infected persons.
Genotype-microbiome-metabolome associations in early childhood, and their link to BMI and childhood obesity
Authors: Aparicio Andrea , Sun Zheng , Gold Diane R. , Litonjua Augusto A. , Weiss Scott T. , Lee-Sarwar Kathleen , Liu Yang-Yu 
Published: November 2023

AbstractThe influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10−6. We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children’s BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children’s BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.
Connectome reorganization associated with temporal lobe pathology and its surgical resection
Authors: Larivière Sara , Park Bo-yong , Royer Jessica , DeKraker Jordan , Ngo Alexander , Sahlas Ella , Chen Judy , Rodríguez-Cruces Raúl , Weng Yifei , Frauscher Birgit , Liu Ruoting , Wang Zhengge , Shafiei Golia , Mišić Bratislav , Bernasconi Andrea , Bernasconi Neda , Fox Michael D. , Zhang Zhiqiang , Bernhardt Boris C. 
Published: November 2023

AbstractNetwork neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain’s structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n= 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age-and sex-matched healthy controls who underwent comparable imaging (n= 31). Core to our analysis was the projection of high-dimensional structural connectome data—derived from diffusion MRI tractography from each subject—into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre-to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical-imaging signature underlying this pre-to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency, and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and inter-individual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.
Management of Antipsychotics in Primary Care: Insights from Healthcare Professionals and Policy Makers in the UK
Authors: Woodall Alan A. , Abuzour Aseel S. , Wilson Samantha A. , Mair Frances S. , Buchan Iain , Sheard Sally B. , Atkinson Paul , Joyce Dan W. , Symon Pyers , Walker Lauren E. 
Published: November 2023

ABSTRACTIntroductionAntipsychotic medication is increasingly prescribed to patients with serious mental illness. Patients with serious mental illness often have cardiovascular and metabolic comorbidities, and antipsychotics independently increase the risk of cardiometabolic disease. Despite this, many patients prescribed antipsychotics are discharged to primary care without planned psychiatric review. We explore perceptions of healthcare professionals and managers/planners of policy regarding management of antipsychotics in primary care.MethodsQualitative study using semi-structured interviews with 11 general practitioners (GPs), 8 psychiatrists, and 11 managers/planners of policy in the United Kingdom. Interviews were studied using inductive thematic analysis.ResultsRespondents reported competency gaps that impaired ability to manage patients prescribed antipsychotic medications holistically, arising from inadequate postgraduate training and professional development. GPs lacked confidence to manage antipsychotic medications alone; psychiatrists lacked skills to address cardiometabolic risks and did not perceive this as their role. Communication barriers, lack of integrated care records, limited psychology provision, lowered expectation of patients with serious mental illness by professionals, and pressure to discharge from hospital resulted in patients in primary care becoming ‘trapped’ on antipsychotics, inhibiting opportunities to deprescribe. Organisational and contractual barriers between organisations exacerbate this risk, with socioeconomic deprivation and lack of access to non-pharmacological alternatives driving overprescribing. GPs and psychiatrists voiced professional fears of being blamed if an event causing harm occurred after stopping an antipsychotic, which inhibited deprescribing. A range of actions to overcome these barriers were suggested.ConclusionsPeople prescribed antipsychotics experience a fragmented health system and suboptimal care. Many simple steps could be taken to improve quality of care for this population but inadequate availability of non-pharmacological alternatives and socioeconomic factors increasing mental distress need key policy changes to improve the current situation.
Prognostic Value of Angiography-derived Microcirculatory Resistance in Patients undergoing Rotational Atherectomy
Authors: Zhang Xi , Jin Qing , He Jiaji , Zhao Tao , He Guiping , Xue Qiang , Guang Xuefeng 
Published: November 2023

AbstractBACKGROUNDRotational atherectomy (RA) is predominantly employed in the treatment of severe calcification lesions in patients with coronary atherosclerotic heart disease (CAD). Studies focusing on the assessment of postoperative microvascular dysfunction (CMD) after RA and related prognosis are scarce.AIMSwe attempted to investigate the predictive significance of coronary angiography-derived microcirculatory resistance (AMR) in patients with coronary RA.METHODSThis retrospective study analyzed the data from 114 patients who were successfully treated between January 2019 and September 2022. Coronary microcirculatory function after RA was assessed using AMR. Patients were categorized into CMD and non-CMD groups depending on a postoperative AMR of ≥2.5 mmHg-s/cm. Patients were followed up for postoperative major adverse cardiovascular events (MACE).RESULTSWe analyzed the data from 114 patients, and post-RA, the mean AMR, mean QFR, and the percentage of CMDs were significantly higher compared to those before RA. MACE occurred in 14 (12.3%) patients after a year of follow-up. A higher proportion of patients in the MACE group showed post-RA AMR of ≥2.5 mmHg-s/cm (57.1% vs. 27.0%, P=0.048). Cox regression analysis showed that AMR ≥2.5 mmHg-s/cm (HR=3.86, 95%CI. 1.28-11.63, P=0.016) and renal insufficiency (HR=9.92, 95%CI: 2.06-47.83, P=0.004) were independent predictors of MACE. Logistic regression analyses showed the length of the RA operative area and diabetes mellitus (DM) were related to post-RA CMD.CONCLUSIONIn patients with CAD treated with RA, AMR ≥2.5 mmHg-s/cm independently predicted post-RA MACE; furthermore, the operative length of RA and the comorbid DM were associated with CMD following RA.
N-terminal toxin signal peptides efficiently load therapeutics into a natural nano-injection system
Authors: Steiner-Rebrova Eva M. , Ejaz Rooshanie N. , Kielkopf Claudia S. , Ruiz Mar Pérez , Marín-Arraiza Leyre , Hendriks Ivo A. , Nissen Jakob Nybo , Pozdnyakova Irina , Pape Tillmann , Regaiolo Alice , Götz Kira , Heermann Ralf , Rasmussen Simon , Nielsen Michael Lund , Taylor Nicholas M. I. 
Published: November 2023

AbstractTargeted delivery of therapeutics to specific cells is a major bottleneck towards personalized medicine. The extracellular injection system (eCIS) ofSerratia entomophila, the antifeeding prophage (Afp), promises potential for drug delivery purposes. However, the precise mechanism of action, toxin location, and Afp loading remain unclear. Here, we reveal a minimal N-terminal signal peptide (NtSP) of the toxin Afp18, that plays a key role in toxin packing. By engineering fusion proteins, we demonstrate that Afp18’s NtSP can shuttle effectors for Afp loading. We packed non-eCIS effectors, including CRISPR-Cas protein CasΦ-2 from Biggiephage, and a human antimicrobial peptide, LL37, into Afp. Additionally, NtSPs from eCIS effectors of other species facilitate loading of CasΦ-2 into Afp. We observed cargo being packed inside the Afp tail tube through cryo-EM single particle analysis. The presented results enhance our understanding of eCIS toxin packing and contribute to their development as targeted delivery systems.TeaserA novel use of the Afp nano injection system’s N-terminal signal peptide in targeted therapeutics delivery
De novobasecalling of m6A modifications at single molecule and single nucleotide resolution
Authors: Cruciani Sonia , Delgado-Tejedor Anna , Pryszcz Leszek P. , Medina Rebeca , Llovera Laia , Novoa Eva Maria 
Published: November 2023

ABSTRACTRNA modifications hold pivotal roles in shaping the fate and function of RNA molecules. Although nanopore sequencing technologies have proven successful at transcriptome-wide detection of RNA modifications, current algorithms are limited to predicting modifications at a per-site level rather than within individual RNA molecules. Herein, we introducem6ABasecaller, an innovative method enabling direct basecalling of m6A modifications from raw nanopore signals within individual RNA molecules. This approach facilitatesde novoprediction of m6A modifications with precision down to the single nucleotide and single molecule levels, without the need of paired knockout or control conditions. Using them6ABasecaller, we find that the median transcriptome-wide m6A modification stoichiometry is ∼10-15% in human, mouse and zebrafish. Furthermore, we show that m6A modifications affect polyA tail lengths, exhibit a propensity for co-occurrence within the same RNA molecules, and show relatively consistent stoichiometry levels across isoforms. We further validate them6ABasecallerby treating mESC with increasing concentrations of STM2457, a METTL3 inhibitor as well as in inducible METTL3 knockout systems. Overall, this work demonstrates the feasibilityde novobasecalling of m6A modifications, opening novel avenues for the application of nanopore sequencing to samples with limited RNA availability and for which control knockout conditions are unavailable, such as patient-derived samples.
Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses
Authors: Warren Cody J. , Barbachano-Guerrero Arturo , Bauer Vanessa L. , Stabell Alex C. , Dirasantha Obaiah , Yang Qing , Sawyer Sara L. 
Published: November 2023

AbstractSimian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, both prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the viruses that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4 orthologs are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquiredCD4gene sequences from 32 gorilla individuals of two species, and identified alleles that encode 8 unique CD4 protein variants. Functional testing of these identified variant-specific differences in susceptibility to virus entry. By engineering single point mutations from resistant gorilla CD4 variants into the permissive human CD4 receptor, we demonstrate that acquired substitutions in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistantCD4alleles in ape species harboring SIV endemically (gorillas and chimpanzees), but not in other ape species that lack SIV infections (bonobos and orangutans). Taken together, our results show that SIV has placed intense selective pressure on apeCD4, acting to propagate SIV-resistant alleles in chimpanzee and gorilla populations.