bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug-like small molecules that inhibit expression of the oncogenic microRNA-21
Authors: Shortridge Matthew D. , Chaubey Bhawna , Zhang Huanyu J. , Pavelitz Thomas , Olsen Gregory L. , Calin George A. , Varani Gabriele 
Published: May 2022

AbstractWe report the discovery of a series of drug-like small molecules which bind specifically to the precursor of the oncogenic and pro-fibrotic microRNA-21 with mid-nanomolar affinity. These molecules are highly ligand-efficient (MW<330) and display specific biochemical and cellular activity by suppressing maturation of miR-21, thereby providing an avenue towards therapeutic intervention in multiple diseases where miR-21 is abnormally expressed. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change, which is not observed in other miRNA precursors. The most potent ofthesecompounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells.
Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome
Authors: Li Zhen , Klein Jenny A. , Rampam Sanjeev , Kurzion Ronni , Patel Yesha , Haydar Tarik F , Zeldich Ella 
Published: May 2022

AbstractThe intellectual disability (ID) in Down syndrome (DS) is thought to result from a variety of developmental deficits such as alterations in neural progenitor division, neurogenesis, gliogenesis, cortical architecture, and reduced cortical volume. However, the molecular processes underlying these neurodevelopmental changes are still elusive, preventing an understanding of the mechanistic basis of ID in DS. In this study, we used a pair of isogenic (trisomic and euploid) induced pluripotent stem cell (iPSC) lines to generate cortical spheroids (CS) that model the impact of trisomy 21 on brain development. CS contain neurons, astrocytes, and oligodendrocytes and they are widely used to approximate early neurodevelopment. Using single cell RNA sequencing (scRNA-seq), we uncovered cell type-specific transcriptomic changes in the trisomic CS. In particular, we found that excitatory neuron populations were most affected and that a specific population of cells with a transcriptomic profile resembling layer IV cortical neurons displayed the most profound divergence in developmental trajectory between trisomic and euploid genotypes. We also identified candidate genes potentially driving the developmental asynchrony between trisomic and euploid excitatory neurons. Direct comparison between the current isogenic CS scRNA-seq data and previously published datasets revealed several recurring differentially expressed genes between DS and control samples. Altogether, our study highlights the power and importance of cell type-specific analyses within a defined genetic background, coupled with broader examination of mixed samples, to comprehensively evaluate cellular phenotypes in the context of DS.
Passive surveillance of human-biting ticks correlates with town-level disease rates in Massachusetts
Authors: Lavoie Nathalie , Xu Guang , Brown Catherine , Ledizet Michel , Rich Stephen M. 
Published: May 2022

AbstractWe assessed the temporal and spatial distribution of Borrelia burgdorferi, Borrelia miyamotoi, Babesia microti, and Anaplasma phagocytophilum among human-biting Ixodes scapularis ticks in Massachusetts using ticks submitted to the TickReport pathogen passive surveillance program. From January 2015 to December 2017, Ixodes scapularis was the most frequently submitted tick species (n=7462). B. burgdorferi prevalence increased in ticks during the study period in adults and nymphs (37.1-39.1% in adults, 19.0%-23.9% in nymphs). The proportion of B. microti infected ticks increased from 5.7% to 8.1% in adult ticks but remained constant in nymphs (5.4-5.6%). Stable or decreasing annual prevalence of B. miyamotoi (2.2 – 2.2% in adults, 1.0-1.9% in nymphs) and A.phagocytophilum (7.6-7.2% in adults, 5.0-4.0% in nymphs) were detected. Coinfections were observed and included all pathogen combinations.Ticks were submitted year-round and had stable infection rates. The temporal pattern of B. burgdorferi- positive nymphs aligned with reported cases of Lyme disease, as did positive B. microti nymphs and babesiosis. A similar situation is seen with B. miyamotoi with an insignificant fall peak in cases. Anaplasmosis demonstrated a significant bimodal distribution with reported cases peaking in the spring and fall. This pattern is similar to that of A. phagocytophilum-infected adult ticks.B. microti infected nymphs were significantly predictive of town-level babesiosis incidence and A. phagocytophilum infected adults were significantly predictive of town-level anaplasmosis incidence in a spatially adjusted negative binomial model. Unlike field collection studies, the high number of ticks submitted provides a high-resolution picture of pathogen prevalence and provides data relevant to human health at the town level. Through temporal and geographic analyses we demonstrate concordance between our passive surveillance tick pathogen data and state reports of tickborne disease.
Adherence to the HIV early infant diagnosis testing protocol among HIV exposed infants in a hard-to-reach fishing community in Uganda
Authors: Remegio Ndyanabo , Nalugya Aisha , Ssekamatte Tonny , Nakafero Mary , Kisakye Angela , Mukose Aggrey David 
Published: May 2022

AbstractBackgroundInfants born to HIV-infected mothers are at a high risk of acquiring the infection. The World Health Organization (WHO) recommends early diagnosis of HIV-exposed infants (HEIs) through deoxyribonucleic acid polymerase chain reaction (DNA PCR) and rapid HIV testing. Early detection of paediatric HIV is critical for access to antiretroviral therapy treatment (ART) and child survival. There’s, however, limited evidence of the adherence to early infant diagnosis (EID) of HIV testing protocol among HEIs in fishing communities in Uganda. This study assessed adherence to EID of HIV testing protocol among HIV-exposed infants in a hard-to-reach fishing community in Uganda.MethodsWe conducted a cross-sectional study employing quantitative data collection methods among HEIs in selected healthcare facilities in Buvuma islands, Buvuma district. We obtained secondary data from mother-infant pair files enrolled on the EID program using a data extraction tool. Data were analysed using STATA Version 14. Modified poisson regression analysis was used to determine the factors associated with non-adherence to the 1st DNA PCR test among HIV-exposed infants enrolled into care.ResultsNone of the HIV-exposed infants had done all the EID tests prescribed by the HIV testing protocol within the recommended time frame for the period of January 2014-December 2016. Adherence to the 1st and 2nd DNA PCR, and rapid HIV tests was 39.5%, 6.1% and 81.0% respectively. Being under the care of single mothers (PR=1.11, 95% CI: 1.01-1.23, p=0.023) and cessation of breast feeding (PR=0.90, 95% CI: 0.83-0.98, p=0.025) were significantly associated with non-adherence to the 1st DNA PCR.ConclusionNone of the HIV-exposed infants adhered to all the EID tests of HIV testing protocol. Adherence to the 1st DNA PCR was positively associated with being a single mother and exclusive breast feeding. Therefore, single mothers and those who stop breastfeeding should be supported to ensure timely EID.
A 5-year Review of Incidence, Presentation and Management of Bartholin Gland Cysts and Abscesses in a Tertiary Hospital, Yenagoa, South-South Nigeria
Authors: Oriji PC , Allagoa DO , Ubom AE , Oriji VK 
Published: May 2022

ABSTRACTBackgroundBartholin gland cysts and abscesses are common in women of reproductive age and declines after menopause. Organisms implicated in Bartholin abscess include, Neisseria gonorrhoeae, Chlamydia trachomatis, Escherichia coli, Staphylococcus aureus and Bacterioides spp.AimTo determine the incidence, presentation and management of Bartholin gland cysts and abscesses at the Federal Medical Centre, Yenagoa, Bayelsa State, South-South Nigeria, over a five-year period.Settings and DesignThis retrospective study was conducted in the Gynaecological Unit of the Federal Medical Centre, Yenagoa, Bayelsa State, South-South, Nigeria, between January 1, 2016 and December 31, 2020.Materials and MethodsRelevant data were retrieved, entered into a pre-designed proforma, and analysed.Statistical AnalysisStatistical Package for the Social Sciences version 25.0 was used for data analysis. Results were presented in frequencies and percentages for categorical variables.ResultsThere were 2,478 gynaecological cases managed in our Centre; out of which there were 26 cases of Bartholin cyst and abscess, giving an incidence of 1.05%. Most of the women were ≤ 30 years (14, 53.8%), single (17, 65.4%), nulliparous (13, 50.0%), traders (11, 42.3%), with only primary/secondary education (18, 69.2%). The left Bartholin gland was the most frequently affected (17, 65.4%). A positive microbial culture was obtained in 84% of cases, with Staphylococcus aureus and Escherichia coli being the isolated organisms. Marsupialisation was the treatment modality in all the patients.ConclusionWomen of reproductive age-group should be counselled on this condition and encouraged to keep good perineal hygiene and better sexual conduct so as to reduce the risk of Bartholin cysts and abscesses.
A Simulator for Somatic Evolution Study Design
Authors: Srivatsa Arjun , Lei Haoyun , Schwartz Russell 
Published: May 2022

AbstractMotivationSomatic evolution plays a key role in development, cell differentiation, and normal aging, but also diseases such as cancer, which is now mainly thought of as a disease of genetic and epigenetic modification. Understanding mechanisms of somatic mutability — variant types and frequencies, phylogenetic structure, mutational signatures, and clonal heterogeneity — and how they can vary between cell lineages will likely play a crucial role in biological discovery and medical applications. This need has led to a proliferation of new technologies for profiling single-cell variation, each with distinctive capabilities and limitations that can be leveraged alone or in combination with other technologies. The enormous space of options for assaying somatic variation, however, presents unsolved informatics problems with regards to selecting optimal combinations of technologies for designing appropriate studies for any particular scientific questions. Versatile simulation tools are needed to make it possible to explore and optimize potential study designs if researchers are to deploy multiomic technologies effectively.ResultsIn this paper, we present a simulator allowing for the generation of synthetic data from a wide range of clonal lineages, variant classes, and sequencing technology choices, intended to provide a platform for effective study design in somatic lineage analysis. Our simulation framework allows for the assessment of study design setups and their statistical validity in determining different ground-truth cancer mechanisms. The user is able to input various properties of the somatic evolutionary system, mutation classes (e.g., single nucleotide polymorphisms, copy number changes, and classes of structural variation), and biotechnology options (e.g., coverage, bulk vs single cell, whole genome vs exome, error rate, number of samples) and can then generate samples of synthetic sequence reads and their corresponding ground-truth parameters for a given study design. We demonstrate the utility of the simulator for testing and optimizing study designs for various experimental queries.Contactrussells@andrew.cmu.eduAvailabilityhttps://github.com/CMUSchwartzLab/MosaicSim
Angiotensin II regulates the neural expression of subjective fear in humans - precision pharmaco-neuroimaging approach
Authors: Zhang Ran , Zhao Weihua , Qi Ziyu , Xu Ting , Zhou Feng , Becker Benjamin 
Published: May 2022

AbstractBackgroundRodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear.MethodsIn a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined.ResultsAT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (1) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (2) does not affect reactivity to novel oddballs.ConclusionsThese results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.
Distinct Mechanisms of Innate and Adaptive Immune Regulation Underlie Poor Oncologic Outcomes Associated with KRAS-TP53 Co-Alteration in Pancreatic Cancer
Authors: Datta Jashodeep , Bianchi Anna , De Castro Silva Iago , Deshpande Nilesh U. , Cao Long Long , Mehra Siddharth , Singh Samara , Rafie Christine , Sun Xiaodian , Chen Xi , Dai Xizi , Colaprico Antonio , Sharma Prateek , Dosch Austin R. , Pillai Asha , Hosein Peter J. , Nagathihalli Nagaraj S. , Komanduri Krishna V. , Wilson Julie M. , Ban Yuguang , Merchant Nipun B. 
Published: May 2022

ABSTRACTCo-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8+ T-cell-excluded immune signatures. Leveraging in silico, in vitro, and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS-TP53 co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53 co-altered and KRAS-altered/TP53WT tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53 co-altered PDAC. Immune subtyping of KRAS-TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53 co-altered “immunoregulatory program” predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.
Accelerated aging induced by stress in experimental murine ocular hypertension
Authors: Xu Qianlan , Rydz Cezary , Nguyen Huu Viet Anh , Rocha Lorena , Palomino La Torre Claudia , Lee Irene , Cho William , Jabari Mary , Donello John , Weinreb Robert N. , Lyon David C. , Ju Won-Kyu , Foik Andrzej , Skowronska-Krawczyk Dorota 
Published: May 2022

ABSTRACTAging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited, therefore we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on epigenetic level. We demonstrate that program activated by hypertension is similar to natural aging, and that one of the earliest pathways activated upon stress is senescence. Finally, we show that multiple instances of pressure elevation cause accelerated aging of young retina as measured on transcriptional and epigenetic level. Our work emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related eye-diseases, including glaucoma.
Resolution of the curse of dimensionality in single-cell RNA sequencing data analysis
Authors: Imoto Yusuke , Nakamura Tomonori , Escolar Emerson G. , Yoshiwaki Michio , Kojima Yoji , Yabuta Yukihiro , Katou Yoshitaka , Yamamoto Takuya , Hiraoka Yasuaki , Saitou Mitinori 
Published: May 2022

AbstractSingle-cell RNA sequencing (scRNA-seq) can determine gene expression in numerous individual cells simultaneously, promoting progress in the biomedical sciences. However, scRNA-seq data are high-dimensional with substantial technical noise, including dropouts. During analysis of scRNA-seq data, such noise engenders a statistical problem known as the curse of dimensionality (COD). Based on high-dimensional statistics, we herein formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), for high-dimensional data with random sampling noise. We show that RECODE consistently eliminates COD in relevant scRNA-seq data with unique molecular identifiers. RECODE does not involve dimension reduction and recovers expression values for all genes, including lowly expressed genes, realizing precise delineation of cell-fate transitions and identification of rare cells with all gene information. Compared to other representative imputation methods, RECODE employs different principles and exhibits superior overall performance in cell-clustering and single-cell level analysis. The RECODE algorithm is parameter-free, data-driven, deterministic, and high-speed, and notably, its applicability can be predicted based on the variance normalization performance. We propose RECODE as a general strategy for preprocessing noisy high-dimensional data.
Mechanical communication-induced cell directional migration and branching connections mediated by calcium channels, integrin β1 and N-cadherin
Authors: Ouyang Mingxing , Zhu Yiming , Wang Jiajia , Zhang Qingyu , Bu Bing , Guo Jia , Deng Linhong 
Published: May 2022

AbstractCell-cell mechanical communications at large spatial scale (above hundreds of micrometers) have been increasingly recognized in recent decade, which shows importance in tissue-level assembly and morphodynamics. The involved mechanosensing mechanism and resulted physiological functions are still to be fully understood. Recent work showed that traction force sensation in the matrix induces cell communications for self-assembly. Here, based on the experimental model of cell directional migration on Matrigel hydrogel containing 0.5 mg/ml type I collagen, we studied the mechano-responsive pathways for cell distant communications. Airway smooth muscle (ASM) cells assembled network structure on the hydrogel, whereas stayed isolated individually when cultured on glass without force transmission. Cell directional migration, or network assembly was significantly attenuated by inhibited actomyosin activity, or inhibition of inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel or SERCA pump on endoplasmic reticulum (ER) membrane, or L-type calcium channel on the plasma membrane. Inhibition of integrin β1 with siRNA knockdown reduced cell directional migration and branching assembly, whereas inhibition of cell junctional N-cadherin with siRNA had little effect on distant attractions but blocked branching assembly. Our work demonstrated that the ER calcium channels and integrin are mechanosensing signals for cell mechanical communications regulated by actomyosin activity, while N-cadherin is responsible for traction force-induced cell stable connections in the assembly.
A de novo MS1 feature detector for the Bruker timsTOF Pro
Authors: Wilding-McBride Daryl , Webb Andrew I. 
Published: May 2022

1AbstractIdentification of peptides by analysis of data acquired by the two established methods for bottom-up proteomics, DDA and DIA, relies heavily on the fragment spectra. In DDA, peptide features detected in mass spectrometry data are identified by matching their fragment spectra with a peptide database. In DIA, a peptide’s fragment spectra are targeted for extraction and matched with observed spectra. Although fragment ion matching is a central aspect in most peptide identification strategies, the precursor ion in the MS1 data reveals important characteristics as well, including charge state, intensity, monoisotopic m/z, and apex in retention time. Most importantly, the precursor’s mass is essential in determining the potential chemical modification state of the underlying peptide sequence. In the timsTOF, with its additional dimension of collisional cross-section, the data representing the precursor ion also reveals the peptide’s peak in ion mobility. However, the availability of tools to survey precursor ions with a wide range of abundance in timsTOF data across the full mass range is very limited.Here we present a de novo feature detector called three-dimensional intensity descent (3DID). 3DID can detect and extract peptide features down to a configurable intensity level, and finds many more features than several existing tools. 3DID is written in Python and is freely available with an open-source MIT license to facilitate experimentation and further improvement (DOI 10.5281/zenodo.6513126). The dataset used for validation of the algorithm is publicly available (ProteomeXchange identifier PXD030706).2Author SummaryIn the identification of peptides in mass spectrometry data, much attention has been given to the targeting and extraction of mass spectra produced by fragmentation of precursor ions. However, important information about the peptide is revealed by the data representing the precursor ion itself, such as the peptide’s charge state, mass-to-charge ratio, intensity, and retention time. The timsTOF produces the additional dimension of ion mobility, which provides richer information about the precursor. Although tools exist for the analysis of timsTOF data, they are hampered by limited dynamic range. In this work, we describe a de novo feature detector called 3DID that detects peptide features across the full mass range. Our detector can detect more peptides than existing tools across a broader range of abundance, which enables more comprehensive analysis of the data. We believe 3DID will make a valuable contribution to the proteomics toolbox.