bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIFiA: Self-supervised Approach for Protein Functional Annotation from Single-Cell Imaging Data
Authors: Razdaibiedina Anastasia , Brechalov Alexander , Friesen Helena , Usaj Mojca Mattiazzi , Masinas Myra Paz David , Suresh Harsha Garadi , Wang Kyle , Boone Charles , Ba Jimmy , Andrews Brenda 
Published: February 2023

AbstractFluorescence microscopy data describe protein localization patterns at single-cell resolution and have the potential to reveal whole-proteome functional information with remarkable precision. Yet, extracting biologically meaningful representations from cell micrographs remains a major challenge. Existing approaches often fail to learn robust and noise-invariant features or rely on supervised labels for accurate annotations. We developed PIFiA, (ProteinImage-basedFunctionalAnnotation), a self-supervised approach for protein functional annotation from single-cell imaging data. We imaged the global yeast ORF-GFP collection and applied PIFiA to generate protein feature profiles from single-cell images of fluorescently tagged proteins. We show that PIFiA outperforms existing approaches for molecular representation learning and describe a range of downstream analysis tasks to explore the information content of the feature profiles. Specifically, we cluster extracted features into a hierarchy of functional organization, study cell population heterogeneity, and develop techniques to distinguish multi-localizing proteins and identify functional modules. Finally, we confirm new PIFiA predictions using a colocalization assay, suggesting previously unappreciated biological roles for several proteins. Paired with a fully interactive website (https://thecellvision.org/pifia/), PIFiA is a resource for the quantitative analysis of protein organization within the cell.
AIM (Angular Indication Measurement)- Visual Acuity: An adaptive, self-administered, and generalizable vision assessment method used to measure visual acuity
Authors: Skerswetat Jan , He Jingyi , Shah Jay Bijesh , Aycardi Nicolas , Freeman Michelle , Bex Peter John 
Published: February 2023

AbstractThis proof-of-concept study introduces Angular Indication Measurement and applies it to VA (AIM-VA). First, we compared the ability of AIM-VA and ETDRS to detect defocus and astigmatic blur in 22 normally-sighted adults. Spherical and cylindrical lenses (±0.00D, +0.25D, +0.50D, +0.75D, +1.00D, +2.00D and +0.50D, +1.00D, +2.00D each at 0°, 90°, 135°, respectively) in the dominant eye induced blur. Second, we compared repeatability over two tests of AIM-VA and ETDRS. A 2-way-ANOVA showed a main effect for defocus-blur and test with no interaction. A 3-way-ANOVA for the astigmatism experiment revealed main effects for test type, blur, and direction and with no interactions. Planned multiple comparisons showed AIM had greater astigmatic-induced VA loss than ETDRS. Bland-Altman plots showed small bias and no systematic learning effect for either test type and improved repeatability with >2 adaptive steps for AIM-VA. AIM-VA’s ability to detect defocus was comparable with that of an ETDRS letter chart and showed greater sensitivity to astigmatic blur, and AIM-VA’s repeatability is comparable with ETDRS when using 2 or more adaptive steps. AIM’s self-administered orientation judgment approach is generalizable to interrogate other visual functions, e.g., contrast, color, motion, stereo-vision.
Toxin/Antitoxin Systems Induce Persistence and Work in Concert with Restriction/Modification Systems to Inhibit Phage
Authors: Fernández-García Laura , Song Sooyeon , Kirigo Joy , Battisti Michael E. , Huelgas-Méndez Daniel , García-Contreras Rodolfo , Petersen Maiken E. , Tomás María , Wood Thomas K. 
Published: February 2023

ABSTRACTMyriad bacterial anti-phage systems have been described and often the mechanism of programmed cell death is invoked for phage inhibition. However, there is little evidence of ‘suicide’ under physiological conditions for these systems. Instead of death to stop phage propagation, we show here that persister cells, i.e., transiently-tolerant, dormant, antibiotic-insensitive cells, are formed and survive using theEscherichia coliC496_10 tripartite toxin/antitoxin system MqsR/MqsA/MqsC to inhibit T2 phage. Specifically, MqsR/MqsA/MqsC inhibited T2 phage by one million-fold and reduced T2 titers by 500-fold. During T2 phage attack, in the presence of MqsR/MqsA/MqsC, evidence of persistence include the single-cell physiological change of reduced metabolism (via flow cytometry), increased spherical morphology (via transmission electron microscopy), and heterogeneous resuscitation. Critically, we found restriction-modification systems (primarily EcoK McrBC) work in concert with the toxin/antitoxin system to inactivate phage, likely while the cells are in the persister state. Phage attack also induces persistence inKlebsiellaandPseudomonasspp. Hence, phage attack invokes a stress response similar to antibiotics, starvation, and oxidation, which leads to persistence, and this dormant state likely allows restriction/modification systems to clear phage DNA.
The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC
Authors: Lupo Francesca , Pezzini Francesco , Fiorini Elena , Adamo Annalisa , Veghini Lisa , Bevere Michele , Frusteri Cristina , Delfino Pietro , D’Agosto Sabrina , Andreani Silvia , Piro Geny , Malinova Antonia , De Sanctis Francesco , Pasini Davide , Lawlor Rita T. , Hwang Chang-il , Carbone Carmine , Amelio Ivano , Bailey Peter , Bronte Vincenzo , Tuveson David , Scarpa Aldo , Ugel Stefano , Corbo Vincenzo 
Published: February 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few available therapeutic options. Two transcriptional cancer cell states have been consistently reported in PDAC, with the basal-like/squamous phenotype displaying a more aggressive biological behavior. Genetic and epigenetic dysregulation of the axon guidance pathway are common in PDAC, yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in sustaining the progression of PDAC. We integrated available transcriptomic datasets of human PDAC within situhybridization analyses of patients’ tissues to find that SEMA3A is expressed by stromal cells and selectively enriched in epithelial cells of the basal-like/squamous subtype. We found that both cell-intrinsic and cell extrinsic factors instructing the basal-like/squamous subtype induce expression of SEMA3A in PDAC cells.In vitro, SEMA3A promoted cell migration as well as anoikis resistance. At molecular level, these phenotypes were associated with increased FAK signaling and enrichment of gene programs related to cytoskeleton remodeling. Accordingly, SEMA3A provided mouse PDAC cells with greater metastatic competence. In mouse orthotopic allografts, SEMA3A remodeled the TME by favoring infiltration of tumor-associated macrophages and exclusion of T cells. Mechanistically, SEMA3A functioned as chemoattractant for macrophages and favored their polarization towards an M2-like phenotype. In SEMA3Ahightumors, depletion of macrophages resulted in greater intratumor infiltration by CD8+ T cells and increased sensitivity of these tumors to chemotherapy. Overall, we show that SEMA3A contributes to the malignant phenotype of basal-like PDAC.
A top-down slow breathing circuit that alleviates negative affect
Authors: Jhang Jinho , Liu Shijia , O’Keefe David D. , Han Sung 
Published: February 2023

SummaryBreathing is profoundly influenced by both behavior and emotion1–4and is the only physiological parameter that can be volitionally controlled4–6. This indicates the presence of cortical-to-brainstem pathways that directly control brainstem breathing centers, but the neural circuit mechanisms of top-down breathing control remain poorly understood. Here, we identify neurons in the dorsal anterior cingulate cortex (dACC) that project to the pontine reticular nucleus caudalis (PnC) and function to slow breathing rates. Optogenetic activation of this corticopontine pathway (dACC→PnC neurons) in mice slows breathing and alleviates behaviors associated with negative emotions without altering valence. Calcium responses of dACC→PnC neurons are tightly correlated with changes in breathing patterns entrained by behaviors, such as drinking. Activity is also elevated when mice find relief from an anxiety-provoking environment and slow their breathing pattern. Further, GABAergic inhibitory neurons within the PnC that receive direct input from dACC neurons decrease breathing rate by projecting to pontomedullary breathing centers. They also send collateral projections to anxiety-related structures in the forebrain, thus comprising a neural network that modulates breathing and negative affect in parallel. These analyses greatly expand our understanding of top-down breathing control and reveal circuit-based mechanisms by which slow breathing and anxiety relief are regulated together.
Specialized late cingulo-opercular network activation elucidates the mechanisms underlying decisions about ambiguity
Authors: Pierce Jordan E. , Petro Nathan M. , Clancy Elizabeth , Gratton Caterina , Petersen Steven E. , Neta Maital 
Published: February 2023

AbstractCortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggests that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.
Partialin vivoreprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction
Authors: Kim Jumee , Kim Somi , Lee Seung-Yeon , Jo Beom-Ki , Oh Ji-Young , Kwon Eun-Ji , Kim Keun-Tae , Adpaikar Anish Ashok , Kim Eun-Jung , Jung Han-Sung , Hong Chang Pyo , Kim Jong Kyoung , Koo Bon Kyoung , Cha Hyuk-Jin 
Published: February 2023

AbstractTissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming process that leads to the emergence of injury-responsive cells with fetal-like characteristics in the intestinal epithelium. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells through forced partial reprogrammingin vivousing “Yamanaka factors” (Oct4, Sox2, Klf4, and c-Myc: OSKM). The OSKM-induced dedifferentiation showed similar molecular features of intestinal regeneration, including a rapid transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing a gene signature of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following ionizing radiation-induced acute tissue damage. In contrast to normal intestinal regeneration, which involves epi-mesenchymal crosstalk through induction ofPtgs2(encoding Cox2) upon injury, the OSKM expression promotes the autonomous production of prostaglandin E2 via epithelialPtgs1(encoding Cox1) expression. These results indicate that prostaglandin synthesis is a common mechanism for intestine epithelial regeneration but involves a different enzyme (Ptgs1for Cox1) when partial reprogramming is directly applied to the intestinal epithelium.
Historical demography and species distribution models shed light on past speciation in primates of northeast India
Authors: Trivedi Mihir , Arekar Kunal , Umapathy Govindhaswamy 
Published: February 2023

AbstractObjectivesTo ascertain the effect of historical demography and past climate change as the drivers of diversity in northeast India.Materials and methodsWe took the variant called whole genome files of nine species present in the northeast India from Primate genome sequencing consortium work and assessed each species historic effective population size by using Multiple Sequentially Markovian Coalescent (MSMC) tool. We also constructed species distribution models on past (Pliocene and Pleistocene) and present climate with Maxent, by utilizing publicly available distribution data for each species.ResultsWe got the effective population sizes for 10 million years ago at most, though we considered the data only till 3.3 million years. All species showed rise and decline at various time periods. The species distribution models showed disparate distribution at all three time points with a genera-wise pattern emerging.DiscussionWe found that the evolutionary trajectories of all the four genera into consideration,Macaca, Trachypithecus, HoolockandNycticebusare different from each other. Species inMacacalooks to be evolved in northeast as well as come from southeast Asia. Some species ofTrachypithecusseems to radiated in the northeast India. Similarly,Hoolockhas evolved in the region andNycticebusis predicted have arrived from Indochina in the region. Hence, this study provides unique insights to the evolutionary dynamics for primate species in the northeast India.
INPP5D/SHIP1 regulates inflammasome activation in human microglia
Authors: Chou Vicky , Fancher Seeley B. , Pearse Richard V. , Lee Hyo , Lam Matti , Seyfried Nicholas T. , Bennett David A. , De Jager Phillip L. , Menon Vilas , Young-Pearse Tracy L. 
Published: February 2023

ABSTRACTMicroglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is largely restricted to microglia. Examination of prefrontal cortex across a large cohort revealed reduced full length INPP5D protein levels in AD patient brains compared to cognitively normal controls. The functional consequences of reduced INPP5D activity were evaluated in human induced pluripotent stem cell derived microglia (iMGLs), using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of iMGLs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGLs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.
Design-Rules for Stapled Alpha-Helical Peptides with On-Target In Vivo Activity: Application to Mdm2/X dual antagonists
Authors: Chandramohan Arun , Josien Hubert , Yuen Tsz Ying , Duggal Ruchia , Spiegelberg Diana , Yan Lin , Angela Juang Yu-Chi , Ge Lan , Aronica Pietro , Kaan Kristal , Lim Yee Hwee , Peier Andrea , Sherborne Brad , Hochman Jerome , Lin Songnian , Biswas Kaustav , Henry Brian , Nestor Marika , Verma Chandra S , Lane David , Sawyer Tomi , Garbaccio Robert , Kannan Srinivasaraghavan , Kannan Srinivasaraghavan , Brown Christopher J. , Johannes Charles W , Partridge Anthony William 
Published: February 2023

AbstractStapled α-helical peptides can bind to and modulate historically intractable targets while addressing the traditional liabilities associated with peptide therapeutics. However, their pipeline advancement has been impeded by the challenges of identifying peptides with sufficient cellular uptake to engage the target protein while lacking off-target toxicities. Here, we advance the field to arrive at a workflow for identifying advanced stapled peptide lead molecules with on-target in vivo activity with no off-target cell proliferation effects. Specifically, we generated a >350-member library based on ATSP-7041, a stapled peptide Mdm2(X) antagonist with validated on-target cellular effects but with significant off-target activity. Key insights from library analysis include 1) a clear correlation between lipophilicity and permeability, 2) removal of positive charge to avoid off-target toxicities, 3) judicious placement of anionic residues to enhance peptide solubility/behavior, 4) optimization of C-terminal length and helicity to enhance cell activity, 5) optimization of staple type/number to avoid polypharmacology. Incorporation of one or more of these attributes led to molecules with improved in vitro and in vivo activities (up to a >292x improved cell proliferation EC50). A subset of peptides were devoid of off-target cell proliferation effects in cell lines lacking wild-type p53 protein (up to a >3800x on-target index). This latter improvement contrasted with clinical Mdm2 antagonistic molecules. Application of these ‘design rules’ to a distinct Mdm2(X) peptide series resulted in rapid improvement in cellular activity (>150x) and removal of off-target toxicities. Overall, the detailed workflow outlined here should help researchers identify stapled α-helical peptides for therapeutic impact.
The ancestral shape of the access proton path of mitochondrial ATP synthases revealed by a split subunit-a
Authors: Wong Jonathan E. , Zíková Alena , Gahura Ondřej 
Published: February 2023

AbstractThe passage of protons across membranes through F1Fo-ATP synthases spins their rotors and drives synthesis of ATP. While the principle of torque generation by proton transfer is known, the mechanisms and routes of proton access and release and their evolution are not fully understood. Here, we show that the entry site and path of protons in the lumenal half-channel of mitochondrial ATP synthases are largely defined by a short N-terminal α-helix of subunit-a. InTrypanosoma bruceiand other Euglenozoa, the α-helix is part of another polypeptide chain that is a product of subunit-a gene fragmentation. This α-helix and other elements forming the proton pathway are widely conserved across eukaryotes and in Alphaproteobacteria, the closest extant relatives of mitochondria, but not in other bacteria. The α-helix blocks one of two proton routes found inEscherichia coli, resulting in the single proton entry site in mitochondrial and alphaproteobacterial ATP synthases. Thus, the shape of the access half-channel predates eukaryotes and originated in the lineage from which mitochondria evolved by endosymbiosis.
Investigation of co-encapsulation of pancreatic beta cells and curcumin within alginate microcapsules
Authors: Hosseinzadeh Zahra , Alemzadeh Iran , Vossoughi Manouchehr 
Published: February 2023

1.AbstractCell encapsulation is an ideal approach for the replacement of pancreatic function in Type 1 diabetes. Poor biocompatibility of microcapsules generates an inflammatory response in the implantation site and induces fibrosis infiltration, which causes microencapsulated cell death and graft failure. To prevent inflammation after implantation, composite microcapsules which exhibit anti-inflammatory properties were designed. This study is about co-encapsulating beta cells and curcumin within 1.5% alginate by the jet-breaking regime of the syringe pump. The microcapsules size distribution and rate of the alginate solution were characterized to find uniform particles. Micro-size particles were attained at a rate of 25 ml/min. Uniform spherical microcapsules (200–300 μm) were created in large amounts in a short period. Microcapsule breakage was less than 3% during 7 days and demonstrated the stability of the encapsulation method. Insulin secretion and cell viability assays were performed 1, 3, and 7 days after microencapsulation by GSIS and MTT assays. No significant differences in the amount of insulin secretion and beta cell viability were observed among free cells, alginate microcapsules, and curcumin-alginate microcapsules during 7 days (P > 0.05). Therefore, curcumin and alginate membrane did not show any harmful impacts on the function and survival of the beta cells.
Task shifting healthcare services in the post-COVID world: A scoping review
Authors: Das Shukanto , Grant Liz 
Published: February 2023

AbstractTask shifting (TS) redistributes services from specialised to less-qualified providers. Need for TS was intensified during COVID-19 pandemic. We locate evidences of TS across all health conditions to answer: (A) What role has TS played in services delivery since the onset of the pandemic? (B) How has the pandemic impacted strategies of TS globally? We searched five databases in October 2022: Medline, CINHAL Plus, Elsevier, Global Health and Google Scholar. 35 citations were selected. Data was analysed thematically and reported as per PRSIMA-ScR. We used WHO health systems framework and emergent themes to discuss findings. TS was observed in countries of all income-levels. 63% (n=22) articles discussed what impact TS had in COVID-19 care, mental healthcare, care for HIV, sexual and reproductive health, nutrition and rheumatoid diseases. Others (n=13) highlight how pandemic altered TS strategies in mental healthcare, HIV services, hypertension and diabetes and emergency services. Studies varied in reporting TS; majority using terms “task shifting”, followed by “task sharing”, “task shifting and sharing” and “task delegation”. TS affected every block of health system. TS to non-specialists and non-healthcare staff improved services. Modifying roles through training and collaboration strengthened workforce. TS diagnostics increased access to medicines and technologies. Strategic leadership was key. Research on financing TS during pandemics is required. Stakeholders generally accepted TS. Shifting staff between programs led to unintended service incapacities. Pandemic affected strategies of TS. Training, providing care, follow-ups and consultations went digital. Virtually-delivered interventions improved outcomes. Accessibility to digital technology presented barriers. COVID-19 modified health-seeking behaviour. Patients preferred teleconsultations and online-symptom checkers. Organisations altered operating procedures and patient-flow pathways and added precautions to protect staff. Risks of spreading COVID-19 prompted facilities to reconsider TS. TS improved outcomes by filling workforce gaps and increasing access. We recommend TS to improve services delivery during the pandemic and beyond.