bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temperature impacts on dengue incidence are nonlinear and mediated by climatic and socioeconomic factors
Authors: Kirk Devin , Straus Samantha , Childs Marissa L. , Harris Mallory , Couper Lisa , Davies T. Jonathan , Forbes Coreen , Gehman Alyssa-Lois , Groner Maya L. , Harley Christopher , Lafferty Kevin D. , Savage Van , Skinner Eloise , O’Connor Mary , Mordecai Erin A. 
Published: June 2022

ABSTRACTTemperature can influence mosquito-borne diseases like dengue. These effects are expected to vary geographically and over time in both magnitude and direction and may interact with other environmental variables, making it difficult to anticipate changes in response to climate change. Here, we investigate global variation in temperature–dengue relationship by analyzing published correlations between temperature and dengue and matching them with remotely sensed climatic and socioeconomic data. We found that the correlation between temperature and dengue was most positive at intermediate (near 24°C) temperatures, as predicted from the thermal biology of the mosquito and virus. Positive temperature–dengue associations were strongest when temperature variation and population density were high and decreased with infection burden and rainfall mean and variation, suggesting alternative limiting factors on transmission. Our results show that while climate effects on diseases are context-dependent they are also predictable from the thermal biology of transmission and its environmental and social mediators.
Vulnerable Brain Networks Associated with Risk for Alzheimer’s Disease
Authors: Mahzarnia Ali , Stout Jacques A , Anderson Robert J , Moon Hae Sol , Han Zay Yar , Beck Kate , Browndyke Jeffrey N , Dunson David B. , Johnson Kim G , O’Brien Richard J , Badea Alexandra 
Published: June 2022

AbstractBrain connectomes provide untapped potential for identifying individuals at risk for Alzheimer’s disease (AD), and can help provide novel targets based on selective circuit vulnerability. Age, APOE4 genotype, and female sex are thought to contribute to the selective vulnerability of brain networks in Alzheimer’s disease, in a manner that differentiates pathological versus normal aging. These brain networks may predict pathology otherwise hard to detect, decades before overt disease manifestation and cognitive decline. Uncovering network based biomarkers at prodromal, asymptomatic stages may offer new windows of opportunity for interventions, either therapeutic or preventive. We used a sample of 72 people across the age span to model the relationship between Alzheimer’s disease risk and vulnerable brain networks. Sparse Canonical Correlation analysis (SCCA) revealed relationships between brain subgraphs and AD risk, with bootstrap based confidence intervals. When constructing a composite AD risk factor based on sex, age, genotype, the highest weight was associated with genotype. Next, we mapped networks associated with auditory, visual, and olfactory memory, and identified networks extending beyond the main nodes known to be involved in these functions. The inclusion of cognitive metrics in a composite risk factor pointed to vulnerable networks, and associated with the specific memory tests. These regions with the highest cumulative degree of connectivity in our studies were the pericalcarine, insula, banks of the superior sulcus and cerebellum. To help scale up our approach, we extended Tensor Network Principal Component Analysis (TNPCA) to evaluate AD risk related subgraphs, introducing CCA components and sparsity. When constructing a composite AD risk factor based on sex, age, and genotype, and family risk factor the most significant risk was associated with age. Our sparse regression based predictive models revealed vulnerable networks associated with known risk factors. The prediction error was 17% for genotype, 24% for family risk factor, and 5 years for age. Age prediction in groups including MCI and AD subjects involved several regions that were not prominent for age prediction otherwise. These regions included the middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. The joint estimation of AD risk and connectome based mappings involved the cuneus, temporal, and cingulate cortices known to be associated with AD, and add new candidates, such as the cerebellum, whose role in AD is to be understood. Our predictive modeling approaches for AD risk factors represent a stepping stone towards single subject prediction, based on distances from normative graphs.
A loss of crAssphage stability in the human gut virome is associated with obesity and metabolic syndrome
Authors: Cervantes-Echeverría Melany , Gallardo-Becerra Luigui , Cornejo-Granados Fernanda , Leyva Adrian Ochoa 
Published: June 2022

AbstractViral metagenomics studies of the human gut microbiota unravel differences in phage populations between healthy and disease, stimulating interest in the role that phages play in bacterial ecosystem regulation. CrAssphages are not only the most abundant viruses but also are a common component of the gut phageome across human populations. However, the role of crAssphages in obesity (O) and obesity with metabolic syndrome (OMS) remains largely unknown. Therefore, we explored the role that crAssphages have on both diseases in a children’s cohort. We found decreased crAssphage abundance, prevalence, richness, and diversity in O and OMS compared to normal-weight (NW), suggesting a loss of crAssphages stability in the human phageome associated with the disease. Interestingly, when we analyzed the abundance of host crAssphages bacteria, we found that Bacteroidetes, Bacteroidia, and Bacteroidales were significantly decreased in O and OMS, suggesting a possible relation with the loss of crAssphages stability. Regarding crAssphage taxonomy, a significantly decreased abundance of the crAssphage Alpha subfamily and the Alpha_1 and Alpha_4 genus and a significant overabundance of the Delta_8 was found in OMS. A strong taxonomical signature of obesity is the over-abundance of Bacilli, which also were significantly increased in O and OMS. Notably, we found a significant negative correlation between crAssphages and Bacilli abundances, suggesting an association between the decreased abundance of crAssphage and the over-abundance of Bacilli in OMS. Furthermore, we found a loss of crAssphage stability in the human virome associated with the presence of obesity, having a more significant impact on obesity with metabolic syndrome, suggesting that these bacteriophages could play an essential role in inhibiting metabolic syndrome in obese individuals. Our results open a promising treatment for these diseases through fecal crAssphage transplantation.
A Mechanistic Study on the Cellular Uptake, Intracellular Trafficking, and Antisense Gene Regulation of Bottlebrush Polymer-Conjugated Oligonucleotides
Authors: Zhang Lei , Wang Yuyan , Chen Peiru , Wang Dali , Zhang Zheyu , Wang Ruimeng , Kang Xi , Fang Yang , Lu Hao , Cai Jiansong , Ren Mengqi , Dong Sijia , Zhang Ke 
Published: June 2022

ABSTRACTWe have developed a non-cationic transfection vector in the form of a bottlebrush polymer-antisense oligonucleotide (ASO) conjugate. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency in vivo while suppressing non-antisense side effects. Nonetheless, there still lacks a mechanistic understanding regarding the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA. Here, we show that the pacDNA enters human non-small cell lung cancer cells (NCI-H358) predominantly by scavenger receptor-mediated endocytosis and macropinocytosis, and trafficks via the endolysosomal pathway within the cell. The pacDNA significantly reduces a target gene expression (KRAS) in the protein level but not in the mRNA level, despite that the transfection of free ASOs causes ribonuclease H1 (RNase H)-dependent degradation of KRAS mRNA. In addition, the antisense activity of pacDNA is independent of ASO chemical modification, suggesting that the pacDNA functions as a steric blocker.TOC
High Mortality among Older Patients Hospitalized with COVID-19 during the First Pandemic Wave
Authors: Kempker Russell R , Rebolledo Paulina A , Rollin Francois , Gurbani Saumya , Schechter Marcos C. , Wilhoite David , Bogard Sherri N. , Watkins Stacey , Duggal Aarti , John Nova , Kapuria Malavika , Terry Charles , Yang Philip , Dale Gordon , Mora Ariana , Preslar Jessica , Sandor Kaitlin , Wang Yun F (Wayne) , Woodworth Michael H , Kempker Jordan A 
Published: June 2022

AbstractBackgroundUnderstanding the local epidemiology, including mortality, of COVID-19 is important for guiding optimal mitigation strategies such as vaccine implementation, need for study of more effective treatment, and redoubling of focused infection control measures.MethodsA retrospective observational cohort study design was utilized. We included adult patients diagnosed in the hospital or emergency department with COVID-19 from March 8, 2020 through May 17, 2020 at Grady Memorial Hospital (Atlanta, GA). Medical chart data abstraction was performed to collect clinical, laboratory and outcome data. Death, defined as inpatient mortality or discharge to hospice, was the primary outcome.ResultsAmong 360 persons with laboratory-confirmed COVID-19, 50% were ≥ 60 years, and most (80%) were Black and had a BMI ≥25 kg/m2 (64%). A total of 53 patients (15%) had an outcome of death with the majority (n=46, 88%) occurring in persons ≥ 60 years. Persons ≥ 60 years were less likely to have typical COVID-19 symptoms while more likely to have multiple comorbidities, multifocal pneumonia, and to be admitted to intensive care. The death rate was 27% among persons ≥60 years versus 4% in those <60 years (p<.01). Furthermore, most deaths (n=40, 75%) occurred among residents of long-term care facilities (LCFs).ConclusionsWe describe early COVID-19 cases among predominantly Black and older patients from a single center safety net hospital. COVID-19 related mortality occurred predominantly among older patients from LCFs highlighting the need for improved preparedness and supporting prioritization of vaccination efforts in such settings.
The layered costs and benefits of translational redundancy
Authors: Raval Parth K , Ngan Wing Yui , Gallie Jenna , Agashe Deepa 
Published: June 2022

ABSTRACTThe rate and accuracy of translation hinges upon multiple components – including transfer RNA (tRNA) pools, tRNA modifying enzymes, and rRNA molecules – many of which are redundant in terms of gene copy number or function. It has been hypothesized that the redundancy evolves under selection, driven by its impacts on growth rate. However, we lack empirical measurements of the fitness costs and benefits of redundancy, and we have poor understanding of how this redundancy is organized across components. We manipulated redundancy in multiple translation components of Escherichia coli by deleting 28 tRNA genes, 3 tRNA modifying systems, and 4 rRNA operons in various combinations. We find that redundancy in tRNA pools is beneficial when nutrients are plentiful, and costly under nutrient limitation. This nutrient-dependent cost of redundant tRNA genes stems from upper limits to translation capacity and growth rate, and therefore varies as a function of the maximum growth rate attainable in a given nutrient niche. The loss of redundancy in rRNA genes and tRNA modifying enzymes had similar nutrient-dependent fitness consequences. Importantly, these effects are also contingent upon interactions across translation components, indicating a layered hierarchy from copy number of tRNA and rRNA genes to their expression and posttranscriptional modification. Overall, our results indicate both positive and negative selection on redundancy in translation components, depending on a species’ evolutionary history with feasts and famines.
Evaluation of targeted oxidative stress induced by oxygen-ozone gas mixtures in vitro after ischemic induction
Authors: Orlandin Jessica Rodrigues , Santos Sarah Ingrid Pinto , Machado Luciana Cristina , Neto Paulo Fantinato , Bressan Fabiana Fernandes , Pieri Naira Caroline Godoy , Recchia Kaiana , Coutinho Meline de Paula , Ferreira Pinto Priscilla Avelino , Santucci Annalisa , Travagli Valter , Ambrosio Carlos Eduardo 
Published: June 2022

ABSTRACTEncephalic vascular accident, or stroke, is the most common pathology of the central nervous system in humans. It is the second leading cause of death, as well as physical and cognitive disabilities, in developing countries. It is a vascular disorder that may present in an ischemic (more common) or hemorrhagic form. Ozone is a gas capable of oxidizing double bonds of organic molecules, thereby producing lipoperoxides and aldehydes. Stimulation of the immune and antioxidant system, and improvement in tissue vascularization and oxygenation, are few among several effects exerted by ozone. Ozone therapy has previously been shown to be effective in neuromodulation, neuroprotection, and nerve regeneration. The present study aimed to evaluate the effect of targeted mild ozone after inducing cerebral ischemia in vitro. The experiment was divided into two steps; in the first step, neuroblastoma lineage cells (SH-SY5Y) were subjected to 24 hours of hypoxia in an incubator culture chamber. Treatment with different concentrations of ozone (2–10 µg/mL), followed by an 2,5-diphenyl-2H-tetrazolium bromide assay, indicated a possible neuroregenerative effect at low concentrations. The same protocol was applied to canine amniotic membrane stem cells that were evaluated via colorimetric assay spectrophotometry, fluorescence microscopy, and flow cytometry. The metabolic conditions and cellular regeneration in cells at low ozone concentrations (3–8 µg/mL) correlated with lower levels of apoptosis and oxidative stress compared to cells not subjected to hypoxia. High concentrations of ozone (18–30 µg/mL) promoted an increase in rate of apoptosis and cell death. Therefore, we developed a novel protocol that mimics ozone therapy for ischemic stroke, using ozonized culture medium after hypoxia induction. Although more studies are needed to open new avenues for translational medicine, we conclude that ozone has a dose-dependent hormetic effect and can reverse the effect of ischemia in vitro at low concentrations.
Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer’s disease
Authors: Grone Brian P. , Zalocusky Kelly A. , Hao Yanxia , Yoon Seo Yeon , Arriola Patrick , Huang Yadong 
Published: June 2022

AbstractApolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.
Identification of chemo-sensory genes from antennae of female banana pseudostem weevil, Odoiporous longicollis by transcriptomics approach
Authors: Mani Kannan , Balakrishnan Padmanaban , Soroker Victoria 
Published: June 2022

AbstractIn the present study, the female O. longicollis antennal transcriptome was constructed by Illumina Hiseq 2500™ sequencing, with the aim of discovering olfaction-related genes. Totally 12, 411 unigenes were identified from the transcriptome assembly and the putative genes functions were annotated using gene ontology tools. We identified 46 putative chemosensory unigenes likely essential for insect olfaction including 19 odorant binding proteins, 3 Niemann–Pick type C (NPC) protein, 6 odorant receptors, 15 ionotropic receptors, and 3 sensory neuron membrane proteins. The key function of these chemosensory genes in the antennae are discussed. Phylogenetic analysis of NPC revealed that the identified proteins had a close relationship with Coleopterans than other insects. This is the first ever report on identification of olfactory genes from O. longicollis which may provide new leads for control of this major pest.
Smart-design of universally decorated nano-particles for drug delivery applications driven by active transport
Authors: Halbi Gal , Fayer Itay , Aranovich Dina , Brik Ashraf , Granek Rony , Bernheim-Groswasser Anne 
Published: June 2022

AbstractTargeting the cell nucleus remains a challenge for drug delivery. Here we present a universal platform for smart design of nano-particles (NPs) decoration that allows recruitment of multiple dynein motors to drive their active motion towards the nucleus. The uniqueness of our approach is based on using: (i) a spacer polymer, commonly Biotin-Polyethylene-glycol-thiol (B-PEG-SH), whose grafting density and molecular weight can be tuned thereby allowing NP transport optimization, and (ii) protein binding peptides, like cell penetrating, NLS, or cancer targeting, peptides. Universal chemistry is employed to link peptides to the PEG free-end. To manifest our platform, we use a SV40T large antigen-originating NLS peptide. Our modular design allows tuning the number of recruited motors, and to replace the NLS by a variety of other localization signal molecules. Our control of the NP decoration scheme, and the modularity of our platform, carries great advantage for nano-carrier design for drug delivery applications.
Structural basis for activation of DNMT1
Authors: Kikuchi Amika , Onoda Hiroki , Yamaguchi Kosuke , Kori Satomi , Matsuzawa Shun , Chiba Yoshie , Tanimoto Shota , Yoshimi Sae , Sato Hiroki , Yamagata Atsushi , Shirouzu Mikako , Adachi Naruhiko , Sharif Jafar , Koseki Haruhiko , Nishiyama Atsuya , Nakanishi Makoto , Defossez Pierre-Antoine , Arita Kyohei 
Published: June 2022

AbstractDNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA recognition helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.
Revealing invisible cell phenotypes with conditional generative modeling
Authors: Lamiable Alexis , Champetier Tiphaine , Leonardi Francesco , Cohen Ethan , Sommer Peter , Hardy David , Argy Nicolas , Massougbodji Achille , Del Nery Elaine , Cottrell Gilles , Kwon Yong-Jun , Genovesio Auguste 
Published: June 2022

AbstractBiological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and observation. Aside from dramatic events such as cell division or cell death, most cell phenotypic changes that keep cells alive are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. While we show that deep learning models can leverage invisible features from microscopy images, to discriminate between close conditions, these features can yet hardly be observed and therefore interpreted. In this work, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases such as high concentration drug treatments, nuclear translocation and golgi apparatus assays. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs or low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to the accessible discovery of biological and disease biomarkers.
Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer
Authors: Kandala Sridhar , von Voithenberg Lena Voith , Chocarro Sara , Ramos Maria , Keding Johanna , Brors Benedikt , Imbusch Charles D. , Sotillo Rocio 
Published: June 2022

AbstractChromosomal instability (CIN), the inability to correctly segregate chromosomes during cell division, is a common characteristic of solid tumors. CIN contributes to tumor evolution by promoting intratumor heterogeneity, thus facilitating resistance to cancer therapies.In vitrostudies have demonstrated that cells with complex karyotypes are recognized and eliminated by natural killer (NK) cells. Paradoxically, it has also been observed that human tumors with high levels of CIN have an immunosuppressive phenotype. It remains unclear which CIN-associated molecular features alter immune recognition during tumor evolution.Previous studies with Polo-like kinase 1 (Plk1) overexpression in Her2-positive breast tumors, resulted in increased levels of CIN and delayed tumorigenesis. Using this mouse model, we show that high CIN tumors activate a senescence-associated secretory phenotype (SASP) and become immune evasive by activating RELB signaling and upregulating PD-L1 in a non-cell-autonomous manner. Single-cell RNA sequencing of immune cells from early-stage induced mammary glands revealed that macrophages, NK cells, B cells and regulatory T cells are programmed to a suppressive phenotype during tumor development. In human tumors, we further establish the importance of RELB/p38 signaling in understanding the interplay between CIN and the immune system, highlighting the need for novel adjuvant therapies in the context of chromosomally unstable tumors.