bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and functional properties of a plant NRAMP related aluminum transporter
Authors: Ramanadane Karthik , Liziczai Márton , Markovic Dragana , Straub Monique S. , Rosalen Gian T. , Udovcic Anto , Dutzler Raimund , Manatschal Cristina 
Published: December 2022

AbstractThe transport of transition metal ions by members of the SLC11/NRAMP family constitutes a ubiquitous mechanism for the uptake of Fe2+and Mn2+across all kingdoms of life. Despite the strong conservation of the family, two of its branches have evolved a distinct substrate preference with one mediating Mg2+uptake in prokaryotes and another the transport of Al3+into plant cells. Our previous work on the SLC11 transporter fromEggerthella lentarevealed the basis for its Mg2+selectivity (Ramanadane et al., 2022). Here we have addressed the structural and functional properties of a putative Al3+transporter fromSetaria italica.We show that the protein transports diverse divalent metal ions and binds the trivalent ions Al3+and Ga3+, which are both presumable substrates. Its cryo-EM structure displays an occluded conformation that is closer to an inward-than an outward-facing state with a binding site that is remodeled to accommodate the increased charge density of its transported substrate.
The lipid transfer proteins Nir2 and Nir3 sustain phosphoinositide signaling and actin dynamics during phagocytosis
Authors: Kaba Mayis , Carreras-Sureda Amado , Nunes-Hasler Paula , Demaurex Nicolas 
Published: December 2022

AbstractChanges in membrane phosphoinositides and local Ca2+elevations at sites of particle capture coordinate the dynamic remodeling of the actin cytoskeleton during phagocytosis. Here, we show that the phosphatidylinositol (PI) transfer proteins PITPNM1 (Nir2) and PITPNM2 (Nir3) maintain PI(4,5)P2 homeostasis at phagocytic cups, thereby promoting actin contractility and the sealing of phagosomes. Nir3 and to a lesser extent Nir2 accumulated in ER cisternae juxtaposed to phagocytic cups when expressed in phagocytic mouse fibroblasts. CRISPR-Cas9 editing of Nir2 and Nir3 genes decreased plasma membrane PI(4,5)P2 levels, store-operated Ca2+entry (SOCE), and receptor-mediated phagocytosis, stalling particle capture at cup stage. Re-expression of either Nir2 or Nir3 restored phagocytosis, but not SOCE, proportionally to the PM PI(4,5)P2 levels. Phagosomes forming in Nir2/3-edited cells had decreased overall PI(4,5)P2 levels but normal periphagosomal Ca2+signals. Nir2/3 editing reduced the density of contractile actin rings at sites of particle capture, causing repetitive low-intensity contractile events indicative of abortive phagosome closure. We conclude that Nir-mediated lipid transfer maintains phosphoinositide homeostasis at phagocytic cups, thereby sustaining the signals that initiate the remodeling of the actin cytoskeleton during phagocytosis.Summary statementChanges in membrane phosphoinositides coordinate actin remodeling during phagocytosis, but whether lipid transport proteins contribute to this process is not known. Here, we show that the phosphatidylinositol transfer proteins Nir2 and Nir3 are recruited to phagocytic cups and drive the formation of contractile actin rings during particle engulfment. Using gene editing and re-expression, we show that Nir2 and Nir3 maintain PI(4,5)P2 signaling competence at phagocytic cups and promote the actin-dependent sealing of phagocytic vacuoles. These observations establish that lipid transport proteins maintain the phosphoinositide signals that drive the remodeling of the actin cytoskeleton during phagocytosis.
Proximate causes and risks of illegal grazing in Serengeti National Park: Perceptions of livestock keepers
Authors: Matungwa Lameck Emmanuel , Kegamba Juma Joseph , Kisingo Alex Wilbard , Masuruli Masuruli Baker 
Published: December 2022

ABSTRACTEnsuring the sustainability of protected areas for biodiversity conservation is a global issue that requires urgent attention for better conservation outcomes. Serengeti National Park (SNP) is a major tourist destination in Tanzania and offers diverse and spectacular wildlife attractions. The park is also a World Heritage Site, and there is no provision for legal grazing within the park. Understanding the proximate causes of illegal grazing of livestock in SNP and the perception of livestock keepers of the risks taken are critical to planning effective and sustainable mitigation strategies. This study used a semi-structured questionnaire to investigate the proximate causes of livestock grazing in the park and the perceptions of livestock keepers about the risks undertaken. We found that insufficient pasturage and water for cattle in the areas of stay, and the large number of cattle competing for common pasturage are perceived by the respondents as the proximate causes of livestock transgression into SNP. In addition to this, the free-range grazing system in Tanzania, the lack of land use plans, and climate change may be the main reasons for the decrease of pastures and the scarcity of water in the respondent’s areas and, therefore, lead to livestock transgression into SNP for supplementary forage and water. Furthermore, the results indicate that regardless of the number of cattle that the livestock keepers own, the majority fear being arrested inside the park by law enforcement patrols (wildlife rangers). However, most of Large Herders and Very Large Herders do not fear dangerous wild animals that might attack them or their livestock because they have different mechanisms of defense. We recommend that the responsible authorities consider revising the existing policy and promote more intensive livestock husbandry that encourages the management of pastures for livestock, emphasizes land use plans, and constructs farm dams and ponds for livestock keepers on the village land to increase retention by catchment and retention of rainy season water.
SARS-CoV-2 RNA and viable virus contamination of hospital emergency department surfaces and association with patient COVID-19 status and aerosol generating procedures
Authors: Roberts Scott C. , Barbell Elliana S. , Barber Doug , Dahlberg Suzanne E. , Heimer Robert , Jubanyik Karen , Parwani Vivek , Pettigrew Melinda M. , Tanner Jason M. , Ulrich Andrew , Wade Martina , Wyllie Anne L. , Yolda-Carr Devyn , Martinello Richard A. , Tanner Windy D. 
Published: December 2022

AbstractBackgroundInfectious aerosols and droplets generated by SARS-CoV-2–positive patient aerosol generating procedures (AGPs), coughing, or exhalation could potentially contaminate surfaces, leading to indirect SARS-CoV-2 spread via fomites. Our objective was to determine SARS-CoV-2 surface contamination frequency in Emergency Department (ED) patient rooms with respect to patient SARS-CoV-2 status and AGP receipt.MethodsSwabs were collected from fixed surfaces or equipment in the rooms of patients under investigation for COVID-19 or known to be SARS-CoV-2-positive. Environmental swabs were tested for SARS-CoV-2 RNA by RT-qPCR; RNA-positive samples were cultured in Vero E6 cells. Room contamination was also evaluated by clinical severity of COVID-19 and time since symptom onset.ResultsIn total, 202 rooms were sampled: 42 SARS-CoV-2–positive AGP patient rooms, 45 non-AGP SARS-CoV-2–positive patient rooms, and 115 SARS-CoV-2–negative AGP patient rooms. SARS-CoV-2 RNA was detected on 36 (3.6%) surfaces from 29 (14.4%) rooms. RNA contamination was detected more frequently in rooms occupied by non-AGP SARS-CoV-2– positive patients than SARS-CoV-2-positive AGP patients (28.9% vs 14.3%, p=0.078). Infectious virus was cultured from one non-AGP SARS-CoV-2-positive patient room. There was no significant difference in room positivity according to COVID-19 severity or time since symptom onset.ConclusionSARS-CoV-2 RNA contamination of ED room surfaces was highest and most frequent in rooms occupied by SARS-CoV-2–positive patients who did not undergo an AGP, which may be attributable to disease stage and viral shedding; however, there was no difference in room contamination according to COVID-19 severity or time since symptom onset.
Calculation and meaning of “excess mortality”: A comparison of Covid- and pre-Covid mortality data in 31 Eurostat countries from 1965 to 2021
Authors: Gill Bernhard , Kehler Theresa , Schneider Michael 
Published: December 2022

0)AbstractDetermining “excess mortality” makes it possible to compare the burden of disasters between countries and over time, and thus also to evaluate the success of mitigation measures. However, the debate on Covid-19 has exposed that calculations of excess mortalities vary considerably depending on the method and its specification. Moreover, it is often unclear what exactly is meant by “excess mortality”. We define excess mortality as the excess over the number of deaths that would have been expected counter-factually, i.e. without the catastrophic event in question. That is, we include all normally occurring flu and heat waves, which are excluded by some authors with the consequence that they almost always record low expected values and correspondingly high excess mortality rates. Based on this definition, we use a very parsimonious calculation method that is easy to understand even for laypersons, namely the linear extrapolation of death figures from previous years to determine the excess mortality during the Covid-19 pandemic. But unlike other literature on this topic, we first evaluated and optimised the specification of our method using a larger historical data set in order to identify and minimise estimation errors and biases. The result shows that the excess mortality rates continuously published by international statistical offices – OECD and Eurostat – are often inflated and would have exhibited considerable excess mortalities in many countries and periods before Covid-19, if this value had already been of public interest at that time. It also reveals that mortality rates already fluctuated strongly in the past and that in a third of the countries studied, individual values from the past exceed the current fluctuations due to the Covid-19 pandemic. Three conclusions can be drawn from this study and its findings: 1) All calculation methods for current figures should first be evaluated against past figures. 2) The definition of excess mortality used should be made explicit. 3) Statistical offices should provide more realistic estimates.
Perils of the nighttime: impact of behavioral timing and preference on mental and physical health in 73,888 community-dwelling adults
Authors: Lok Renske , Weed Lara , Winer Joseph , Zeitzer Jamie M. 
Published: December 2022

AbstractImportanceHuman mental and physical health is influenced by both the inclination to sleep at specific times (chronotype) as well as the actual sleep timing (behavior). How the alignment between these impacts mental and physical health has not been well described.ObjectiveThe goal of this study is to examine the impact of chronotype, actual timing of behavior, and the alignment between the two on a variety of mental and physical health outcomes.DesignA cohort analysis of the UK Biobank (2006 to Current).SettingOutpatient.ParticipantsCommunity-dwelling adults (n=73,888).ExposureAd libitumbehavior for one week.Main Outcome(s) and Measure(s)Sleep time preference (chronotype), one week of wrist-worn accelerometry (actigraphy), and demographic variables were collected. Actigraphy was analyzed using non-parametric methods to determine the actual timing of behavior. Prevalence and likelihood (odds-ratios) of developing mental health disorders (mental, behavioral, and neurodevelopmental disorders, generalized anxiety disorder, depression) and physical health disorders (including metabolic disorder, diabetes, obesity, hypertension, circulatory disorder, digestive disorder, respiratory disorder, and all-cause cancer) were calculated and corrected for common demographic variables (sex, age, body mass index, material deprivation, sleep duration).ResultsOur final sample was 56% female, 63.5 [56.3 - 68.6] years in age, with a Body Mass Index of 26.0 [23.6 - 29.0], Townsend Deprivation Indices of −2.45 [−3.82 - −0.17], and self-reported sleep duration of 7 [6 - 8] hours. As compared to morning-types with early behavior (aligned), morning-types with late behavior (misaligned) had an increased risk of both mental (OR=1.52±0.06, p<0.001) and physical (OR=1.45±0.03, p<0.001) health disorders. As compared to evening-types with late behavior (aligned), however, evening-types with early behavior (misaligned) had a decreased risk of both mental (OR=0.85±0.06, p=0.002) and physical (OR=0.66±0.03, p<0.001) disorders.Conclusion/RelevanceDespite potential misalignment between sleep and circadian rhythms, going to sleep late is associated with worse mental and physical health in both morning- and evening-types.
Evidence suggesting creatine as a new central neurotransmitter: presence in synaptic vesicles, release upon stimulation, effects on cortical neurons and uptake into synaptosomes and synaptic vesicles
Authors: Bian Xiling , Zhu Jiemin , Jia Xiaobo , Liang Wenjun , Yu Sihan , Li Zhiqiang , Zhang Wenxia , Rao Yi 
Published: December 2022

AbstractThe discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
Rational design of chemically controlled antibodies and protein therapeutics
Authors: Marchand Anthony , Bonati Lucia , Shui Sailan , Scheller Leo , Gainza Pablo , Rosset Stéphane , Georgeon Sandrine , Tang Li , Correia Bruno E. 
Published: December 2022

ABSTRACTProtein-based therapeutics such as monoclonal antibodies and cytokines are important therapies in various pathophysiological conditions such as oncology, auto-immune disorders, and viral infections. However, the wide application of such protein therapeutics is often hindered by dose-limiting toxicities and adverse effects, namely cytokine storm syndrome, organ failure and others. Therefore, spatiotemporal control of the activities of these proteins is crucial to further expand their application. Here, we report the design and application of small molecule-controlled switchable protein therapeutics by taking advantage of a previously engineered OFF-switch system. We used Rosetta modeling suite to computationally optimize the affinity between B-cell lymphoma 2 (Bcl-2) protein and a previously developed computationally designed protein partner (LD3) to obtain a fast and efficient heterodimer disruption upon addition of a competing drug (Venetoclax). The incorporation of the engineered OFF-switch system intoαCTLA4, anti-HER2 antibodies or an Fc-fused IL-15 cytokine demonstrated an efficient disruption in vitro, as well as fast clearance in vivo upon addition of the competing drug Venetoclax. These results provide a proof-of-concept for the rational design of controllable biologics by introducing a drug-induced OFF-switch into existing protein-based therapeutics.
Genetic characterization of the zoonotic parasiteAncylostoma caninumin the central and eastern USA
Authors: Quintana Theresa A. , Johnson William L. , Ritchie Deb , Smith Vicki , Martin Katy A. , McMahan Krysta , Brewer Matthew T. , Jesudoss Chelladurai Jeba R. J. 
Published: December 2022

AbstractAncylostoma caninumis the most common nematode parasite of dogs in the United States. This study aimed to describe the molecular epidemiology ofA. caninumisolates from the central and eastern states of the U.S. using the partial mitochondrialcox1gene and to compare them with those reported globally. We isolated eggs from fecal samples of dogs and characterized each isolate based oncox1sequences. A total of 60 samples originating from Kansas, Iowa, New York, Florida, and Massachusetts were included. 25 haplotypes were identified in the U.S. dataset with high haplotype diversity (0.904). Sequence data were compared to sequences from other world regions available in GenBank. Global haplotype analysis demonstrated 35 haplotypes with a haplotype diversity of 0.931. Phylogenetic and network analysis provide evidence for the existence of moderate geographical structuring of A.caninumhaplotypes. Our results provide an updated summary of A.caninumhaplotypes and data for neutral genetic markers with utility for tracking hookworm populations. Sequences have been deposited in GenBank (ON980650-ON980674). Further studies of isolates from other regions are essential to understand the genetic diversity of this parasite.
Targeting Spike Glycans to Inhibit SARS-CoV2 Viral Entry
Authors: Guseman Alex J. , Rennick Linda J. , Nambulli Sham , Roy Chandra N. , Martinez David R. , Yang Darian T. , Bhinderwhala Fatema , Vergara Sandra , Baric Ralph S. , Ambrose Zandrea , Duprex W. Paul , Gronenborn Angela M. 
Published: December 2022

AbstractSARS-CoV-2 Spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the Spike protein.Burkholderia oklahomensisagglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the Spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical tools, we demonstrate that the interaction is avidity driven and that BOA crosslinks the Spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that glycan-targeting molecules have the potential to be pan-coronavirus inhibitors.
Lower childhood subjective social status is associated with greater neural responses to ambient auditory deviance
Authors: Hao Yu , Hu Lingyan 
Published: December 2022

AbstractHumans’ early life experience varies by socioeconomic status, raising the question of how this difference is reflected in the adult brain. An important aspect of brain function is the ability to detect salient ambient changes while focusing on a task. Here we ask whether perceived childhood social standing is reflected by the way young adults’ brain signals correlate with detecting changes in irrelevant information. In two studies (total N = 58), we examine electrical brain responses in the frontocentral region to a series of auditory tones, consisting of “standard” stimuli (80%) and “deviant” stimuli (20%) interspersed randomly, while participants were engaged in various visual tasks. Both studies showed stronger automatic change detection indexed by mismatch negativity (MMN) in lower-SES individuals, regardless of the sound’s features, emotional content, or study type. Moreover, we observed a larger MMN in lower-SES participants, even though they did not show differences in brain and behavior responses to the attended task and did not involuntarily orient more attention to deviance, as indexed by the P3a. The study indicates that individuals with lower subjective social status may have an increased ability to automatically detect changes in their environment, which may suggest their adaptation to their childhood environments.
Distinct chromatin scanning modes lead to targeting of compacted chromatin by pioneer factors FOXA1 and SOX2
Authors: Lerner Jonathan , Katznelson Andrew , Zhang Jingchao , Zaret Kenneth S. 
Published: December 2022

SUMMARYPioneer transcription factors, by interacting with nucleosomes, can scan silent, compact chromatin to target gene regulatory sequences, enabling cooperative binding events that modulate local chromatin structure and gene activity. However, pioneer factors do not target all of their cognate motifs and it is unclear whether different pioneers scan compact chromatin the same way. Surprisingly, combined approaches of genomics and single-molecule tracking show that to target DNase-resistant, low-histone turnover sites, pioneer factors can use opposite dynamics of chromatin scanning. FOXA1 uses low nucleoplasmic diffusion and stable chromatin interactions, whereas SOX2 uses high nucleoplasmic diffusion and transient interactions, respectively. Despite such differences, FOXA1 and SOX2 scan low-mobility, silent chromatin to similar extents, as mediated by protein domains outside of the respective DNA binding domains. By contrast, the non-pioneer HNF4A predominantly targets DNase-sensitive, nucleosome-depleted regions. We conclude that the targeting of compact chromatin sites by pioneer factors can be through distinct dynamic processes.