bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance
Authors: Yamada Saeko , Nagafuchi Yasuo , Wang Min , Ota Mineto , Hatano Hiroaki , Takeshima Yusuke , Okubo Mai , Kobayashi Satomi , Sugimori Yusuke , Nakano Masahiro , Yoshida Ryochi , Hanata Norio , Suwa Yuichi , Tsuchida Yumi , Iwasaki Yukiko , Sumitomo Shuji , Kubo Kanae , Shimane Kenichi , Setoguchi Keigo , Azuma Takanori , Kanda Hiroko , Shoda Hirofumi , Zhang Xuan , Yamamoto Kazuhiko , Ishigaki Kazuyoshi , Okamura Tomohisa , Fujio Keishi
Published: December 2022

Objectives

Little is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that predict treatment resistance.

Methods

We isolated 18 peripheral blood immune cell subsets of 55 pre-treatment RA patients and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterized. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative polymerase chain reaction (qPCR) and mass cytometric analysis cohorts. We also characterized the identified population by synovial single cell RNA-seq analysis.

Results

Immune cells of RA patients were characterized by enhanced interferon and IL6-JAK-STAT3 signaling that demonstrate partial normalization after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of pre-dendritic cells (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signaling was negatively correlated to pre-DC gene expression. qPCR and mass cytometric analysis in independent cohorts validated that the pre-DC associated gene expression and the proportion of pre-DC were significantly higher before treatment in treatment-resistant patients. A cluster of synovial DCs showed both features of pre-DC and proinflammatory conventional DC2s.

Conclusions

An increase in pre-DC in peripheral blood predicted RA treatment resistance. Pre-DC could have pathophysiological relevance to RA treatment response.

Key messages

What is already known about this subject?

Limited information is available about the immune cells that are associated with RA treatment resistance.

What does this study add?

RA treatment resistance can be predicted by an increase in pre-DC in peripheral blood prior to treatment.

The expression of genes reflecting an increase in pre-DC is negatively correlated to the type I interferon signature, which is associated with good therapeutic response.

Synovial pre-DC-like cells are proinflammatory cDC2s.

How might this impact on clinical practice or future developments?

Stratified treatment of RA is possible using pre-DC as a biomarker, and it might be possible to develop new therapies for treatment-resistant RA by targeting pre-DC.
Unbiased single cell spatial analysis localises inflammatory clusters of immature neutrophils-CD8 T cells to alveolar progenitor cells in fatal COVID-19 lungs
Authors:   COSMIC – COVID-19 Lung Single Cell Mass Cytometry Imaging Consortium STUDY, Weeratunga Praveen , Denney Laura , Bull Joshua A. , Repapi Emmanouela , Sergeant Martin , Etherington Rachel , Vuppussetty Chaitanya , Turner Gareth D.H. , Clelland Colin , Cross Amy , Issa Fadi , de Andrea Carlos Eduardo , Bermejo Ignacio Melero , Sims David , McGowan Simon , Zurke Yasemin-Xiomara , Ahern David J. , Gamez Eddie C , Whalley Justin , Richards Duncan , Klenerman Paul , Monaco Claudia , Udalova Irina A. , Dong Tao , Ogg Graham , Knight Julian C. , Byrne Helen M. , Taylor Stephen , Ho Ling-Pei
Published: December 2022

Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we developed a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method revealed a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and cytotoxic CD8 T cells, was found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings provide new insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.

Graphical abstract
Development and validation of the Behavioral Health Acuity Risk model: a predictive model for suicide prevention through clinical interventions
Authors: Digumarthi Varun , Strange Heather E , Norman Heather B , Ayers Derek , Patel Raj , Hegarty Karen E
Published: December 2022

Common suicidal ideation screening tools used in healthcare settings rely on the willingness of the patient to express having suicidal thoughts. We present an automatic and data-driven risk model that examines information available in the medical record captured during the normal course of care. This model uses random forests to assess the likelihood of suicidal behavior in patients aged seven or older presenting at any healthcare setting. The Behavioral Health Acuity Risk (BHAR) model achieves an area under the receiver operating curve (AUC) of 0.84 and may be used on its own or as a component of a comprehensive suicidal behavior risk assessment.
Genome-wide association study of obstructive sleep apnea in the Million Veteran Program uncovers genetic heterogeneity by sex
Authors: Sofer Tamar , Kurniansyah Nuzulul , Murray Michael , Ho Yuk-Lam , Huffman Jennifer E. , Cho Kelly , Wilson Peter W.F. , Gottlieb Daniel J
Published: December 2022

Background

Genome-wide association studies (GWAS) for obstructive sleep apnea (OSA) are limited due to the underdiagnosis of OSA, leading to misclassification of OSA, which consequently reduces statistical power. We performed a GWAS of OSA in the Million Veteran Program (MVP) of the U.S. Department of Veterans Affairs (VA) healthcare system, where OSA prevalence is close to its true population prevalence.

Methods

We performed GWAS of 568,576 MVP participants, stratified by biological sex and by harmonized race/ethnicity and genetic ancestry (HARE) groups of White, Black, Hispanic, and Asian individuals. We considered both BMI adjusted (BMI-adj) and unadjusted (BMI-unadj) models. We replicated associations in independent datasets, and analyzed the heterogeneity of OSA genetic associations across HARE and sex groups. We finally performed a larger meta-analysis GWAS of MVP, FinnGen, and the MGB Biobank, totaling 916,696 individuals.

Findings

MVP participants are 91% male. OSA prevalence is 21%. In MVP there were 18 and 6 genome-wide significant loci in BMI-unadj and BMI-adj analyses, respectively, corresponding to 21 association regions. Of these, 17 were not previously reported in association with OSA, and 13 replicated in FinnGen (False Discovery Rate p-value<0.05). There were widespread significant differences in genetic effects between men and women, but less so across HARE groups. Meta-analysis of MVP, FinnGen, and MGB biobank revealed 17 additional, novel, genome-wide significant regions.

Interpretation

Sex differences in genetic associations with OSA are widespread, likely associated with multiple OSA risk factors. OSA shares genetic underpinnings with several sleep phenotypes, suggesting shared etiology and causal pathways.

Funding

Described in acknowledgements.
Fingerprint: An AI-based method for detection of mislabeled CT studies in clinical trials
Authors: Edenbrandt Lars , Enqvist Olof , Gillberg Tony
Published: December 2022

The manual step of replacing the identification number of each subject in clinical trials with the correct trial identification number is critical. Mislabeling studies may lead to excluding subjects or visits or to false study results. This article presents an automated AI-based method to detect if a pair of de-identified CT studies has been obtained from the same subject.

Approach

An automated segmentation of bones in CT is performed using Organ Finder (SliceVault AB, Malmö, Sweden). Corresponding bones from the two images are aligned using Iterative closest point. The percentage of vertices in the smaller mesh with residuals below 1.5 mm is used as a measure of similarity, theanatomical match. If the anatomical match is less than 80% for the left and right hip bone and the left and right scapula, the two CT studies are classified as being obtained from different subjects. The Fingerprint method was tested on a group of 58 patients, who each had two CT studies obtained at different occasions. From the 116 CT studies 6,612 unique pairs of CT from different patients and 58 pairs from the same patient could be selected.

Results

The Fingerprint method classified all 6,612 pairs of CT studies from different patients correctly (sensitivity 100%; 95% confidence interval 99-100%) and all 58 pairs of CT studies from the same patients correctly (specificity 100%; 95% confidence interval 94-100%).

Conclusion

This study shows how an AI-based method can be used to accurately detect if a pair of de-identified CT studies has been obtained from two different subjects.
Structure and regulation of full-length human leucine-rich repeat kinase 1
Authors: Metcalfe R.D. , Fiesco J.A. Martinez , Zhang P.
Published: December 2022

The two human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases which serve to regulate fundamental cellular processes, with both implicated in human disease. Despite recent experimentally determined structures of LRRK2, the structure and exact molecular mechanisms regulating the activity of the LRRK1, and differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer, and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces which serve to control kinase activity, which are further validated experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2, implying functional differences in both proteins. Overall, our results provide new structural insights into the activation of the human LRRKs for understanding the physiology and pathology of these proteins.
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

The 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

Changes 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 statement

Changes 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

Ensuring 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

Background

Infectious 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.

Methods

Swabs 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.

Results

In 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.

Conclusion

SARS-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)

Determining “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

Importance

Human 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.

Objective

The 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.

Design

A cohort analysis of the UK Biobank (2006 to Current).

Setting

Outpatient.

Participants

Community-dwelling adults (n=73,888).

Exposure

Ad 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).

Results

Our 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/Relevance

Despite 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

The 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

Protein-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

Ancylostoma 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

SARS-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

Humans’ 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

Pioneer 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.
Combining mutation and recombination statistics to infer clonal families in antibody repertoires
Authors: Spisak Natanael , Dupic Thomas , Mora Thierry , Walczak Aleksandra M.
Published: December 2022

B-cell repertoires are characterized by a diverse set of receptors of distinct specificities generated through two processes of somatic diversification: V(D)J recombination and somatic hypermutations. B cell clonal families stem from the same V(D)J recombination event, but differ in their hypermutations. Clonal families identification is key to understanding B-cell repertoire function, evolution and dynamics. We present HILARy (High-precision Inference of Lineages in Antibody Repertoires), an efficient, fast and precise method to identify clonal families from high-throughput sequencing datasets. HILARy combines probabilistic models that capture the receptor generation and selection statistics with adapted clustering methods to achieve consistently high inference accuracy. It automatically leverages the phylogenetic signal of shared mutations in difficult repertoire subsets. Exploiting the high sensitivity of the method, we find the statistics of evolutionary properties such as the site frequency spectrum anddN/dSratio do not depend on the junction length. We also identify a broad range of selection pressures scanning two orders of magnitude.
Discovering individual-specific gait signatures from data-driven models of neuromechanical dynamics
Authors: Winner Taniel S. , Rosenberg Michael C. , Jain Kanishk , Kesar Trisha M. , Ting Lena H. , Berman Gordon J.
Published: December 2022

Locomotion results from the interactions of highly nonlinear neural and biomechanical dynamics. Accordingly, understanding gait dynamics across behavioral conditions and individuals based on detailed modeling of the underlying neuromechanical system has proven difficult. Here, we develop a data-driven and generative modeling approach that recapitulates the dynamical features of gait behaviors to enable more holistic and interpretable characterizations and comparisons of gait dynamics. Specifically, gait dynamics of multiple individuals are predicted by a dynamical model that defines a common, low-dimensional, latent space to compare group and individual differences. We find that highly individualized dynamics – i.e., gait signatures – for healthy older adults and stroke survivors during treadmill walking are conserved across gait speed. Gait signatures further reveal individual differences in gait dynamics, even in individuals with similar functional deficits. Moreover, components of gait signatures can be biomechanically interpreted and manipulated to reveal their relationships to observed spatiotemporal joint coordination patterns. Lastly, the gait dynamics model can predict the time evolution of joint coordination based on an initial static posture. Our gait signatures framework thus provides a generalizable, holistic method for characterizing and predicting cyclic, dynamical motor behavior that may generalize across species, pathologies, and gait perturbations.

Author Summary

In this manuscript, we introduce a novel, machine learning-based framework for quantifying, characterizing, and modifying the underlying neuromechanical dynamics that drive unique gait patterns. Standard methods for evaluating movement typically focus on extracting discrete gait variables ignoring the complex inter-limb and inter-joint spatiotemporal dependencies that occur during gait. Popular physiologically realistic modeling approaches encode these spatiotemporal dependencies but are too complex to characterize individual differences in the factors driving unique gait patterns or disorders. To circumvent these modeling complications, we develop a phenomenological model of gait that enables more holistic and interpretable characterizations of gait, encoding these complex spatiotemporal dependencies between humans’ joint angles arising from joint neural and biomechanical constraints. Our coined ‘gait signature’ framework provides a path towards understanding the neuromechanics of locomotion. This framework has potential utility for clinical researchers prescribing individualized therapies for pathologies or biomechanists interested in animal locomotion or other periodic movements assessed across different pathologies, neural perturbations, and or conditions.
Identification and Elimination of Antifungal Tolerance inCandida auris
Authors: Koohi Samira Rasouli , Shankarnarayan Shamanth A. , Galon Clare Maristela , Charlebois Daniel A.
Published: December 2022

Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogenC. aurisis of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure inC. aurishas been recently attributed to antifungal “tolerance”. Tolerance is a phenomenon whereby a slow growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays together with image analysis to investigate antifungal tolerance inC. auristo all three classes of antifungal drugs used to treat invasive candidiasis. We find that 1)C. aurisis tolerant to several common fungistatic and fungicidal drugs, which in some cases can be visually detected after 24 hours, as well as after 48 hours, of antifungal drug exposure; 2) the tolerant phenotype reverts to the susceptible phenotype inC. auris; and 3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine reduces or eliminates tolerance and resistance in patient-derivedC. aurisisolates. These results suggest that tolerance contributes to treatment failure inC. aurisinfections for a broad range of antifungal drugs and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.
History-dependent muscle resistance to stretch remains high after small, posturally-relevant pre-movements
Authors: Horslen Brian C. , Milburn Gregory N. , Blum Kyle P. , Simha Surabhi N. , Campbell Kenneth S. , Ting Lena H.
Published: December 2022

The contributions of intrinsic muscle fiber resistance during mechanical perturbations to standing and other postural behaviors are unclear. Muscle stiffness, a traditional metric for estimating muscle’s intrinsic resistance to stretch, is known to vary depending on the current level and history of the muscle’s activation, as well as the muscle’s recent movement history; this property has been referred to as history dependence or muscle thixotropy. However, we currently lack sufficient data about the degree to which muscle stiffness is modulated across posturally-relevant characteristics of muscle stretch and activation. Here, we characterized the history dependence of muscle’s resistance to stretch in single, permeabilized, activated, muscle fibers in posturally-relevant stretch conditions and activation levels. We used a classic paired muscle stretch paradigm, varying the amplitude of a “conditioning” triangular stretch-shorten cycle followed by a “test” ramp-and-hold imposed after a variable inter-stretch interval. We tested low (<15%), intermediate (15-50%) and high (>50%) muscle fiber activation levels, evaluating short-range stiffness and total impulse in the test stretch. Muscle fiber resistance to stretch remained high at conditioning amplitudes of <1% L0 and inter-stretch intervals of >1 s, characteristic of healthy standing postural sway. A ~70% attenuation of muscle resistance to stretch was reached at conditioning amplitudes of >3% L0 and inter-stretch intervals of <0.1s, characteristic of larger, faster postural sway in balance-impaired individuals. Overall, amplitude and inter-stretch interval interact to disrupt myofilaments such that intrinsic resistance to stretch is attenuated if the stretch is large enough and/or frequent enough.

Summary Statement

Intrinsic muscle fiber resistance to stretch is preserved after small, slow pre-movements based on healthy postural sway, but markedly reduced as pre-movements increase to emulate abnormal postural sway.
LSD use in the United States: Examining user demographics and their evolution from 2015-2019
Authors: Weleff Jeremy , Anand Akhil , Dewey Elizabeth N. , Barnett Brian S.
Published: December 2022

Background

Lysergic acid (LSD) use has risen in the United States (US) in recent years amid increased interest in therapeutic applications of psychedelics. Despite this, contemporary epidemiological investigations of LSD users are few. To expand the literature on this topic, we sought to characterize past-year LSD users in the US and investigate recent demographic evolution within this population.

Methods

Using National Survey on Drug Use and Health (NSDUH) data from 2015-2019, we investigated correlates of past-year LSD use and associated changes over the study period.

Results

Past-year LSD use increased by 47% from 2015 to 2019 (0.59% to 0.87%). However, among people reporting past-year hallucinogen use disorder there was no significant proportional increase in LSD users. Notable correlates of LSD use on multivariable analysis were: increased LSD access, lower perceived risk of trying LSD, Asian race, low income, fewer children in the home, history of ever selling drugs, being approached by someone selling drugs in the past month, lack of influence of religious beliefs on decision-making, and past-year suicide attempt among people age 18 and older. We found no associations with unemployment, arrest history, past-year psychological distress, or sexually transmitted infections. From 2015 to 2019, the proportion of respondents reporting past-year LSD use who were pregnant, age 26-34, and married increased. Past-year LSD use among lifetime users of methamphetamine also rose.

Conclusions

Though still uncommonly used in the US, LSD’s societal acceptance may be increasing. Overall, LSD does not appear to contribute significantly to the country’s public health problems.

Highlights:

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For the last few years, NSDUH data has shown an increase in LSD use

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Despite this, rates of reported hallucinogen use disorder have not proportionally increased

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Evidence shows increasing societal acceptance for LSD use

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The proportion of respondents reporting past-year LSD use who were pregnant, age 26-34, and married increased

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Past-year LSD use among lifetime users of methamphetamine also rose
Dopaminergic Medication Accentuates Fecal Gut Microbiome Changes in Parkinson’s Disease
Authors: Boertien Jeffrey M , Pereira Pedro AB , Laine Pia , Paulin Lars , van der Zee Sygrid , Auvinen Petri , Scheperjans Filip , van Laar Teus
Published: December 2022

Fecal gut microbiota changes are associated with Parkinson’s disease (PD). However, disease related changes cannot readily be discerned from medication effects, as almost all participants in previous studies were using PD medication, and conclusive longitudinal data related to treatment initiation is lacking. Here, fecal gut microbiota composition was assessed in 62de novoPD participants who were untreated at baseline and used PD medication at one-year follow-up, by means of 16S-sequencing. In addition, participants were stratified for the type of dopaminergic medication.

Overall gut microbiota composition did not differ between baseline and one-year follow-up, but was associated with levodopa dose and levodopa equivalent daily dose (LEDD). Several differentially abundant taxa are in line with previously described changes in PD. These included reduced levels of amplicon sequence variants (ASVs) belonging toFaecalibacterium prausnitziiand Lachnospiraceae in all participants at follow-up, and increased levels of an ASV belonging toBifidobacteriumin dopamine agonist users. The family Bifidobacteriaceae was increased in dopamine agonist users who only used pramipexole. Levodopa dose was inversely related to the abundance of the families Ruminococcaceae and Lachnospiraceae, and the genusLachnospiraceae ND3007 group. PD medications exert a measurable and dose-dependent effect on gut microbiota composition and accentuate several previously described gut microbiota changes in PD. Detailed knowledge of medication effects should be part of future trial designs of gut microbiome studies in PD and are necessary to interpret previously published data.
Bird song comparison using deep learning trained from avian perceptual judgments
Authors: Zandberg Lies , Morfi Veronica , George Julia , Clayton David F. , Stowell Dan , Lachlan Robert F.
Published: December 2022

Our understanding of bird song, a model system for animal communication and the neurobiology of learning, depends critically on making reliable, validated comparisons between the complex multidimensional syllables that are used in songs. However, most assessments of song similarity are based on human inspection of spectrograms, or computational methods developed from human intuitions. Using a novel automated operant conditioning system, we collected a large corpus of zebra finches’ (Taeniopygia guttata) decisions about song syllable similarity. We use this dataset to compare and externally validate similarity algorithms in widely-used publicly available software (Raven, Sound Analysis Pro, Luscinia). Although these methods all perform better than chance, they do not closely emulate the avian assessments. We then introduce a novel deep learning method that can produce perceptual similarity judgements trained on such avian decisions. We find that this new method outperforms the established methods in accuracy and more closely approaches the avian assessments. Inconsistent (hence ambiguous) decisions are a common occurrence in animal behavioural data; we show that a modification of the deep learning training that accommodates these leads to the strongest performance. We argue this approach is the best way to validate methods to compare song similarity, that our dataset can be used to validate novel methods, and that the general approach can easily be extended to other species.