bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Analysis of Right Ventricular Metabolic Reprogramming in Pre-clinical Rat Models of Severe Pulmonary Hypertension-induced Right Ventricular Failure
Authors: Banerjee Somanshu , Hong Jason , Umar Soban
Published: March 2022

Background

Pulmonary hypertension (PH) leads to right ventricular (RV) hypertrophy and failure (RVF). The precise mechanisms of the metabolic basis of maladaptive PH-induced RVF (PH-RVF) are yet to be fully elucidated. Here we performed a comparative analysis of RV-metabolic reprogramming in MCT and Su/Hx rat models of severe PH-RVF using targeted metabolomics and multi-omics.

Methods

Male Sprague Dawley rats (250-300gm; n=15) were used. Rats received subcutaneous monocrotaline (60mg/kg; MCT; n=5) and followed for ∼30-days or Sugen (20mg/kg; Su/Hx; n=5) followed by hypoxia (10%O2; 3-weeks) and normoxia (2-weeks). Controls received saline (Control; n=5). Serial echocardiography was performed to assess cardiopulmonary hemodynamics. Terminal RV-catheterization was performed to assess PH. Targeted metabolomics was performed on RV tissue using UPLC-MS. RV multi-omics analysis was performed integrating metabolomic and transcriptomic datasets using Joint Pathway Analysis (JPA).

Results

MCT and Su/Hx rats developed severe PH, RV-hypertrophy and decompensated RVF. Targeted metabolomics of RV of MCT and Su/Hx rats detected 126 and 125 metabolites respectively. There were 28 and 24 metabolites significantly altered in RV of MCT and Su/Hx rats, respectively, including 11 common metabolites. Common significantly upregulated metabolites included aspartate and GSH, whereas downregulated metabolites included phosphate,α-ketoglutarate, inositol, glutamine, 5-Oxoproline, hexose phosphate, creatine, pantothenic acid and acetylcarnitine. JPA highlighted common genes and metabolites from key pathways such as glycolysis, fatty acid metabolism, oxidative phosphorylation, TCA cycle etc.

Conclusions

Comparative analysis of metabolic reprogramming of RV from MCT and Su/Hx rats reveals common and distinct metabolic signatures which may serve as RV-specific novel therapeutic targets for PH-RVF.
Seqrutinator: Non-Functional Homologue Sequence Scrutiny for the Generation of large Datatsets for Protein Superfamily Analysis
Authors: Amalfitano Agustín , Stocchi Nicolás , Atencio Hugo Marcelo , Villarreal Fernando , ten Have Arjen
Published: March 2022

Background

In recent years protein bioinformatics has resulted in many good algorithms for multiple sequence alignment (MSA) and phylogeny. Little attention has been paid to sequence selection whereas notably recently published complete proteomes often have many sequences that are partial or derive from pseudogenes. Not only do these sequences add noise to the MSA, phylogeny and other downstream computational analyses, they also instigate many errors in the processing of the MSAs and downstream analyses, including the phylogeny.

Objective

This work aims to provide and test an objective, automated but flexible pipeline for the scrutiny of sequence sets from large, complex, eukaryotic protein superfamilies. The pipeline should classify sequences with high precision and recall as either functional or non-functional. The pipeline should classify no or only a few SwissProt sequences as non-functional (high precision) and sequences from other related superfamilies as non-functional (high recall) and result in a demonstrably much improved MSA (high performance).

Results

Seqrutinator is a pipeline that consists of five modules written in Python3 that identify and remove sequences that are likely Non-Functional Homologues (NFH). Here we tested the pipeline using three complex plant superfamilies (BAHD, CYP and UGT) that act in specialized metabolism, using the complete proteomes of 16 plant species as input and SwissProt as a control. Only 1.94% of SwissProt sequences with wetlab evidence were identified as NFH and all sequences from other related superfamilies were removed. Most NFH sequences are partial but, interestingly, their removal results in highly improved MSAs. a few but significant sequences that instigate large gaps were found. The five modules show similar behaviour when applied to the 16 sequence sets of the three analysed superfamilies. Pipelines with different module orders result in similar classifications and, moreover, show that different modules often detect the same sequences.

Conclusion and perspective

Seqrutinator forms a consistent pipeline for sequence scrutiny that does result in sequence sets that generate high fidelity MSAs. Recovery analyses show the method has high precision and recall.
The DNA-based global positioning system—a theoretical framework for large-scale spatial genomics
Authors: Greenstreet Laura , Afanassiev Anton , Kijima Yusuke , Heitz Matthieu , Ishiguro Soh , King Samuel , Yachie Nozomu , Schiebinger Geoffrey
Published: March 2022

We present GPS-seq, a theoretical framework that enables massively scalable, optics-free spatial transcriptomics. GPS-seq combines data from high-throughput sequencing with manifold learning to obtain the spatial transcriptomic landscape of a given tissue section without optical microscopy. In this framework, similar to technologies like Slide-seq and 10X Visium, tissue samples are stamped on a surface of randomly-distributed DNA-barcoded spots (or beads). The transcriptomic sequences of proximal cells are fused to DNA barcodes, enabling the recovery of a transcriptomic pixel image by high-throughput sequencing. The barcode spots serve as “anchors” which also capture spatially diffused “satellite” barcodes, and therefore allow computational reconstruction of spot positions without optical sequencing or depositing barcodes to pre-specified positions. In theory, it could generate 100 mm × 100 mm spatial transcriptomic images with 10-20 μm resolution by localizing 108 DNA-barcoded pixels with a single Illumina NovaSeq run. The general framework of GPS-seq is also compatible with standard single-cell (or single-nucleus) capture methods, and any modality of single-cell genomics, such as sci-ATAC-seq, could be transformed into spatial genomics in this strategy. We envision that GPS-seq will lead to breakthrough discoveries in diverse areas of biology by enabling organ-scale imaging of multiple genomic statuses at single-cell resolution for the first time.
Particle-Swarm Based Modelling Reveals Two Distinct Classes of CRHPVNNeurons
Authors: Lameu Ewandson L. , Rasiah Neilen P. , Baimoukhametova Dinara V. , Loewen Spencer , Bains Jaideep S. , Nicola Wilten
Published: March 2022

Electrophysiological recordings can provide detailed information of single neurons’ dynamical features and shed light into their response to stimuli. Unfortunately, rapidly modeling electrophysiological data for inferring network-level behaviours remains challenging. Here, we investigate how modeled single neuron dynamics lead to network-level responses in the paraventricular nucleus of the hypothalamus (PVN), a critical nucleus for the mammalian stress response. Recordings of corticotropinreleasing hormone neurons from the PVN (CRHPVN) were performed using whole-cell current-clamp. These, neurons, which initiate the endocrine response to stress, were rapidly and automatically fit to a modified Adaptive Exponential Integrate and Fire model (AdEx) with Particle Swarm Optimization (PSO). All CRHPVNneurons were accurately fit by the AdEx model with PSO. Multiple sets of parameters were found that reliably reproduced current-clamp traces for any single neuron. Despite multiple solutions, the dynamical features of the models such as the rheobase current levels, fixed points, and bifurcations, were shown to be stable across fits. We found that CRHPVNneurons can be divided into two sub-types according to their bifurcation at the onset of firing: saddles (integrators) and sub-critical Hopf (resonators). We constructed networks of these fit CRHPVNmodel neurons to investigate the network level responses of CRHPVNneurons. We found that CRHPVN-resonators maintain baseline firing in networks even when all inputs are inhibitory. The dynamics of a small subset of CRHPVNneurons may be critical to maintaining a baseline firing tone in the PVN.

Key Points

Corticotropin-releasing hormone neurons (CRHPVN) in the paraventricular nucleus of the hypothalamus act as the final neural controllers of the stress response.

We developed a rapid computational modeling platform that uses Particle-Swarm Optimization to rapidly and accurately fit biophysical neuron models.

A model was fit to each patched neuron without the use of dynamic clamping, or other procedures requiring sophisticated inputs and fitting procedures. Any neuron undergoing standard current clamping for a few minutes can be fit by this procedure

The dynamical analysis of the modeled neurons shows thatCRHPVNcomes in two specific ‘flavours’: CRHPVN-resonators and CRHPVN-integrators.

Network simulations show thatCRHPVN-resonators are critical to retaining the baseline firing rate of the entire network of CRHPVNneurons as these cells can fire rebound spikes and bursts in the presence of strong inhibitory synaptic input.
The Rise and Fall of Slow Wave Tides: Vacillations of Slow Wave/Spindle Coupling Shift the Composition of Slow Wave Activity Through Sleep Cycles in Accordance with Depth of Sleep
Authors: McConnell Brice V. , Kronberg Eugene , Medenblik Lindsey M. , Kheyfets Vitaly O. , Ramos Alberto R. , Sillau Stefan H. , Pulver Rachelle L. , Bettcher Brianne M.
Published: March 2022

Slow wave activity (SWA) during sleep is associated with synaptic regulation and memory processing functions. Each cycle of non-rapid-eye-movement (NREM) sleep demonstrates a waxing and waning amount of SWA during the transitions between stages N2 and N3 sleep, and the deeper N3 sleep is associated with an increased density of SWA. Further, SWA is an amalgam of different types of slow waves, each identifiable by their temporal coupling to spindle subtypes with distinct physiological features. The objectives of this study were to better understand the neurobiological properties that distinguish different slow wave and spindle subtypes, and to examine the composition of SWA across cycles of NREM sleep. We further sought to explore changes in the composition of NREM cycles that occur among aging adults. To address these goals, we analyzed subsets of data from two well-characterized cohorts of healthy adults: 1) The DREAMS Subjects Database (n=20), and 2) The Cleveland Family Study (n=60). Our analyses indicate that slow wave/spindle coupled events can be characterized as frontal versus central in their relative distribution between electroencephalography (EEG) channels. The frontal predominant slow waves are identifiable by their coupling to late-fast spindles and occur more frequently during stage N3 sleep. Conversely, the central-associated slow waves are identified by coupling to early-fast spindles and favor occurrence during stage N2 sleep. Together, both types of slow wave/spindle coupled events form the composite of SWA, and their relative contribution to the SWA rises and falls across cycles of NREM sleep in accordance with depth of sleep. Exploratory analyses indicated that older adults produce a different composition of SWA, with a shift toward the N3, frontal subtype, which becomes increasingly predominant during cycles of NREM sleep. Overall, these data demonstrate that subtypes of slow wave/spindle events have distinct cortical propagation patterns and differ in their distribution across lighter versus deeper NREM sleep. Future efforts to understand how slow wave sleep and slow wave/spindle coupling impact memory performance and neurological disease may benefit from examining the composition of SWA to avoid potential confounds that may occur when comparing dissimilar neurophysiological events.
The traits of skull anatomy in green frogs of the genus Pelophylax (Anura, Ranidae)
Authors: Natalia Slutska
Published: March 2022

During dissecting skulls of green frogs of the genus Pelophylax it has found that the description of a number bones and cartilaginous structures requires addition and clarification. In addition, previously undescribed details of anatomical structure of the skull of green frogs has revealed. The traits of anatomical structure of skull of green frogs, characteristic for ancestral forms of Anura found too.
Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming in the brain during recovery from experimental stroke
Authors: Loppi Sanna H. , Tavera-Garcia Marco A. , Becktel Danielle A. , Maiyo Boaz K. , Johnson Kristos E. , Schnellmann Rick G. , Doyle Kristian P.
Published: March 2022

The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham operated mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid β-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. These changes correlated with reduced levels of glutamate, dopamine, and adenosine in the ipsilateral hemisphere after stroke. These results indicate that chronic metabolic differences exist between stroked and control tissue, including alterations in fatty acid metabolism and glycolysis for at least 12 weeks after stroke.
Towards a multi-stressor theory for coral reefs in a changing world
Authors: Bieg Carling , Vallès Henri , Tewfik Alexander , Lapointe Brian E. , McCann Kevin S.
Published: March 2022

Coral reefs are facing a constant barrage of human impacts, including eutrophication, overharvesting and climate change. While the local effects of overharvesting have been well-studied, regional nutrient loading from anthropogenic activities on land and global climate change-induced disturbances are increasing in magnitude and necessitating cross-scale multi-stressor approaches for coral reef ecology. Here, we expand on longstanding theory to develop an integrated multi-stressor framework for coral reefs. We show that: i) the geometry of a simple, empirically-motivated model suggests nutrients and harvesting can operate similarly, and synergistically, in driving shifts from coral- to algae-dominated reefs, resulting in clear context-dependent management implications; and ii) this same geometry suggests climate-driven coral mortality can drive the presence of long transients and climate-driven alternate states, even in moderately-impacted ecosystems. Reefs seemingly in a “safe space” based on individual stressors may in fact be much more susceptible to increasingly frequent storms and bleaching events in multi-stressor conditions. By integrating these findings with general ecological and theoretical concepts, we suggest that responses in benthic composition may act as “signatures of change” to multi-stressors, allowing us to develop a predictive and generalizable multi-stressor framework for coral reefs under global change. In line with this theory, we detail empirical evidence from Barbados of historical changes in reef composition and multi-stressor impacts within our framework. By bridging coral reef ecology and general ecological concepts, we can better understand ecosystem functioning and resilience in these important yet highly threatened systems.

Manuscript Highlights

Theoretical understanding of synergistic multi-stressor impacts on coral reefs

Unexpected climate-driven alternate states, related to long transients

Theoretical framework predicts “signatures of change” based on dominant stressor
Structure and influence in an interconnected world: neurocomputational mechanism of real-time distributed learning on social networks
Authors: Jiang Yaomin , Mi Qingtian , Zhu Lusha
Published: March 2022

Many social species are embedded on social networks, including our own. The structure of social networks shapes our decisions by constraining what information we learn and from whom. But how does the brain incorporate social network structures into learning and decision-making processes, and how does learning in networked environments differ from learning from isolated partners? Combining a real-time distributed learning task with computational modeling, fMRI, and social network analysis, we investigated the process by which humans learn from observing others’ decisions on 7-node networks with varying topological structures. We show that learning on social networks can be realized by means similar to the well-established reinforcement learning algorithm, supported by an action prediction error encoded in the lateral prefrontal cortex. Importantly, learning is flexibly weighted toward well-connected neighbors, according to activity in the dorsal anterior cingulate cortex, but only insofar as neighbors’ actions vary in their informativeness. These data suggest a neurocomputational mechanism of network-dependent filtering on the sources of information, which may give rise to biased learning and the spread of misinformation in an interconnected society.
Vaccine Adverse Event Reporting System (VAERS): Evaluation of 31 Years of Reports and Pandemics’ Impact
Authors: Almadani Ohoud A. , Alshammari Thamir M.
Published: March 2022

Background

Vaccine adverse event reporting system (VAERS) was established in the United States (U.S.) as an early warning system with a main purpose of collecting postmarketing adverse events following immunizations (AEFIs) reports to monitor the vaccine safety and to mitigate the risks from vaccines. During the coronavirus diseases 2019 (COVID-19) pandemic, VAERS got more attention as its important role in monitoring the safety of the vaccines. Thus, the aim of this study was to investigate VAERS patterns, reported AEFIs, adverse events of special interest (AESIs), impact of different pandemics since its inception, and surveillance rate of serious vs nonserious AEFIs.

Methods

This was an observational study using VARES data from 2/7/1990 to 12/11/2021. Patterns of reports over years were first described, followed by a comparison of reports statistics per year. Furthermore, a comparison of incidents (death, ER visits, etc.) statistics over years, in addition to statistics of each vaccine were calculated. Moreover, each incident’s statistics for each vaccine were calculated and top vaccines were reported. Finally, survival analysis utilizing cox regression was done, in addition to AESIs distribution stratified by age groups and gender. All analyses were conducted using R (Version 1.4.1717) and Excel for Microsoft 365.

Results

There were 1,396,280 domestic and 346,210 non-domestic reports during 1990-2021, including 228 vaccines. For both domestic and non-domestic reports, year of 2021 had the highest reporting rate (48.52% and 70.33%), in addition a notable changes in AEFIs patterns were recorded during 1991, 1998, 2000, 2006, 2009, 2011, and 2017. AEFIs were as follow: deaths (1.00% and 4.08%), ER or doctor visits (13.37% and 2.27%), hospitalizations (5.84% and 27.78%), lethal threat (1.42% and 4.38%), and disabilities (1.4% and 7.96%). Pyrexia was the top reported symptom during the past 31 years, except for 2021 where headache was the top one. COVID-19 vaccines namely Moderna, Pfizer-Biontech, and Janssen were the top 3 reported vaccines with headache, pyrexia, and fatigue as the top associated AEFIs. Followed by Zoster, Seasonal Influenza, Pneumococcal, and Human papillomavirus vaccines. Myocarditis or Pericarditis were the top reported AESIs (26.95% and 25.84%). Male (HR:1.15, 1.14 - 1.16) for domestic (HR:1.23, 1.22 -1.25) for nondomestic have a higher probability of having serious AEFIs. In addition, age group ≤ 5 years old in domestic and >84 years old in nondomestic have a higher probability of having AEFIs compared to other age groups.

Conclusions

The large data available in VARES make it a useful tool for detecting and monitoring vaccine AEFIs. However, its usability relies on understating the limitations of this surveillance system, the impact of governmental regulations, availability of vaccines, and public health recommendations on the reporting rate.
Enhanced Recovery After Surgery reduced length of stay after colorectal surgery in a small rural hospital in Ontario
Authors: Roldan Hector A. , Brown Andrew R. , Radey Jane , Hogenbirk John C. , Allen Lisa R.
Published: March 2022

Background

Enhanced Recovery After Surgery (ERAS) programs include preoperative, intraoperative and postoperative clinical pathways to improve quality of patient care while reducing length of stay and readmission. This study assessed the feasibility and outcomes of an ERAS protocol for colorectal surgery implemented over two-years in a small, resource-challenged rural hospital.

Study design

A prospective cohort study used retrospectively matched controls to assess the effect of ERAS on LOS in patients undergoing colorectal surgery in a small rural hospital in northern Ontario, Canada. ERAS patients were matched to two patients in the control group based on diagnosis, age and gender. Patients had open or laparoscopic colorectal surgeries, with those in the intervention group treated per ERAS protocol and given instructions on pre- and post-operative self-care.

Results

Most ERAS patients reported adherence to ERAS protocols prior to surgery. Approximately one quarter of patients chose not to complete the postoperative survey. Of those who completed the survey, adherence to protocol was strongest for chewing gum in the days after surgery. Most patients were sitting in a chair for their afternoon meal by the first day and most were walking down the hallway by the second day. The control and ERAS patient groups did not differ significantly (p≥0.07) in age (years, sd=13.1), gender (52% male), nor in the Canadian Classification of Health Interventions 5-character code. The control group significantly higher (p<0.001) malignant neoplasm of colon (C18, 69% vs 35%), and significantly lower malignant neoplasm of rectum (C20, 0% vs 5%), relative to the ERAS group. The control group had an average ln-transformed LOS that was significantly longer (exponentiated as 1.7 days) than ERAS patients (t-test, p<0.001).

Conclusion

This study found that ERAS could be implemented in a small rural hospital and provided evidence for a reduced LOS of approximately two days.
Large-scale analysis and computer modeling reveal hidden regularities behind variability of cell division patterns inArabidopsis thalianaembryogenesis
Authors: Laruelle Elise , Belcram Katia , Trubuil Alain , Palauqui Jean-Christophe , Andrey Philippe
Published: March 2022

Noise plays a major role in cellular processes and in the development of tissues and organs. Several studies have examined the origin, the integration or the accommodation of noise in gene expression, cell growth and elaboration of organ shape. By contrast, much less is known about variability in cell division plane positioning, its origin and links with cell geometry, and its impact on tissue organization. Taking advantage of the first-stereotyped-then-variable division patterns in the embryo of the model plant Arabidopsis thaliana, we combined 3D imaging and quantitative cell shape and cell lineage analysis together with mathematical and computer modeling to perform a large scale, systematic analysis of variability in division plane orientation. Our results reveal that, paradoxically, variability in cell division patterns ofArabidopsisembryos is accompanied by a progressive reduction of cell shape heterogeneity. The paradox is solved by showing that variability operates within a reduced repertoire of possible division plane orientations that is related to cell geometry. We show that in several domains of the embryo, a recently proposed geometrical division rule recapitulates observed variable patterns, thus suggesting that variable patterns emerge from deterministic principles operating in a variable geometrical context. Our work highlights the importance of emerging patterns in the plant embryo under iterated division principles, but also reveal domains where deviations between rule predictions and experimental observations point to additional regulatory mechanisms.
Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
Authors: Brünger Tobias , Pérez-Palma Eduardo , Montanucci Ludovica , Nothnagel Michael , Møller Rikke S. , Schorge Stephanie , Zuberi Sameer , Symonds Joseph , Lemke Johannes R. , Brunklaus Andreas , Traynelis Stephen F. , May Patrick , Lal Dennis
Published: March 2022

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.

We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.

We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our novel 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and fucntional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 neurodevelopmental disorder pathogenic patient variants, and 679 electrophysiological experiments that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain vs. loss-of-channel function.

In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional read-outs and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.
Mitochondrial phosphoproteomes are functionally specialized across tissues
Authors: Hansen Fynn M. , Kremer Laura S. , Karayel Ozge , Kühl Inge , Bludau Isabell , Larsson Nils-Göran , Mann Matthias
Published: March 2022

Mitochondria are essential organelles involved in critical biological processes such as energy metabolism and cell survival. Their dysfunction is linked to numerous human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Furthermore, increasing evidence suggests that phosphorylation may also play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. We hypothesized that recent advances in mass spectrometry (MS)-based proteomics would now enable in-depth measurement to quantitatively profile mitochondrial proteomes along with their matching phosphoproteomes across tissues. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue modulated mitochondrial proteins (mitophos.de). We also uncover tissue-specific repertoires of dozens of kinases and phosphatases. Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on DRP1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.
CD4 binding-site antibodies induced by a subtype B HIV-1 envelope trimer
Authors: Schorcht Anna , van den Kerkhof Tom L.G.M. , Torres Jon , Schermer Edith , LaBranche Celia C. , Bontjer Ilja , Brinkkemper Mitch , Gulzar Naveed , Han Alvin X. , Burger Judith , Ozorowski Gabriel , Scott Jamie K. , Schuitemaker Hanneke , Montefiori David , van Gils Marit J. , Ward Andrew B. , Sanders Rogier
Published: March 2022

In the last decade considerable advances have been made towards the design of HIV-1 vaccines that induce neutralizing antibodies (NAbs). Despite the progress, no vaccine is able to consistently elicited broadly neutralizing antibodies (bNAbs). Here we present a case study of a rabbit that was immunized with a subtype B native like envelope glycoprotein (Env) trimer, AMC016 SOSIP.v4.2, with a dense and intact glycan shield, followed by a trivalent combination of subtype B trimers. After the priming phase serum from this animal neutralized several heterologous subtype B neutralization resistant (tier 2) viruses. Subsequent immunization with the trivalent combination of subtype B trimers further increased the breadth and potency of the NAb response. EM based polyclonal epitope mapping revealed that a cross reactive CD4 binding-site (CD4bs) antibody response, that was present after priming with the monovalent trimer and boosting with the trivalent combination, was most likely responsible for the broad neutralization. While anecdotal, this study provides proof-of-concept that native-like Env trimers are capable of inducing CD4bs-directed bNAb responses and should guide efforts to improve the consistency with which such responses are generated.
Connexin36 expression in the cochlear nucleus complex of the echolocating bat, Eptesicus fuscus
Authors: Accomando Alyssa W. , Johnson Mark A. , McLaughlin Madeline A. , Simmons James A. , Simmons Andrea Megela
Published: March 2022

Gap junctions and electrical synapses in the central nervous system are associated with rapid temporal processing and coincidence detection. Using histology, immunohistochemistry, and in situ hybridization, we investigated the distribution of Connexin36 (Cx36), a protein that comprises neuronal gap junctions, throughout the cochlear nucleus complex of the echolocating big brown bat, Eptesicus fuscus, a species exhibiting extreme behavioral sensitivity to minute temporal changes in ultrasonic echoes. For comparison, we visualized Cx36 expression in the cochlear nucleus of transgenic Cx36 reporter mice, species that hear ultrasound but do not echolocate. We observed Cx36 expression in the anteroventral and dorsal cochlear nucleus, with more limited expression in the posteroventral cochlear nucleus, of both species. Several different morphological cell types were labeled, including globular and spherical bushy, octopus, stellate, and fusiform cells. Labeled Cx36 puncta were also observed. Cx36 expression in the bat was spread throughout a relatively smaller area of the cochlear nucleus than in the mouse, even though the bat cochlear nucleus is hypertrophied. In the bat, the anteroventral cochlear nucleus showed higher percent area label than the dorsal cochlear nucleus, with a trend towards the opposite result in the mouse. The presence of gap junctions appears to be a conserved feature of the mammalian cochlear nucleus and thus not uniquely tied to the temporal hyperacuity of echolocation.
Competitive membrane wetting of polymer blends in artificial cells initiates phase separation and promotes fractionation
Authors: Watanabe Chiho , Furuki Tomohiro , Kanakubo Yuki , Kanie Fumiya , Koyanagi Keisuke , Takeshita Jun , Yanagisawa Miho
Published: March 2022

Biomolecular condensates driven by liquid–liquid phase separation (LLPS) have received attention as novel activity regulators of living organisms. In intracellular LLPS, an important question is what type of biomolecules form condensates under what conditions. In this regard, possible interactions between biomolecules have been investigated. Recently, LLPS condensates have been reported to regulate the membrane structure upon wetting. However, the possibility of membrane wetting, in which the membrane conversely regulates the LLPS, remains unexplored. Using droplets of short polyethylene glycol and long dextran blends encapsulated with a lipid membrane, we demonstrate that membrane wetting regulates LLPS in cell-size spaces and alters the equilibrium state. In smaller droplets, the two-phase region expands beyond the bulk system, and the fractionation degree increases, particularly during the separation between short PEG and long dextran. We explain the space-size dependent LLPS based on the competitive membrane wetting between the polymers. Smaller droplets promote the membrane wetting of short PEG, which enhances the depletion force between long dextran molecules and finally induces LLPS. This shows that competition for membrane wettability among various molecules can regulate LLPS in cell-size spaces, rendering this LLPS principle feasible in living cells.
Environmental risks and occupational health hazards of bidi workers and their communities in India: protocol for systematic scoping review
Authors: Tyagi Jyoti , Beri Deepti , Bhaumik Soumyadeep
Published: March 2022

Background

Tobacco consumption is a leading preventable cause of disease and premature deaths. In India bidis are the most common form of smoking tobacco product. Bidi manufacturing is an agro-forest based cottage industry and is generally rolled at home. These workers are exposed to nicotine, tar and other particles through skin leading to occupational health risks in not only themselves but also in their families and communities. There are concerns on environmental risks of bidi manufacturing in home too.

Aim

To assess the environmental risks and occupational health hazards of bidi workers and their communities in India.

Method

We will conduct a scoping review to identify, map and analyse evidence around environmental risks and occupational health hazards in bidi workers and their families and communities. We will search in seven electronic databases (PubMed, EMBASE+EMBASE Classic, CINAHL, Environment complete-EBSCO, GreenFILE-EBSCO, Web of Science and WHO-IRIS). Screening will be done independently by at least two reviewers, with disagreements resolve by consensus. We will extract data for the included studies using a standardised data extraction in an independent fashion, with disagreements resolved by consensus. We will conduct a narrative synthesis.
Impact assessment of mobility restrictions, testing, and vaccination on the COVID-19 pandemic in India
Authors: Shin Jeonghyun , Khuong Quynh Long , Abbas Kaja , Oh Juhwan
Published: March 2022

Background

Before the availability of vaccines, countries largely relied on mobility restriction and testing to mitigate the COVID-19 pandemic. Our aim is to assess the combined impact of mobility restriction, testing, and vaccination on the COVID-19 pandemic in India.

Methods

We conducted a multiple regression analysis to assess the impact of mobility, testing, and vaccination on COVID-19 incidence between April 28, 2021 to November 24, 2021 using data from Our World in Data and Google Mobility Report. The 7-day moving average was applied to offset the daily fluctuations in the mobility and testing. Each independent variable was lagged to construct a temporal relationship, and waning vaccination efficacy was taken into consideration. We performed additional analysis for three time periods between March 28, 2020 to November 24, 2021 (1st: March 28, 2020 ∼ October 7, 2020, 2nd: October 8, 2020 ∼ April 27, 2021, 3rd: April 28, 2021 ∼ November 24, 2021) to examine potential heterogeneity over time.

Results

Mobility (0.041, 95% CI: 0.033 to 0.048), testing (-0.008, 95% CI: -0.015 to -0.001), and vaccination (quadratic term: 0.004, 95% CI: 0.003 to 0.005, linear term: -0.130, 95% CI: -0.161 to -0.099) were all associated with COVID-19 incidence. For vaccination rate, the decrease of number of cases demonstrated a U-shaped curve, while mobility showed a positive association and testing showed an inverse association with COVID-19 incidence. Mobility restriction was effective during all three periods – March 28, 2020 to November 24, 2021 (0.009, 0.048, and 0.026 respectively). Testing was effective during the second and third period – October 8, 2020 to November 24, 2021 (-0.036, and -0.006 respectively).

Conclusion

Mobility restriction and testing were effective even in the presence of vaccination. This shows the positive value of mobility restrictions, testing, and vaccination from the health system perspective on COVID-19 prevention and control, especially with continual emergence of variants in India and globally. At the same time, this health system gain must be balanced with the challenges in the delivery of non-COVID health services and broader socio-economic impact in deciding the prolonged continuance of mobility restriction.
Spatial Cluster Modeling of Rodent Infestations and Leptospirosis Risks in SE Asian Urban Areas
Authors: Wibowo Andri , Vazela Erze , Prasetyo Alifa A. , Firdaus Alfian F. , Fajrina Lulu , Annisa Feby , Dinilah Izzah , Nisrina Adinda , Chairunnisa Fayza , Aulia Farras Putri , Megakusuma Diah , Dharmawan M. Adrian
Published: March 2022

Urban areas in the Southeast Asia Region are characterized by rainfall, river networks, and rodent infestations. Combinations of these adverse conditions will lead to the increasing risk of leptospirosis as usually contained in rodents. Then this study aims to assess the spatial pattern of rodent infestations and estimate the potential leptospirosis risks using environmental variables including distance to the river and rainfall in a city in SE Asia. The spatial modeling of rodent infestations was developed based on GIS and interpolation analysis. Meanwhile, the cluster modeling of rodent infestations was developed using the K-means clustering method. The results revealed the rodent infestations represented by two rodent species were Rattus rattus and Rattus norvegicus. R. rattus has a higher abundance than R. norvegicus. In contrast, R. norvegicus has wider distribution areas than R. rattus. Regarding the distribution areas, both species overlapped in the Southern parts of the city. R. rattus and R. norvegicus showed a distinct cluster characterized by a high rodent population with affinity for the nearest river, and this indicates the urban inhabitants near the river have more leptospirosis risk. The model of leptospirosis risks estimated an urban area of 35.182 km2 or 17.56% having leptospirosis potential.
A Qualitative Study Regarding Messages of the COVID-19 Vaccine from Vaccinated Healthcare Providers and Healthy Adults
Authors: Sano Shuji , Sato Satomi , Ohmagari Norio , Takahashi Osamu
Published: March 2022

1.

Background

To promote the vaccination against COVID-19, person-to-person communication from vaccinated people will play an important role. The objectives of this study are to identify what messages were shared by vaccinated people, and the relationship between these messages and their background.

Methods

This study was an exploratory and prospective basis with individual interviews. The participants were healthcare providers and healthy adults who were recruited at a vaccination site in Chuo-City, Tokyo. The online interviews were conducted using a semi-structured interview. Based on the Health Belief Model (HBM), the participants were asked about their perspectives on vaccines and what they talked about after their vaccination. The interviews were categorized into each item of the HBM and analyzed using NVivo software.

Results

During August to October 2021, five healthcare providers and seven healthy adults were enrolled in the study. One healthy adult could not be contacted resulting in a total of 11 participants interviewed. Both the healthcare providers and the healthy adults mainly talked about side effects after their vaccination, and to ease the other persons’ concerns based on their experience. Meanwhile, there were differences in the recommendations for vaccination between the two groups. The healthcare providers were strongly aware of the severity of COVID-19 infection and recommended vaccination to others as a useful measure to suppress becoming severely ill. On the other hand, the healthy adults recommended the vaccine with varying degree depending on their expectations and concerns about the vaccine and external factors such as living with a family member.

Conclusion

Both the healthcare providers and healthy adults shared similar messages to ease the vaccination concerns of others. However, their vaccine recommendation level was varied, which may be influenced not only by expectations and concerns toward the vaccine, but also by external factors such as family members living together.
Strengthening health service delivery and governance through institutionalizing ‘Urban Health Atlas’ - a geo-referenced Information Communication and Technology tool: lessons learned from an implementation research in three cities in Bangladesh
Authors: Shafique Sohana , Bhattacharyya Dipika Shankar , Hossain Tarek , Hasan Shaikh Mehdi , Ahmed Shakil , Islam Rubana , Adams Alayne M.
Published: March 2022

Introduction

Urban health governance in Bangladesh is complex as multiple actors are involved and no comprehensive data are currently available on infrastructure, services, or performance either in public and private sectors of the healthcare system. The Urban Health Atlas (UHA) – a novel and interactive geo-referenced, web-based visualization tool was developed in Bangladesh to provide geospatial and service information to decision makers involved in urban health service planning and governance. Our objective was to study the opportunities for institutionalization of the UHA into government health systems responsible for urban healthcare delivery and document the facilitators and barriers to its uptake.

Methods

This mixed-methods implementation research was carried out during 2017-2019 in three cities in Bangladesh: Dhaka, Dinajpur and Jashore. During the intervention period, six hands-on trainings on UHA were provided to 67 urban health managers across three study sites. Both in-depth and key informant interviews were conducted to understand user experience and document stakeholder perceptions of institutionalizing UHA.

Results

Capacity building on UHA enhanced understanding of health managers around its utility for service delivery planning, decision making and oversight. Uptake of UHA was challenged by inadequate ICT infrastructure, shortage of human resources and general lack of ICT skill among the managers. Motivating key decision makers and stakeholders about the potential of UHA and engaging them from the inception helped the institutionalization process.

Conclusion

While uptake of UHA by government health managers appears possible with dedicated capacity building initiatives, its use and regular update are challenged by multiple factors at the implementation level. A clear understanding of context, actors and system readiness is foundational in determining whether the institutionalization of health ICTs is timely, realistic or relevant.
A mixed methods study of community-based health insurance enrollment trends and underlying challenges in two districts of northeast Ethiopia: a proxy for its sustainability
Authors: Hussien Mohammed , Azage Muluken , Bayou Negalign Berhanu
Published: March 2022

Background

Community-based health insurance initiatives in low- and middle-income countries are plagued by persistently low coverage due to their voluntary orientation. In Ethiopia, the schemes’ membership growth has not been well investigated so far. This study sought to examine the scheme’s enrollment trend over a five-year period, and to explore the various challenges that underpin membership growth from the perspectives of various key stakeholders.

Methods

The study employed a mixed methods case study in two districts of northeast Ethiopia: Tehulederie and Kallu. Quantitative data was collected by reviewing the databases of schemes. Key informant interviews and in-depth interviews were conducted face-to-face with 19 key stakeholders and nine community members, respectively. Study participants were purposely selected using the maximum variation technique. Interviews were audio recorded, transcribed verbatim, and translated into English. Thematic analysis was employed with both deductive and inductive coding approaches.

Results

Enrollment in the two districts has shown an inconsistent trend over the study period (2017 to 2021). The scheme in Tehulederie has a relatively better enrollment trend, particularly in terms of membership retention, which could be due to the strong foundation laid by a rigorous public awareness campaign and technical support during the pilot phase. The challenges contributing to the observed level of performance have been summarized under four main themes that include quality of health care, claims reimbursement for insurance holders, governance practices, and community awareness and acceptability.

Conclusions

The scheme experienced negative growth ratios in both districts with inconsistent trends, showing that the scheme is not functionally viable. It will regress unless relevant stakeholders at all levels of government demonstrate political will and commitment to its implementation, as well as advocate for the community. Interventions should target on the highlighted challenges in order to boost membership growth and ensure the viability of the community-based health insurance.