bluuebunny/crossref_metadata_2025 huggingface dataset:
The transition from animal to human culture—simulating the social protocell hypothesis
Authors: Andersson Claes , Czárán Tamás
Published: January 2023

The origin of human cumulative culture is commonly envisioned as the appearance (some 2.0–2.5 million years ago) of a capacity to faithfully copy the know-how that underpins socially learned traditions. While certainly plausible, this story faces a steep ‘startup problem’. For example, it presumes that ape-like early
Homo
possessed specialized cognitive capabilities for faithful know-how copying and that early toolmaking actually required such a capacity. The social protocell hypothesis provides a leaner story, where cumulative culture may have originated even earlier—as cumulative
systems
of non-cumulative traditions ('institutions' and ‘cultural lifestyles'), via an emergent group-level channel of cultural inheritance. This channel emerges as a side-effect of a specific but in itself unremarkable suite of social group behaviours. It is independent of faithful know-how copying, and an ancestral version is argued to persist in
Pan
today. Hominin cultural lifestyles would thereby have gained in complexity and sophistication, eventually becoming independent units of selection (socionts) via a cultural evolutionary transition in individuality, abstractly similar to the origin of early cells. We here explore this hypothesis by simulating its basic premises. The model produces the expected behaviour and reveals several additional and non-trivial phenomena as fodder for future work.

This article is part of the theme issue ‘Human socio-cultural evolution in light of evolutionary transitions’.
Initial data on Helicobacter pylori resistance in Lebanon
Authors: Osman Marwan , Rafei Rayane , Cummings Kevin J. , Rafei Wassim , Awada Joseph , Moubayed Hayssam , Majzoub Farah , Mallat Hassan , Dabboussi Fouad , Hamze Monzer
Published: January 2023

There is a lack of data regarding the prevalence of antimicrobial-resistant Helicobacter pylori isolates in Lebanon. Here, we aimed to estimate the prevalence of H. pylori infection and clarithromycin resistance in symptomatic patients with suspected peptic ulcers. Eighty-seven patients undergoing routine endoscopy screening for peptic ulcers were selected. Culture and Allplex™ H pylori and ClariR Assay were performed. Antimicrobial susceptibility testing for clarithromycin, tetracycline, levofloxacin, and rifampicin was performed using the E-test method. Overall, 32.2% (28/87) of the patients were found to be positive for H. pylori infection. Five isolates were resistant to clarithromycin, associated with specific point mutations of A2143G (4/5) or A2142G (1/5). The Allplex™ H pylori and ClariR Assay showed a higher sensitivity compared to the standard culture method. Our findings revealed that H. pylori clarithromycin and levofloxacin resistance emerged in Lebanon. The availability of such data is essential in monitoring antimicrobial resistance.
Transcriptional profiling of Pseudomonas aeruginosa mature single- and dual-species biofilms in response to meropenem
Authors: Alam Farhana , Blair Jessica M. A. , Hall Rebecca A.
Published: January 2023

Pseudomonas aeruginosa

is a Gram-negative opportunistic pathogen frequently isolated from chronic infections of the cystic fibrosis lung and burn wounds, and is a major cause of antimicrobial-resistant nosocomial infections.

P. aeruginosa

is frequently co-isolated with the opportunistic fungal pathogen Candida albicans, with the presence of C. albicans in dual-species biofilms promoting tolerance to meropenem. Here, transcription profiling of mature

P. aeruginosa

single- or dual-species biofilms was carried out to understand the molecular mechanism(s) by which C. albicans enhances meropenem tolerance. C. albicans appeared to have a mild impact on the transcriptome of

P. aeruginosa

mature biofilms, with most differentially regulated genes being involved in interkingdom interactions (i.e. quorum sensing and phenazine biosynthesis). The addition of meropenem to mature single- or dual-species biofilms resulted in a significant bacterial transcriptional response, including the induction of the beta-lactamase, ampC, genes involved in biofilm formation.

P. aeruginosa

elicited a similar transcriptional response to meropenem in the presence of C. albicans, but C. albicans promoted the expression of additional efflux pumps, which could play roles in increasing the tolerance of

P. aeruginosa

to meropenem.
Assay development and inhibition of the Mt-DprE2 essential reductase from Mycobacterium tuberculosis
Authors: Batt Sarah M. , Toth Szilvi , Rodriguez Beatriz , Abrahams Katherine A. , Veerapen Natacha , Chiodarelli Giacomo , Cox Liam R. , Moynihan Patrick J. , Lelievre Joel , Fütterer Klaus , Besra Gurdyal S.
Published: January 2023

DprE2 is an essential enzyme in the synthesis of decaprenylphosphoryl-β-d-arabinofuranose (DPA) and subsequently arabinogalactan, and is a significant new drug target for

M. tuberculosis

. Two compounds from the GSK-177 box set, GSK301A and GSK032A, were identified through Mt-DprE2-target overexpression studies. The Mt-DprE1-DprE2 complex was co-purified and a new in vitro DprE2 assay developed, based on the oxidation of the reduced nicotinamide adenine dinucleotide cofactor of DprE2 (NADH/NADPH). The Mt-DprE1-DprE2 complex showed interesting kinetics in both the DprE1 resazurin-based assay, where Mt-DprE2 was found to enhance Mt-DprE1 activity and reduce substrate inhibition; and also in the DprE2 assay, which similarly exhibited substrate inhibition and a difference in kinetics of the two potential cofactors, NADH and NADPH. Although, no inhibition was observed in the DprE2 assay by the two GSK set compounds, spontaneous mutant generation indicated a possible explanation in the form of a pro-drug activation pathway, involving fgd1 and fbiC.
An explainable spatial-temporal graphical convolutional network to score freezing of gait in parkinsonian patients
Authors: Kwon Hyeokhyen , Clifford Gari D. , Genias Imari , Bernhard Doug , Esper Christine D. , Factor Stewart A. , McKay J. Lucas
Published: January 2023

Freezing of gait (FOG) is a poorly understood heterogeneous gait disorder seen in patients with parkinsonism which contributes to significant morbidity and social isolation. FOG is currently measured with scales that are typically performed by movement disorders specialists (ie. MDS-UPDRS), or through patient completed questionnaires (N-FOG-Q) both of which are inadequate in addressing the heterogeneous nature of the disorder and are unsuitable for use in clinical trials The purpose of this study was to devise a method to measure FOG objectively, hence improving our ability to identify it and accurately evaluate new therapies. We trained interpretable deep learning models with multi-task learning to simultaneously score FOG (cross-validated F1 score 97.6%), identify medication state (OFF vs. ON levodopa; cross-validated F1 score 96.8%), and measure total PD severity (MDS-UPDRS-III score prediction error ≤ 2.7 points) using kinematic data of a well-characterized sample of N=57 patients during levodopa challenge tests. The proposed model was able to identify kinematic features associated with each FOG severity level that were highly consistent with the features that movement disorders specialists are trained to identify as characteristic of freezing. In this work, we demonstrate that deep learning models’ capability to capture complex movement patterns in kinematic data can automatically and objectively score FOG with high accuracy. These models have the potential to discover novel kinematic biomarkers for FOG that can be used for hypothesis generation and potentially as clinical trial outcome measures.
Principal-stretch-based constitutive neural networks autonomously discover a subclass of Ogden models for human brain tissue
Authors: St. Pierre Sarah R. , Linka Kevin , Kuhl Ellen
Published: January 2023

The soft tissue of the brain deforms in response to external stimuli, which can lead to traumatic brain injury. Constitutive models relate the stress in the brain to its deformation and accurate constitutive modeling is critical in finite element simulations to estimate injury risk. Traditionally, researchers first choose a constitutive model and then fit the model parameters using tension, compression, or shear experiments. In contrast, constitutive artificial neural networks enable automated model discovery without having to choosing a specific model a priori before learning the model parameters. Here we reverse engineer a constitutive artificial neural network that uses the principal stretches, raised to a wide range of exponential powers, as activation functions for the hidden layer. Upon training, the network autonomously discovers a subclass of models with multiple Ogden terms that outperform popular constitutive models including neo Hooke, Blatz Ko, and Mooney Rivlin. While invariant-based networks fail to capture the pronounced tension-compression asymmetry of brain tissue, our principal-stretch-based network can simultaneously explain tension, compression, and shear data for the cortex, basal ganglia, corona radiata, and corpus callosum. Without fixing the number of terms a priori, our model self-selects the best subset of terms out of more than a million possible combinations, while simultaneously discovering the best model parameters and best experiment to train itself. Eliminating user-guided model selection has the potential to induce a paradigm shift in soft tissue modeling and democratize brain injury simulations.

Our source code, data, and examples are available athttps://github.com/LivingMatterLab/CANN.
Genotype-specific variation in seasonal body condition at a large-effect maturation locus
Authors: House Andrew H. , Debes Paul V. , Kurko Johanna , Erkinaro Jaakko , Primmer Craig R.
Published: January 2023

Organisms utilize varying lipid resource allocation strategies as a means to survive seasonal environmental changes and life-history stage transitions. In Atlantic salmon, a certain lipid threshold is needed to initiate sexual maturation. Because of this, an individual’s maturation schedule may be affected by changes in temperature and food availability across the seasons that create natural fluctuations of lipid reserves.

Recent studies have found a genome region, including the genevgll3,that explains a large proportion of variation for size and age at maturity. Vgll3encodes a transcription co-factor that acts as an inhibitor of adipogenesis in mice and also affects condition factor and other phenotypes in juvenile salmon. However, even with many studies investigating varying temperature effects, there is a lack of temporal studies examining the effects of seasonality on such phenotypes, nor have the effects ofvgll3genotype on condition factor and maturation in different temperatures at different life stages.

Here, we investigate the influence of different larval and juvenile incubation temperatures,vgll3genotype and their interactions on juvenile salmon phenotypes including body condition, and sexual maturation rate. We reared Atlantic salmon for 2 years in varying temperatures with an average 1.76 °C difference between warm and cold treatments in four different larval-juvenile phase treatment groups (Warm-Warm, Warm-Cold, Cold-Warm, and Cold-Cold) until the first occurrence of maturation in males.

We found no effect of larval temperature on the measured phenotypes or maturation rate, suggesting the occurrence of growth compensation over the course of the experiment. Agreeing with previous studies, an increased maturation rate was observed in individuals of the warm juvenile temperature treatment.

In addition, we observed differences in condition factor associated withvgll3genotype, wherebyvgll3*EEindividuals (the genotype associated with early maturation) had a less variable condition factor across the seasons compared to thevgll3*LL(associated with late maturation) individuals.

This result suggests avgll3influence on resource acquisition and allocation strategies, possibly linked with the early maturation process, with individuals carrying the early maturationvgll3genotype having a higher early maturation rate and a higher condition factor in the spring.
Cross-Species Protection to Innate Immunity Mediated by A Bacterial Pigment
Authors: Liu Yiwei , McQuillen Eleanor A. , Rana Pranav S. J. B. , Gloag Erin. S. , Wozniak Daniel J.
Published: January 2023

Bacterial infections are often polymicrobial.Pseudomonas aeruginosaandStaphylococcus aureuscause chronic co-infections, which are more problematic than mono-species infections. We found that the production ofS. aureusmembrane-bound pigment staphyloxanthin (STX), was induced by theP. aeruginosaexoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). The induction phenotype was conserved inP. aeruginosaandS. aureusclinical isolates examined. When subjected to hydrogen peroxide or human neutrophils,P. aeruginosasurvival was significantly higher when mixed with wild-type (WT)S. aureus, compared to a mutant deficient in STX production orP. aeruginosaalone. In a murine wound model, co-infection with WTS. aureus, but not the STX-deficient mutant, enhancedP. aeruginosaburden and disease compared to mono-infection. In conclusion, we discovered a novel role forP. aeruginosaHQNO mediating polymicrobial interactions withS. aureusby inducing STX production, which consequently promotes resistance of both pathogens to innate immune effectors. These results further our understanding of how different bacterial species cooperatively cause co-infections.
High-throughput quantification of camelid cytokine mRNA expression in PBMCs by microfluidic qPCR technology
Authors: Rodon Jordi , Te Nigeer , Ballester Maria , Segalés Joaquim , Vergara-Alert Júlia , Bensaid Albert
Published: January 2023

Camelids are economically and socially important in several parts of the world and might carry pathogens with epizootic or zoonotic potential. However, biological research in these species is limited due to lack of reagents. Here, we developed RT-qPCR assays to quantify a panel of camelid innate and adaptive immune response genes, which can be monitored in a single run. Validation of the assays was performed with PHA, PMA-ionomycin, and Poly I:C-stimulated PBMCs from alpaca, dromedary camel and llama, including normalization by multiple reference genes. Further, comparative gene expression analyses for the different camelid species were performed by a unique microfluidic qPCR assay. Compared to unstimulated samples, PHA and PMA-ionomycin stimulation elicited robust Th1 and Th2 responses in PBMCs from camelid species. Additional activation of type I and type III IFN signalling pathways was described exclusively in PHA-stimulated dromedary lymphocytes, in contrast to those from alpaca and llama. We also found that PolyI:C stimulation induced robust antiviral response genes in alpaca PBMCs. The proposed methodology should be useful for the measurement of immune responses to infection or vaccination in camelid species.
Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors
Authors: Do Hung N. , Wang Jinan , Miao Yinglong
Published: January 2023

G-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and represent primary targets of ∼1/3 of currently marketed drugs. Allosteric modulators have emerged as more selective drug candidates compared with orthosteric agonists and antagonists. However, many X-ray and cryo-EM structures of GPCRs resolved so far exhibit negligible differences upon binding of positive and negative allosteric modulators (PAMs and NAMs). Mechanism of dynamic allosteric modulation in GPCRs remains unclear. In this work, we have systematically mapped dynamic changes in free energy landscapes of GPCRs upon binding of allosteric modulators using the Gaussian accelerated molecular dynamics (GaMD), Deep Learning (DL) and free energy prOfiling Workflow (GLOW). A total of 18 available high-resolution experimental structures of allosteric modulator-bound class A and B GPCRs were collected for simulations. A number of 8 computational models were generated to examine selectivity of the modulators by changing their target receptors to different subtypes. All-atom GaMD simulations were performed for a total of 66 µs on 44 GPCR systems in the presence/absence of the modulator. DL and free energy calculations revealed significantly reduced conformational space of GPCRs upon modulator binding. While the modulator-free GPCRs often sampled multiple low-energy conformational states, the NAMs and PAMs confined the inactive and active agonist-G protein-bound GPCRs, respectively, to mostly only one specific conformation for signaling. Such cooperative effects were significantly reduced for binding of the selective modulators to “non-cognate” receptor subtypes in the computational models. Therefore, comprehensive DL of extensive GaMD simulations has revealed a general dynamic mechanism of GPCR allostery, which will greatly facilitate rational design of selective allosteric drugs of GPCRs.
Multiplepalsgene modules control a balance between immunity and development inCaenorhabditis elegans
Authors: Lažetić Vladimir , Blanchard Michael J. , Bui Theresa , Troemel Emily R.
Published: January 2023

The immune system continually battles against pathogen-induced pressures, which often leads to the evolutionary expansion of immune gene families in a species-specific manner. For example, thepalsgene family expanded to 39 members in theCaenorhabditis elegansgenome, in comparison to a single mammalianpalsortholog. Our previous studies have revealed that two members of this family,pals-22andpals-25, act as antagonistic paralogs to control the Intracellular Pathogen Response (IPR). The IPR is a protective transcriptional response, which is activated upon infection by two molecularly distinct natural intracellular pathogens ofC. elegans– the Orsay virus and the fungusNematocida parisiifrom the microsporidia phylum. In this study, we identify a previously uncharacterized member of thepalsfamily,pals-17, as a newly described negative regulator of the IPR.pals-17mutants show constitutive upregulation of IPR gene expression, increased immunity against intracellular pathogens, as well as impaired development and reproduction. We also find that two other previously uncharacterizedpalsgenes,pals-20andpals-16, are positive regulators of the IPR, acting downstream ofpals-17. These positive regulators reverse the effects caused by the loss ofpals-17on IPR gene expression, immunity and development. We show that the negative IPR regulator protein PALS-17 and the positive IPR regulator protein PALS-20 colocalize inside intestinal epithelial cells, which are the sites of infection for IPR-inducing pathogens. In summary, our study demonstrates that severalpalsgenes from the expandedpalsgene family act as ON/OFF switch modules to regulate a balance between organismal development and immunity against natural intracellular pathogens inC. elegans.

AUTHOR SUMMARY

Immune responses to pathogens induce extensive rewiring of host physiology. In the short term, these changes are generally beneficial as they can promote resistance against infection. However, prolonged activation of immune responses can have serious negative consequences on host health, including impaired organismal development and fitness. Therefore, the balance between activating the immune system and promoting development must be precisely regulated. In this study, we used genetics to identify a gene in the roundwormCaenorhabditis eleganscalledpals-17that acts as a repressor of the Intracellular Pathogen Response (IPR), a defense response against viral and microsporidian infections. We also found thatpals-17is required for the normal development of these animals. Furthermore, we identified two otherpalsgenes,pals-20andpals-16, as suppressors ofpals-17mutant phenotypes. Finally, we found that PALS-17 and PALS-20 proteins colocalize inside intestinal cells, where viruses and microsporidia invade and replicate in the host. Taken together, our study demonstrates a balance between organismal development and immunity that is regulated by several genetic ON/OFF switch ‘modules’ inC. elegans.
Comprehensive analysis of primary immune thrombocytopenia clinical trials in the ClinicalTrials.gov database
Authors: Wang Yacan , Bi Hui , Yang Wen , Wang Honghui , Wang Xiuli , Xie Dongmei , Li Huiting , Zhou Zeping
Published: January 2023

Objective

The purpose is to clarify the overall situation of clinical related to primary immune thrombocytopenia (ITP), to evaluate the difference between published clinical trials and unpublished trials, and to evaluate the relevant information of trial publication.

Methods

Search theClinicalTrials.govdatabase on March 20, 2022 to identify ITP clinical trials and obtain relevant data. Publications in PubMed were searched using standardized methods to identify the publication of completed clinical trials.

Results

Of 341 trials identified, interventional trials were the most common (74.2%, n=253). Interventional trials and observational trials differ in the main research content (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.03-0.015, P=0.000). In terms of published articles, there are few trials involving non drugs (OR 0.23, CI 0.08-0.64, P = 0.005). There were fewer trials with less than 10 participants (OR 1.52, CI 1.06-2.20, P = 0.024). Of the 167 completed trials, 93 (55.7%) were published and 48 (28.7%) uploaded results.

Conclusion

If the main research content involves drugs, trials with a larger number of people are more likely to be published. The publication rate of ITP clinical trials is high, but the submission rate of database results is low. Therefore, more attention should be paid to the submission of clinical trial results in the later stage.
SARS-CoV-2 evolution in the absence of selective immune pressures, results in antibody resistance, interferon suppression and phenotypic differences by lineage
Authors: Willett Julian Daniel Sunday , Gravel Annie , Dubuc Isabelle , Gudimard Leslie , dos Santos Pereira Andrade Ana Claudia , Lacasse Émile , Fortin Paul , Liu Ju-Ling , Cervantes Jose Avila , Galvez Jose Hector , Djambazian Haig Hugo Vrej , Zwaig Melissa , Roy Anne-Marie , Lee Sally , Chen Shu-Huang , Ragoussis Jiannis , Flamand Louis
Published: January 2023

The persistence of COVID-19 is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of Wuhan-like SARS-CoV-2 in Balb/c mice yielded mouse-adapted strains with greater infectivity and mortality. We investigated if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing human ACE2 receptor, in a BSL-3 laboratory without selective pressures, would drive human health-relevant evolution and if evolution was lineage-dependent. Late-passage virus caused more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurred with ade novospike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, was co-inherited at times with spike E1182G per Nanopore sequencing, existing in different quasi-species at others. Both are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2’s tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribute.
In situarchitecture of Opa1-dependent mitochondrial cristae remodeling
Authors: Fry Michelle Y. , Navarro Paula P. , Hakim Pusparanee , Ananda Virly Y. , Qin Xingping , Landoni Juan C. , Rath Sneha , Inde Zintis , Lugo Camila Makhlouta , Luce Bridget E. , Ge Yifan , McDonald Julie L. , Ali Ilzat , Ha Leillani L. , Kleinstiver Benjamin P. , Chan David C. , Sarosiek Kristopher A. , Chao Luke H.
Published: January 2023

Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We performin situcryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.

Highlights

In situultrastructural characterization of mitochondrial cristae with different forms of Opa1.

Mitochondria with predominantly l-Opa1 show crista stacking, longer cristae, reduced globular cristae and an absence of tubular cristae.

Mitochondria with mostly s-Opa1 showed irregular cristae packing with wider cristae junctions and narrower cristae.

l-Opa1 expressing cells with WT-like cristae junction properties, show wild-type apoptotic response and calcium handling.

Imbalance in Opa1 processing show compromised respiratory function and an increase in amorphous cristae.
In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming
Authors: Antunes Ana Vera , Shahinas Martina , Swale Christopher , Farhat Dayana C. , Ramakrishnan Chandra , Bruley Christophe , Cannella Dominique , Corrao Charlotte , Couté Yohann , Hehl Adrian B. , Bougdour Alexandre , Coppens Isabelle , Hakimi Mohamed-Ali
Published: January 2023

Summary paragraph

Sexual reproduction ofToxoplasma gondii, which is restricted to the small intestine of felids, is sparsely documented, due to ethical concerns surrounding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1. In this study, we found that transcription factors AP2XII-1 and AP2XI-2, expressed in tachyzoite stage that causes acute toxoplasmosis, can silence genes necessary for merozoites, a developmental stage critical for sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a drastic change in the transcriptional program, promoting a complete transition from tachyzoites to merozoites. Pre-gametes producedin vitrounder these conditions are characterized by specific protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit the epigenitors MORC and HDAC31, which in turn restrict the accessibility of chromatin to the transcriptional machinery. Thus, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. This effectivein vitroculture of merozoites paves the way to exploreToxoplasmasexual reproduction without the need to infect kittens and has potential for the development of therapeutics to block parasite transmission.
Allosteric communication induced by GTP binding sets off a closed-to-open transition in a bacterial dynamin-like protein
Authors: Schumann Wibke , Strodel Birgit
Published: January 2023

Dynamin superfamily proteins are mechanochemical GTPases that operate in highly oligomeric and highly cooperative superstructures to deform lipid membranes. It is known from the structures of a bacterial dynamin-like protein (BDLP) that binding of GTP and association of BDLP with lipids causes a transition from closed to open hinge 1 that affects oligomerization. We trace this radical, large-scale conformational change at the atomic level with unbiased, replica exchange, and umbrella sampling molecular dynamics simulations. We decipher how GTP loading from the GTPase domain to the distal stalk end is mediated by an allosteric network of salt bridges that act in response to GTP binding and subsequent conformational changes in GTPase domain motifs. Two previously undiscovered motifs have been identified whose movements free the paddle from the GTPase domain, allowing large-scale domain rearrangements. In addition, a novel wide-open state of BDLP reminiscent of human dynamin 1 is discovered. Our results explain several aspects of the BDLP cycle and have broad implications for other members of the dynamin family.
Human tissues exhibit diverse composition of translation machinery
Authors: Anisimova Aleksandra S. , Kolyupanova Natalia M. , Makarova Nadezhda E. , Egorov Artyom A. , Kulakovskiy Ivan V. , Dmitriev Sergey E.
Published: January 2023

While protein synthesis is vital for the majority of cell types of the human body, diversely differentiated cells require specific translation regulation. This suggests specialization of translation machinery across tissues and organs. Using transcriptomic data from GTEx, FANTOM, and Gene Atlas we systematically explored the abundance of transcripts encoding translation factors and aminoacyl-tRNA synthetases (ARSases) in human tissues. We revised a few known and identified several novel translation-related genes exhibiting strict tissue-specific expression. The proteins they encode include eEF1A1, eEF1A2, PABPC1L, PABPC3, eIF1B, eIF4E1B, eIF4ENIF1, and eIF5AL1. Furthermore, our analysis revealed a pervasive tissue-specific relative abundance of translation machinery components (e.g. PABP and eRF3 paralogs, eIF2B subunits, eIF5MPs, and some ARSases), suggesting presumptive variance in the composition of translation initiation, elongation, and termination complexes. These conclusions were largely confirmed by the analysis of proteomic data. Finally, we paid attention to sexual dimorphism in the repertoire of translation factors encoded in sex chromosomes (eIF1A, eIF2γ, and DDX3), and identified testis and brain as organs with the most diverged expression of translation-associated genes.
Schizophrenia, inflammation and temporal change in brain morphology: an omnigenic Mendelian randomization study
Authors: Ren Hongyan , Liu Yunjia , Zhang Yamin , Wang Qiang , Deng Wei , Ma Xiaohong , Zhao Liansheng , Li Xiaojing , Sham Pak , Li Tao
Published: January 2023

The last decades of research in schizophrenia witnessed a shift of etiological speculation from neurotransmitters to inflammation. However, identifying definite inflammatory effectors of schizophrenia remains elusive due to confounding factors such as medication and metabolic status. To tackle this issue, we carried out omnigenic-based Mendelian randomization (MR) analysis to explore the inflammatory responses of schizophrenia and the brain morphological consequences caused by these SCZ-triggering inflammation responses. Our results identified seven SCZ-triggering inflammation markers, with P values surviving the Bonferroni multiple comparisons (B_NGF, P = 1.45 × 10−8; GROA (CXCL1) P = 1.15 × 10−4; IL8, P = 3.64 × 10−7; MCSF, P = 9.30 × 10−4; MCP3 (CCL7), P = 1.3 × 10−6; TNF_β, P = 3.63 × 10−4; CRP, P = 1.71 × 10−32). Further, three of them, GROA (CXCL1), IL8 and CRP, could lead to significant linear change rate of brain morphologies, especially white matter in both cerebral and cerebellum. Our study is the first to use an omnigenic conceptual framework to capture the immune pathology of schizophrenia. Although future studies adopting a different methodology are needed to validate our results, our study provides another piece of evidence that extensive and low-grade neuroinflammation exists in schizophrenia and that some of these inflammation markers could be potential targets for the precise diagnosis and treatment of schizophrenia.
Dopamine enhances population coding of fear in prefrontal cortex
Authors: Lesas Jeremy , Pierre Feugas , Herry Cyril , Dejean Cyril
Published: January 2023

Fear acquisition is a survival strategy enabling the prediction of potential threat on the basis of reliable environmental cues identified through associative learning. In this study we investigated the role of dorsomedial prefrontal cortex (dmPFC) – ventral tegmental area (VTA) coordination in fear acquisition. Despite the implication of a VTA-dmPFC circuit in fear acquisition, the mechanism by which the two structures interact and, most particularly, the manner in which dmPFC neuronal dynamics are impacted by DA remain largely unexplored. The present paper addresses this question by means of behavioral, optogenetic, and electrophysiological experiments. We first characterize the dynamics of VTA neurons and their relation with dmPFC during fear acquisition to then manipulate this dopaminergic inputs to dmPFC and address its role in fear memory expression and its dmPFC neuronal correlates. Our data first unravel that VTA neurons develop a conditioned stimulus coding activity through consecutive pairings with the unconditioned aversive stimulus and maintain this predictive activity overnight. Shutting down these VTA inputs to dmPFC resulted in a reduction in fear behavior and changes in population coding. These alteration were specific to spontaneous expression of fear and the population coding supporting that behavior. Our data show that dopamine role is to increase the accuracy of fear coding in dmPFC.
An investigation of the impact of community controls on commonly reported epidemiological estimates in tuberculosis (TB) household contact study
Authors: Shi Haodong , Li Tenglong
Published: January 2023

Background

Tuberculosis (TB) has long been a major public health problem worldwide. In particular, during the period of the raging covid-19 epidemic, the situation of tuberculosis prevention and control has been critical. However, current TB household contact study describes the general risk of TB in target population and are unable to characterize the individual risk following exposure to active TB cases.

Method

We designed a dynamic simulation program for TB transmission to generate simulated datasets based on historical data on TB infection in four regions of Brazil, conducted a household contact study of household contacts with active TB (n=1711), and added matched (n=1362) and unmatched (n=1276) community control households to generate different datasets, respectively. We estimated the Second attack rate (SAR), Odds ratio, relative risk for each dataset.

Result

Enrolling community controls extends the classical model of infectious disease SAR to TB in a household contact setting. Allowing us to separate the risk of household exposure from the risk of TB infection in the community, thus obtaining separate estimates of SAR and risk of contact with active TB cases. But over-matching for community control can lead to a reduction in the amount of data and even mask certain risk factors.
Oomycete effector AVRblb2 targets cyclic nucleotide-gated channels through calcium sensors to suppress pattern-triggered immunity
Authors: Lee Soeui , Lee Hye-Young , Kang Hui Jeong , Seo Ye-Eun , Lee Joo Hyun , Choi Doil
Published: January 2023

Transient, rapid increase of cytosolic Ca2+upon pathogen infection is essential for plant pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). Several cyclic nucleotide-gated channels (CNGCs) have been implicated; however, their regulatory mechanisms remain elusive. Here, thePhytophthora infestansRXLR effector AVRblb2 family targeted NbCNGC18–20 at the plasma membrane, inhibiting Ca2+influx and PTI. AVRblb2 required calmodulin (CaM) and calmodulin-like (CML) proteins as co-factors to interact withN. benthamianaCNGCs (NbCNGCs), forming the AVRblb2-CaM/CML-NbCNGCs complex. After recognizing PAMPs, NbCNGC18 formed active heteromeric channels with other CNGCs, potentially providing selectivity for diverse signals to fine-tune cytosolic Ca2+levels and responses. AVRblb2 suppressed the Ca2+influx and oxidative burst induced by NbCNGC18 heteromeric complexes. Silencing CNGC18, CNGC20, and CNGC25 compromised the effect of AVRblb2 onP. infestansvirulence, confirming that AVRblb2 contributed to virulence by targeting CNGCs. Our findings delineated the regulatory mechanism and role of effector-targeted Ca2+channels in plant innate immunity.
Assessing the effectiveness of portable HEPA air cleaners for reducing particulate matter exposure in King County, Washington homeless shelters during the COVID-19 pandemic: implications for community congregate settings
Authors: Huang Ching-Hsuan , Bui Thu , Hwang Daniel , Shirai Jeffry , Austin Elena , Cohen Martin , Gould Timothy , Larson Timothy , Novosselov Igor , Tan Shirlee , Seto Edmund
Published: January 2023

Over four thousand portable air cleaners (PACs) with high-efficiency particulate air (HEPA) filters were distributed by Public Health - Seattle & King County to homeless shelters during the COVID-19 pandemic. This study aimed to evaluate the real-world effectiveness of these HEPA PACs in reducing indoor particles and understand the factors that affect their use in homeless shelters. Four rooms across three homeless shelters with varying geographic locations and operating conditions were enrolled in this study. At each shelter, multiple PACs were deployed based on the room volume and PAC’s clean air delivery rate rating. The energy consumption of these PACs was measured using energy data loggers at 1-min intervals to allow tracking of their use and fan speed for three two-week sampling rounds, separated by single-week gaps, between February and April 2022. Total optical particle number concentration (OPNC) was measured at 2-min intervals at multiple indoor locations and an outdoor ambient location. The empirical indoor and outdoor total OPNC were compared for each site. Additionally, linear mixed-effects regression models (LMERs) were used to assess the relationship between PAC use time and indoor/outdoor total OPNC ratios (I/OOPNC). Based on the LMER models, one percent increase in the hourly, daily and total time PACs were used significantly reduced I/OOPNCby 0.34 [95% CI: 0.28, 0.40], 0.51 [95% CI: 0.20, 0.78], 2.52 [95% CI: 1.50, 3.28], respectively, indicating that keeping PACs on resulted in significantly lower I/OOPNCor relatively lower indoor total OPNC than outdoors. The survey suggested that keeping PACs on and running was the main challenge when operating them in shelters. These findings suggested that HEPA PACs were an effective short-term strategy to reduce indoor particle levels in community congregate living settings during non-wildfire seasons and the need for formulating practical guidance for using them in such an environment.
Field assessment of the burden and determinants of malaria transmission to inform tailoring of interventions (microstratification) in Ibadan and Kano metropolis: Study protocol
Authors: Ozodiegwu Ifeoma D. , Ogunwale Akintayo O. , Surakat Olabanji , Akinyemi Joshua O. , Bamgboye Eniola , Fagbamigbe Adeniyi F. , Bello Musa Muhammad , Adamu Al-Mukhtar Y. , Uhomobhi Perpetua , Ademu Cyril , Okoronkwo Chukwu , Adeleke Monsuru , Ajayi IkeOluwapo
Published: January 2023

Introduction

Rapid urbanization in Nigerian cities may likely result in small-scale variation in malaria transmission with a higher malaria burden in informal settlements and slums. However, data is unavailable to quantify city-level variations in transmission risk and to inform selection of appropriate interventions. We are conducting field studies to understand how malaria risk varies at the smallest administrative units (wards) in two major Nigerian cities – Ibadan and Kano – to inform tailoring of interventions for cities in Nigeria’s National Malaria Strategic Plan.

Methods and Analysis

This is a mixed-method research design involving qualitative and quantitative research methods. We will carry out formative qualitative studies to inform sampling strategies for formal settlements, informal settlements and slums and the design of survey questionnaires. Cross-sectional surveys will be conducted in the wet and dry seasons across wards in the study cities and within different settlement types at the household and health facility levels to map all-age and under-five malaria prevalence and evaluate related risk factors. A 12-month longitudinal study among children under the age of 10 years will provide information on malaria seasonality in the two cities and related factors. Entomological surveys will be used to undertaken for eight months (four months in each season) per city to assess local transmission risk in both cities. Descriptive and regression analysis will be applied to study data to assess malaria prevalence, seasonality and related factors. Mathematical models of malaria transmission for each study ward will be developed based on study data to inform assessment of the impact of various intervention scenarios specified by the NMEP on malaria transmission.

Ethics and Dissemination

This protocol has been approved by Nigeria’s National Health Research Committee and relevant institutional Ethical Review Committees. Study results will be disseminated to key stakeholders and study communities.

Strength and Limitations

Strengths

Cross-sectional and longitudinal study sampling procedures and questionnaire design are enhanced by a strong formative research foundation

Study design and site selection are informed by modeling and local knowledge

The combination of human and vector studies will provide detailed information on malaria transmission risk and associated drivers

Limitations

Cross-sectional study may not be powered to measure all-age prevalence as sample size estimation is based on prevalence among children under the age of five years

Study findings may not adequately measure transmission burden and risk factors in unsampled wards
Comparison of external treatment of Acupuncture and moxibustion and intervention of Chinese and Western Medicine on postoperative pain of hemorrhoids: A systematic review and meta-analysis
Authors: Zou XinYan , Liu QiaoQiao , Gao LongXia , Zhao HanQing
Published: January 2023

Objective

To evaluate the clinical efficacy and safety of acupuncture and moxibustion in the treatment of postoperative pain of hemorrhoids compared with traditional Chinese medicine and western medicine.

Methods

The CNKI, pubMed, Cochrane Library, Science Direct, Wan Fang, VIP, CBM, WOS, Bailian Yun Library and other databases were systematically retrieved from 2017 to October 2022 for clinical randomized controlled trials of acupuncture versus traditional Chinese and Western medicine for postoperative pain in hemorrhoids. The two evaluators independently retrieved, sifted through literature and extracted data for inclusion in a randomized controlled trial of acupuncture for the treatment of hemorrhoid pain that matched the study. Literature quality assessment was performed using RevMan5.4 for meta-analysis.

Results

A total of 540 related literature articles were retrieved, of which 139 were from CNKI, 104 from Wan Fang, 104 from VIP26, 7 from PubMed, 9 from Cochrane, 35 from WOS, 173 from China Biomedical Literature Database, 1 from Science Direct and 46 from the Bailian Yun Library, Screening resulted in inclusion of 10 RCTs including 870 patients. Meta analysis showed that there was no significant difference in the degree of pain in 2 hours [MD=0.01, 95%CI (−0.23, 0.24), P ≤ 0.95]. And it showed that the total effective rate of the two groups was [RR=1.14, 95%CI (1.06, 1.24), P ≤ 0.0001], intervention for 2days pain degree was [MD=-0.41, 95%CI (−0.69, 0.13), P ≤ 0.004], the incidence of adverse reaction was [RR=0.15, 95%CI (0.03, 0.79), P=0.03], the difference was statistically significant (P<0.05).

Conclusion

Drug treatment is effective quickly, analgesia effect is better than acupuncture in early treatment, but the effect is not lasting. Acupuncture treatment is slow to start but the effects of acupuncture will gradually become apparent at a later stage. However, due to the low quality of inclusion, multicenter, large sample size and double-blind randomized controlled trials are still needed.
Level of partograph utilization and its predictors among obstetrics care givers in Ilu Aba Bor Zone, Southwest Ethiopia: a cross-sectional study
Authors: Tesfaye Getamesay Aynalem , Chanie Fentaneh Teshome , Gemechu Ebissa Negera
Published: January 2023

Background

Worldwide, several thousands of mothers die per a year due to pregnancy and birth related complications. Most of maternal deaths can be minimized using partograph routinely. In spite of the priceless importance of partograph in reducing maternal death, its level of utilization and associated factors has been little known among obstetrics care providers in Ilu Aba Bor Zone.

Objective

This study aimed at assessing the level of partograph utilization and associated factors among obstetric care givers in Ilu Aba Bor Zone, South West Ethiopia.

Methods

An institution-based cross-sectional study design was employed. A structured self-administered and pretested questionnaire adapted from available literatures were used. In addition to descriptive statistics, logistic regression analysis was applied to assess association.

Results

The level of partograph utilization among obstetrics care providers in the study area was 32.8%. Receiving on-job training on partograph (AOR (Adjusted Odds Ratio) = 2.21, 95%CI (Confidence Interval) = 1.19, 4.11), working in a hospital compared to working in a health center (AOR = 2.43, 95%CI = 1.01, 5.82), having BSc (Bachelor of Science) and above educational status in contrast to having Diploma (AOR = 3.12, 95%CI = 1.59, 6.12), and having partograph in a health facility (AOR= 4.19, 95%CI = 2.12, 8.29) were positively associated with partograph use.

Conclusion

Partograph utilization level was much lower than World Health Organization recommendation. On-job training on partograph, work place, educational status, and partograph availability were predictors of level of partograph utilization among the obstetric care givers.
Evidence for vocal signatures and voice-prints in a wild parrot
Authors: Smeele Simeon Q. , Senar Juan Carlos , Aplin Lucy M. , McElreath Mary Brooke
Published: January 2023

In humans, identity is partly encoded in a voice-print that is carried across multiple vocalisations. Other species also signal vocal identity in calls, such as shown in the contact call of parrots. However, it remains unclear to what extent other call types in parrots are individually distinct, and whether there is an analogous voice-print across calls. Here we test if an individual signature is present in other call types, how stable this signature is, and if parrots exhibit voice-prints across call types. We recorded 5599 vocalisations from 229 individually-marked monk parakeets (Myiopsitta monachus) over a two year period in Barcelona, Spain. We examined five distinct call types, finding evidence for an individual signature in three. We further show that in the contact call, while birds are individually distinct, the calls are more variable than previously assumed, changing over short time scales (seconds to minutes). Finally, we provide evidence for voice-prints across multiple call types, with a discriminant function being able to predict caller identity across call types. This suggests that monk parakeets may be able to use vocal cues to recognise conspecifics, even across vocalisation types and without necessarily needing active vocal signatures of identity.