bluuebunny/crossref_metadata_2025 huggingface dataset:
A candidate locus in the renalase gene and susceptibility to blood pressure responses to the dietary salt
Authors: Heydarpour Mahyar , Parksook Wasita W. , Hopkins Paul N. , Pojoga Luminita H. , Williams Gordon H. , Williams Jonathan S.
Published: February 2023

Background:

High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts.

Methods:

A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting.

Results:

A top signal (rs10887801; beta = 4.57, P = 5.03E − 07) at the renalase gene (RNLS) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP (P ≤ 0.00001) and lower PRA (P = 0.0076) compared with the nonrisk allele.

Conclusion:

We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake.
Reliability of Postoperative Free Flap Monitoring with a Novel Prediction Model Based on Supervised Machine Learning
Authors: Huang Ren-Wen , Tsai Tzong-Yueh , Hsieh Yun-Huan , Hsu Chung-Chen , Chen Shih-Heng , Lee Che-Hsiung , Lin Yu-Te , Kao Huang-Kai , Lin Cheng-Hung
Published: February 2023

Background:

Postoperative free flap monitoring is a critical part of reconstructive microsurgery. However, postoperative clinical assessments rely heavily on specialty-trained staff. Therefore, in regions with limited specialists, the feasibility of performing microsurgery is restricted. This study aims to apply artificial intelligence in postoperative free flap monitoring and validates the ability of machine learning in predicting and differentiating types of postoperative free flap circulation.

Methods:

Postoperative data from 176 patients who received free flap surgery were prospectively collected, including free flap photos and clinical evaluation parameters. The flap circulation outcome variables are normal, arterial insufficiency, and venous insufficiency. The Synthetic Minority Oversampling Technique plus Tomek Links (SMOTE-Tomek) was applied for data balance. Data were divided into 80%: 20% for model training and validation. SHapley Additive exPlanations was used for prediction interpretations of the model.

Results:

A total of 805 data were collected, 555 (69%) were normal flaps, 97 (12%) were flaps with arterial insufficiency, and 153 (19%) were flaps with venous insufficiency. The most effective prediction model was developed based on Random Forest with an accuracy of 98.4%. Temperature and color differences between the flap and the surrounding skin were the most significant contributing factors to predict a vascular compromised flap.

Conclusion:

This study demonstrated the reliability of our machine learning model in differentiating various types of postoperative flap circulation. This novel technique may reduce the burden of free flap monitoring and encourage the broader use of reconstructive microsurgeries in regions with limited staff specialists.
Weight Change Following Switch to Dolutegravir for HIV Treatment in Rural Kenya During Country Roll-Out
Authors: Hickey Matthew D. , Wafula Erick , Ogachi Sabina M. , Ojwando Hellen , Orori Gordon , Adede Richard O. , Garraza Lucas Godoy , Petersen Maya L. , Havlir Diane V. , Balzer Laura B. , Ayieko James
Published: February 2023

Introduction:

Switch to dolutegravir (DTG) in treatment-experienced people living with HIV (PLH) is associated with excess weight gain in some settings; data are limited from rural low-income settings with low obesity prevalence.

Methods:

In rural Kenya, we conducted a retrospective cohort study at 8 HIV clinics and a single-site prospective cohort study including adults switching to DTG during countrywide transition to DTG/tenofovir DF(TDF)/emtricitabine as first-line HIV treatment. In the retrospective analysis, we used preswitch data to model postswitch weight trajectory had each participant not switched to DTG and contrasted observed vs. predicted postswitch weight. In the prospective analysis, we measured weight post-DTG switch and evaluated predictors of 6-month weight change.

Results:

Our retrospective cohort included 4445 PLH who switched to DTG between 2018 and 2020. Mean 12-month weight change was 0.6 kg preswitch and 0.8 kg postswitch. Among those on TDF throughout (n = 3374; 83% on efavirenz preswitch), 12-month postswitch weight was 0.7 kg more than predicted for women (95% CI: 0.4, 1.0) and similar among men (0.04 kg; 95% CI −0.3, 0.4). In our prospective cohort (n = 135, 100% female), mean 6-month weight change was +0.4 kg (IQR −1.1, 2.0 kg). Predicted gain varied by baseline food insecurity: +1.1 kg (95% CI: 0.34, 1.87) among food secure, −0.09 kg (95% CI −0.71, 0.54) among moderate insecure, and +0.27 kg (95% CI −0.82, 1.36) among severe insecurity.

Conclusion:

In contrast to some reports of large weight gain following switch to DTG, we observed small weight increases in women and no weight change in men following DTG switch when on TDF throughout. Weight gain may be attenuated by food insecurity, though was modest even among food secure.
Microgravity and immune cells
Authors: Lv Hongfang , Yang Huan , Jiang Chunmei , Shi Junling , Chen Ren-an , Huang Qingsheng , Shao Dongyan
Published: February 2023

The microgravity environment experienced during spaceflight severely impaired immune system, making astronauts vulnerable to various diseases that seriously threaten the health of astronauts. Immune cells are exceptionally sensitive to changes in gravity and the microgravity environment can affect multiple aspects of immune cells through different mechanisms. Previous reports have mainly summarized the role of microgravity in the classification of innate and adaptive immune cells, lacking an overall grasp of the laws that microgravity effects on immune cells at different stages of their entire developmental process, such as differentiation, activation, metabolism, as well as function, which are discussed and concluded in this review. The possible molecular mechanisms are also analysed to provide a clear understanding of the specific role of microgravity in the whole development process of immune cells. Furthermore, the existing methods by which to reverse the damage of immune cells caused by microgravity, such as the use of polysaccharides, flavonoids, other natural immune cell activators etc. to target cell proliferation, apoptosis and impaired function are summarized. This review will provide not only new directions and ideas for the study of immune cell function in the microgravity environment, but also an important theoretical basis for the development of immunosuppression prevention and treatment drugs for spaceflight.
Bone conduction facilitates self-other voice discrimination
Authors: Orepic Pavo , Kannape Oliver Alan , Faivre Nathan , Blanke Olaf
Published: February 2023

One's own voice is one of the most important and most frequently heard voices. Although it is the sound we associate most with ourselves, it is perceived as strange when played back in a recording. One of the main reasons is the lack of bone conduction that is inevitably present when hearing one's own voice while speaking. The resulting discrepancy between experimental and natural self-voice stimuli has significantly impeded self-voice research, rendering it one of the least investigated aspects of self-consciousness. Accordingly, factors that contribute to self-voice perception remain largely unknown. In a series of three studies, we rectified this ecological discrepancy by augmenting experimental self-voice stimuli with bone-conducted vibrotactile stimulation that is present during natural self-voice perception. Combining voice morphing with psychophysics, we demonstrate that specifically self-other but not familiar-other voice discrimination improved for stimuli presented using bone as compared with air conduction. Furthermore, our data outline independent contributions of familiarity and acoustic processing to separating the own from another's voice: although vocal differences increased general voice discrimination, self-voices were more confused with familiar than unfamiliar voices, regardless of their acoustic similarity. Collectively, our findings show that concomitant vibrotactile stimulation improves auditory self-identification, thereby portraying self-voice as a fundamentally multi-modal construct.
Effects of different acute stressors on the regulation of appetite genes in the carp (Cyprinus carpioL.) brain
Authors: Pawlak Paulina , Burren Alexander , Seitz Andreas , Pietsch Constanze
Published: February 2023

Our understanding of the timing of stress responses and specific roles of different regulatory pathways that drive stress responses is incomplete. In particular, the regulation of appetite genes as a consequence of exposure to different stressors has not been studied in sufficient detail in fish. Therefore, a stress trial was conducted with koi carp, aiming at identifying typical effects of stress on regulation of appetite genes. The stressors tank manipulation, air exposure and feed rewarding were chosen. The responses to these stressors were evaluated 10, 30 and 60 min after the stressors were applied. Orexigenic and anorexigenic genes were investigated in four different brain regions (telencephalon, hypothalamus, optic tectum and rhombencephalon). The results show that, apart from the typical appetite regulation in the hypothalamus, the different brain regions also display pronounced responses of appetite genes to the different stressors. In addition, several genes in the serotonergic, dopaminergic and gaba-related pathways were investigated. These genes revealed that rearing in pairs of two and opening of the tank lid affected anorexigenic genes, such ascartandcck,which were not changed by air exposure or feed rewarding. Moreover, distress and eustress led to limited, but distinguishable gene expression pattern changes in the investigated brain regions.
Ancient DNA of narrow-headed vole reveal common features of the Late Pleistocene population dynamics in cold-adapted small mammals
Authors: Baca Mateusz , Popović Danijela , Agadzhanyan Alexander K. , Baca Katarzyna , Conard Nicholas J. , Fewlass Helen , Filek Thomas , Golubiński Michał , Horáček Ivan , Knul Monika V. , Krajcarz Magdalena , Krokhaleva Maria , Lebreton Loïc , Lemanik Anna , Maul Lutz C. , Nagel Doris , Noiret Pierre , Primault Jérome , Rekovets Leonid , Rhodes Sara E. , Royer Aurélien , Serdyuk Natalia V. , Soressi Marie , Stewart John R. , Strukova Tatiana , Talamo Sahra , Wilczyński Jarosław , Nadachowski Adam
Published: February 2023

The narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of the collared lemming and common vole have revealed dynamic population histories shaped by climatic fluctuations. To investigate the extent to which species with similar adaptations share common evolutionary histories, we generated a dataset comprised the mitochondrial genomes of 139 ancient and 6 modern narrow-headed voles from several sites across Europe and northwestern Asia covering approximately the last 100 thousand years (kyr). We inferred Bayesian time-aware phylogenies using 11 radiocarbon-dated samples to calibrate the molecular clock. Divergence of the main mtDNA lineages across the three species occurred during marine isotope stages (MIS) 7 and MIS 5, suggesting a common response of species adapted to open habitat during interglacials. We identified several time-structured mtDNA lineages in European narrow-headed vole, suggesting lineage turnover. The timing of some of these turnovers was synchronous across the three species, allowing us to identify the main drivers of the Late Pleistocene dynamics of steppe- and cold-adapted species.
Herbivory selects for tolerance and constitutive defence across stages of community succession
Authors: Kalske Aino , Kessler André
Published: February 2023

Plants defend themselves from herbivory by either reducing damage (resistance) or minimizing its negative fitness effects with compensatory growth (tolerance). Herbivore pressure can fluctuate from year to year in an early secondary successional community, which can create temporal variation in selection for defence traits. We manipulated insect herbivory and successional age of the community as agents of natural selection in replicated common gardens with the perennial herb
Solidago altissima
. In these genotypic selection experiments, herbivory consistently selected for better defended plants in both successional communities. Herbivore suppression increased plant survival and the probability of flowering only in mid-succession. Despite these substantial differences in the effects of herbivory between early and mid-succession, the selection on defence traits did not change. Succession affected selection only on aboveground biomass, with positive selection in early but not mid-succession, suggesting an important role of competition in the selective environment. These results demonstrate that changes in the community that affect key life-history traits in an individual species can occur over very short timescales in a dynamic secondary successional environment. The resulting community context-driven variation in natural selection may be an important, yet overlooked, contributor to adaptive mosaics across populations.
Signatures of contextual interference in implicit sensorimotor adaptation
Authors: Tsay Jonathan S. , Irving Carolyn , Ivry Richard B.
Published: February 2023

Contextual interference refers to the phenomenon whereby a blocked practice schedule results in faster acquisition but poorer retention of new motor skills compared to a random practice schedule. While contextual interference has been observed under a broad range of tasks, it remains unclear if this effect generalizes to the implicit and automatic recalibration of an overlearned motor skill. To address this question, we compared blocked and random practice schedules in a visuomotor rotation task that isolates implicit adaptation. In experiment 1, we found robust signatures of contextual interference in implicit adaptation: compared to participants tested under a blocked training schedule, participants tested under a random training schedule exhibited a reduced rate of learning during the training phase but better retention during a subsequent no-feedback assessment phase. In experiment 2, we again observed an advantage in retention following random practice and showed that this result was not due to a change in context between the training and assessment phases (e.g. a blocked training schedule followed by a random assessment schedule). Taken together, these results indicate that contextual interference is not limited to the acquisition of new motor skills but also applies to the implicit adaptation of established motor skills.
Barnettozyma menglunensis f.a., sp. nov., a novel yeast species isolated from rotting wood
Authors: Qiao Ya-Zhuo , Chen Xue , Hui Feng-Li
Published: February 2023

A novel yeast species is described based on three strains isolated from rotting wood samples from Xishuangbanna Tropical Rainforest in Yunnan Province, PR China. Strain NYNU 1811121 was isolated in Menglun, Mengla, while strains NYNU 18982 and NYNU 181096 were recovered in Mengyang, Jinghong. Analysis of the sequences of the D1/D2 domain of the large subunit rRNA gene and the internal transcribed spacer (ITS) region (ITS1-5.8S–ITS2) revealed that the novel strains were closely related to the type strain of [Candida]sanyiensis, but with 6.9 % nucleotide substitutions in the D1/D2 domain and 8.2 % substitutions in the ITS region. The three novel strains can also be distinguished fromC. sanyiensisin terms of the ability to assimilate trehalose andd-gluconate and to grow at 35 °C, as well as the inability to ferment glucose. Based on molecular analyses and phenotypic characteristics, the nameBarnettozyma menglunensisf.a., sp. nov. is proposed with the holotype CBS 16011T(MycoBank 845375).
Acute care disruptions due to information technology failures in the Netherlands from 2000 to 2020
Authors: van Boven Liselotte S. , Kusters Renske W.J. , Klokman Vincent W. , Dameff Christian , Barten Dennis G.
Published: February 2023

Background

Healthcare organizations are becoming increasingly dependent on Information technology (IT) for the provision of routine services. IT failures within hospital systems can impact acute patient care, including emergency department (ED) closure and the cancellation of operations. This study aims to gain insight into the impact of hospital IT failures in the Netherlands on acute care delivery and to provide recommendations for future preparedness.

Methods

This is a systematic scoping review of major acute care disruptions in Dutch hospitals between 2000 and 2020. Incidence of etiology, duration, ED diversion, and closure of multiple locations was evaluated. IT failures were included when associated with the closure of hospital departments and/or evacuations.

Results

Thirty-nine IT failures resulting in acute care disruption were identified. The majority occurred between 2010 and 2020 (n=37, 95%). Of the 39 events, 33 (85%) were primary IT failures and were mainly caused by computer network and/or hospital software failure. Secondary events predominantly resulted from power failure. Most events (n= 36, 92%) were resolved within minutes to hours. All events were associated with an ED closure, 27 (69%) with an operating room (OR) stop and two (5%) with external hospital evacuation of one or more patients. Furthermore, 17 incidents (44%) involved multiple hospital locations, and seven (41%) of these involved closure of multiple locations with an ED.

Conclusion

The impact of IT failures on acute care disruptions in the Netherlands has considerably increased since 2010. This stresses the urge to improve IT security and business continuity in today’s hospitals.

PUBLIC INTEREST SUMMARY

As the healthcare industry is becoming increasingly digitalized, technological failure potentially has a major impact on hospitals and patient care continuity. The current study found that Information Technology (IT) failures in Dutch hospitals between 2000 and 2020 are increasingly associated with acute care disruptions. IT failures were mainly caused by software or hardware failures or by power outages. Preventive measures and emergency planning may lessen the impact and ensure improved business- and patient care continuity.
Designed Transmembrane Proteins Inhibit the Erythropoietin Receptor in a Custom Binding Topology
Authors: Mravic Marco , He Li , Kratochvil Huong , Hu Hailin , Nick Sarah E. , Bai Weiya , Edwards Anne , Jo Hyunil , Wu Yibing , DiMaio Daniel , DeGrado William F.
Published: February 2023

Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design ofde novoTM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation.In vitro,the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom designed topologies.
CellWalker: A user-friendly and modular computational pipeline for morphological analysis of microscopy images
Authors: Khare Harshavardhan , Dongo Mendoza Nathaly , Zurzolo Chiara
Published: February 2023

The implementation of computational tools for analysis of microscopy images has been one of the most important technological innovations in biology, providing researchers unmatched capabilities to comprehend cell shape and connectivity. Most available tools frequently focus either on segmentation or morphological analysis, thus not providing an inclusive pipeline. We introduce CellWalker, a computational pipeline that streamlines and connects the segmentation step with the morphological analysis in a modular manner. This python-based pipeline starts with ‘visible-source’ IPython notebooks for segmentation of 2D/3D microscopy images using deep learning and visualization of the segmented images. The next module of CellWalker runs inside Blender, an open-source computer graphics software. This addon provides several morphometric analysis tools that can be used to calculate distances, volume, surface areas and to determine cross-sectional properties. It also includes tools to build skeletons, calculate distributions of sub-cellular organelles. Overall, CellWalker provides practical tools for segmentation and morphological analysis of microscopy images in the form of an open-source and modular pipeline which allows a complete access to fine-tuning of algorithms through visible source code while still retaining a result-oriented interface.

Contact

harshkhare@gmail.com,chiara.zurzolo@pasteur.fr

Availability and implementation

CellWalker source code is available on GitHub (https://github.com/utraf-pasteur-institute/CellWalker-notebooksandhttps://github.com/utraf-pasteur-institute/CellWalker-blender) under a GPL-3 license.
Robustness of Hill’s overlapping-generation method for calculatingNeto extreme patterns of reproductive success
Authors: Waples Robin S.
Published: February 2023

For species with overlapping generations, the most widely-used method to calculate effective population size (Ne) is Hill’s, the key parameter for which is lifetime variance in offspring number (Vk•). Hill’s model assumes stable age structure and constant abundance, and sensitivity to those assumptions has been evaluated previously. Here I evaluate robustness of Hill’s model to extreme patterns of reproductive success, whose effects have not been previously examined: 1) very strong reproductive skew; 2) strong temporal autocorrelations in individual reproductive success; and 3) strong covariance of individual reproduction and survival. Genetic drift (loss of heterozygosity and increase in allele-frequency variance) was simulated in age-structured populations using methods that: generated no autocorrelations or covariances (Model NoCor); or created strong positive (Model Positive) or strong negative (Model Negative) temporal autocorrelations in reproduction and covariances between reproduction and survival. Compared to Model NoCor, the other models led to greatly elevated or reducedVk•, and hence greatly reduced or elevatedNe, respectively. A new index is introduced (ρα,α+), which is the correlation between 1) the number of offspring produced by each individual at the age at maturity (α), and 2) the total number of offspring produced during the rest of their lifetimes. Mean ρα,α+was ≈0 under Model NoCor, strongly positive under Model Positive, and strongly negative under Model Negative. Even under the most extreme reproductive scenarios in Models Positive and Negative, whenVk•was calculated from the realized population pedigree and used to calculateNein Hill’s model, the result accurately predicted the rate of genetic drift in simulated populations. These results held for scenarios where age-specific reproductive skew was random (variance≈mean) and highly overdispersed (variance up to 20 times the mean). Collectively, these results are good news for researchers as they demonstrate the robustness of Hill’s model even to extreme repro0ductive scenarios.
Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome
Authors: Sun Xiaoyi , Liu Jin , Ma Qing , Wang Xiaoqin , Wei Dongtao , Chen Yuan , Liu Bangshan , Huang Chu-Chung , Zheng Yanting , Wu Yankun , Chen Taolin , Cheng Yuqi , Xu Xiufeng , Gong Qiyong , Si Tianmei , Qiu Shijun , Lin Ching-Po , Cheng Jingliang , Tang Yanqing , Wang Fei , Qiu Jiang , Xie Peng , Li Lingjiang , Wang Wenxu , He Yong ,   DIDA-MDD Working Group, Xia Mingrui
Published: February 2023

Major depressive disorder (MDD) is the most burdensome psychiatric disorder characterized by remarkably heterogeneous clinical phenotypes. It remains challenging to delineate the heterogeneity of neurobiological abnormalities underlying the clinical variance and, on this basis, to identify neurophysiological subtypes of MDD patients. Here, using a large multisite resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls, we generated lifespan normative models of functional connectivity strengths, mapped the heterogeneity of patients’ individual deviations, and identified neurobiological MDD subtypes. MDD patients showed positive deviations mainly in the default mode and subcortical areas, and negative deviations widely distributed over the cortex. However, there was a great inter-subject heterogeneity as indicated by that no more than 3.14% of patients deviated from the normative range for any brain region. Two neurophysiological MDD subtypes were identified. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas, and negative deviations in the sensorimotor, dorsal and ventral attention areas, while subtype 2 showed a moderate but conversed deviation pattern. The severe-deviation subtype had older age, higher medicated proportion, and higher Suicide item score, while the moderate-deviation subtype showed higher Work and Activities and Depressed Mood item scores. Moreover, the baseline deviations in the severe-deviation subtype were predictive of 6-month antidepressant treatment effects in a subsample. To our knowledge, the current study is the largest multisite analysis of neurophysiological MDD subtyping to date and the findings shed light on our understanding of the biological mechanisms underlying the intersubject heterogeneity of clinical phenotypes, which are informative for the development of personalized treatments for this disorder.
Single-cell transcriptomic analysis of mouse liver reveals nonparenchymal cells’ intricate responses to PCB126 exposure
Authors: Xu Fengjun , Fu Yulong , Yang Jiaxuan , Yu Chunna , Shen Chaofeng
Published: February 2023

Polychlorinated biphenyls (PCBs) are ubiquitous and representative pollutants that pose great health risks. While cells’ responses to dioxin-like PCBs tend to be studied on a bulk scale, few studies have been made from a single-cell level. Here, by using single-cell RNA sequencing, we depicted a detailed landscape of hepatic nonparenchymal cells’ intricate responses to PCB126 exposure. A total of 13 clusters were identified. Notably, PCB126 exposure resulted in cell-type-specific gene expression profiles and genetic pathways. By analyzing genes related to aryl hydrocarbon receptors, we discovered that PCB126 induced the canonical genomic AhR pathway mainly in endothelial cells. In contrast, other cell types showed little induction. Enrichment pathway analysis indicated that immune cells changed their transcriptional patterns in response to PCB126. ScRNA-seq is a powerful tool to dissect underlying mechanisms of chemical toxicity regarding biological heterogeneity. Taken together, our study not only extends our current understanding of PCB126 toxicity, but also emphasizes the importance ofin vivocell heterogeneity in environmental toxicology.
Neural Systems Underlying the Implementation of Working Memory Removal Operations
Authors: DeRosa Jacob , Kim Hyojeong , Lewis-Peacock Jarrod , Banich Marie T.
Published: February 2023

Recently multi-voxel pattern analysis has verified the removal of information from working memory (WM) via three distinct operationsreplacement, suppression, orclearingcompared to information beingmaintained(Kim et al., 2020). Univariate analyses and classifier importance maps indicate that some brain regions commonly contribute to these operations. This study aimed to use multivariate approaches to determine whether, within these commonly activated brain regions, each of these operations is being represented in a similar or distinct manner. To do so, we usedLeiden community detectionto identify brain networks that are characterized by similar multi-voxel patterns of activity with regard to these WM operations. Four networks were identified. The Visual Network shows similar multi-voxel patterns formaintainandreplace, which are highly dissimilar fromsuppressandclear, suggesting this network differentiates whether an item is held in WM or not. The Somatomotor Network shows distinct multi-voxel patterns forclearrelative to the other operations, suggesting that this network diff in clearing information from WM. The Default Mode Network has distinct patterns forsuppressandclear, also suggesting that clearing information from WM is distinct from suppressing it. The Frontoparietal Control Network displays distinct multi-voxel patterns for each of the four operations, suggesting that this network has high involvement in regulating the flow of information within WM. These results indicate that how information is removed from WM depends on distinct brain networks that each have a particular manner in which their co-activation patterns represent these operations.

SIGNIFICANCE STATEMENT

The ability to actively remove, manipulate and maintain information in working memory (WM) is required for encoding of new information and for controlling thoughts. This study revealed that different brain networks show characteristic multi-voxel activity patterns across four distinct WM operations: maintenance of information, replacement of one item by another, suppression of a specific item, and clearing the mind of all thought. One network, the Frontoparietal Control Network, differentiates all four operations, suggesting it may play a critical role in the controlled removal of information from WM.
A dynamic inflammation model for neutrophil and monocyte responses in sepsis, trauma and surgery patient clusters
Authors: Browning B. , Couenne F. , Bordes C. , Fayolle L. , Venet F. , Textoris J. , Monneret G. , Tayakout-Fayolle M.
Published: February 2023

Time series clustering is applied to inflammation and neutrophil cell development markers, CD16 and CD10, in sepsis, trauma and surgery patients and a dynamical model with an inflammation function,F, is used to represent their evolution over a two month period. Five patient clusters are identified, characterised and evaluated against medical assessment scores and the literature. A dynamical model for neutrophil and monocyte cell counts and maturity has been constructed based on mass balances and cell kinetics in both blood and bone marrow. Cell proliferation and flow rates, as well as expression of monocyte HLA-DR, depend on concentrations of pro- and anti- inflammatory cytokines, IL6 and IL10, viaF. A good fit with the data is obtained for each cluster and the estimated parameters correlate to illness severity. The model is a potential tool for simulation of immunomodulatory therapies.
Out-of-equilibrium gene expression fluctuations in presence of extrinsic noise
Authors: Biondo Marta , Singh Abhyudai , Caselle Michele , Osella Matteo
Published: February 2023

Cell-to-cell variability in protein concentrations is strongly affected by extrinsic noise, especially for highly expressed genes. Extrinsic noise can be due to fluctuations of several possible cellular factors connected to cell physiology and to the level of key enzymes in the expression process. However, how to identify the predominant sources of extrinsic noise in a biological system is still an open question. This work considers a general stochastic model of gene expression with extrinsic noise represented as colored fluctuations of the different model rates, and focuses on the out-of-equilibrium expression dynamics. Combining analytical calculations with stochastic simulations, we fully characterize how extrinsic noise shapes the protein variability during gene activation or inactivation, depending on the prevailing source of extrinsic variability, on its intensity and timescale. In particular, we show that qualitatively different noise profiles can be identified depending on which are the fluctuating parameters. This indicates an experimentally accessible way to pinpoint the dominant sources of extrinsic noise using time-coarse experiments.

Author summary

Genetically identical cells living in the same environment may differ in their phenotypic traits. These differences originate from the inherent stochasticity in all cellular processes, starting from the basic process of gene expression. At this level, large part of the variability comes from cell-to-cell differences in the rates of the molecular reactions due to stochasticity in the level of key enzymes or in physiological parameters such as cell volume or growth rate. Which expression rates are predominantly affected by these so-called “extrinsic” fluctuations and how they impact the level of protein concentration are still open research questions. In this work, we tackle the protein fluctuation dynamics while approaching a steady state after gene activation or repression in presence of extrinsic noise. Our analytical results and simulations show the different consequences of alternative dominant sources of extrinsic noise, thus providing an experimentally-accessible way to distinguish them in specific systems.
Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders
Authors: Li Yen-Der , Ma Michelle W. , Hassan Muhammad Murtaza , Hunkeler Moritz , Teng Mingxing , Puvar Kedar , Lumpkin Ryan , Sandoval Brittany , Jin Cyrus Y. , Ficarro Scott B. , Wang Michelle Y. , Xu Shawn , Groendyke Brian J. , Sigua Logan H. , Tavares Isidoro , Zou Charles , Tsai Jonathan M. , Park Paul M. C. , Yoon Hojong , Majewski Felix C. , Marto Jarrod A. , Qi Jun , Nowak Radosław P. , Donovan Katherine A. , Słabicki Mikołaj , Gray Nathanael S. , Fischer Eric S. , Ebert Benjamin L.
Published: February 2023

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define atrans-labeling covalent molecular glue mechanism, which we term “template-assisted covalent modification”. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes “template-assisted covalent modification” as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.
Comparisons of paternity success for resident and non-resident males and their influences on paternal sibling cohorts in Japanese macaques on Shodoshima Island
Authors: Ishizuka Shintaro , Inoue Eiji
Published: February 2023

In group-living mammals, reproductive success can be attributed to both resident and non-resident males. However, the reproductive success of non-resident males has rarely been investigated at an individual level. As male reproductive success is highly skewed towards specific males, often the most dominant males, the percentage of similar-aged paternal siblings within groups is expected to increase. However, the extent to which each male contributes to the production of cohorts of paternal siblings remains unclear. Here we examined the paternity of 46 offspring born over five consecutive years in a group of Japanese macaquesMacaca fuscataon Shodoshima Island. We quantitatively assessed paternity success for males, including both resident and non-resident males, and the percentages of paternal sibling dyads in the same age cohorts produced by those males. Non-resident males sired neither higher nor lower percentage of offspring compared to resident males, indicating that various males, including non-resident males, usually partake in the within-group breeding of macaque groups. These are possibly because female preference of mating partners can change over time. Subadult males had a lower percentage of paternity success, which may be because females may not prefer the physically immature subadult males. Various males, including non-resident males, contributed to the creation of paternal sibling in the same age cohort. The overall results suggest that not only resident but also non-resident males play an important role in shaping within-group kin structures. Future studies are required to examine how paternal siblings interact with each other.
Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models
Authors: Chin Randall M. , Rakhit Rishi , Ditsworth Dara , Wang Chengzhong , Bartholomeus Johan , Liu Song , Mody Akash , Laishu Alex , Eastes Andrea , Tai Chao , Kim Roy Y. , Li Jessica , Hansberry Steven , Khasnavis Saurabh , Rafalski Victoria , Herendeen Donald , Garda Virginia , Phung Jennie , de Roulet Daniel , Ordureau Alban , Harper J. Wade , Johnstone Shawn , Stöhr Jan , Hertz Nicholas T.
Published: February 2023

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD.

Highlights

Discovery of a plasma Parkinson’s Disease biomarker candidate, pS65-Ubiquitin (pUb)

Plasma pUb levels correlate with disease status and progression in PD patients.

Identification of a potent, brain penetrant PINK1 activator, MTK458

MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complex

MTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson’s models
Maribacter halichondrissp. nov., isolated from the marine spongeHalichondria panicea
Authors: Steiner Leon X. , Wiese Jutta , Rahn Tanja , Borchert Erik , Slaby Beate M. , Hentschel Ute
Published: February 2023

A new member of the familyFlavobacteriaceae(termed Hal144T) was isolated from the marine breadcrumb spongeHalichondria panicea. Sponge material was collected in 2018 at Schilksee which is located in the Kiel Fjord (Baltic Sea, Germany). Phylogenetic analysis of the full-length Hal144T16S rRNA gene sequence revealed similarities from 94.3% - 96.6% to the nearest type strains of the genusMaribacter. The phylogenetic tree depicted a cluster of strain Hal144Twith its closest relativesMaribacter aestuariiGY20T(96.6%) andMaribacter thermophilusHT7-2T(96.3%). Genome comparisons of strain Hal144TwithMaribacterspp. type strains exhibited average nucleotide identities in the range of 75% - 76% and digital DNA-DNA hybridization values in the range of 13.1% - 13.4%. Strain Hal144Twas determined to be Gram-negative, mesophilic, strictly aerobic, flexirubin positive, resistant to aminoglycoside antibiotics, and able to utilize N-acetyl-β-D-glucosamine. Optimal growth occurred at 25 – 30 °C, within a salinity range of 2 - 6% sea salt, and a pH range between 5 - 8. The major fatty acids identified were C17:03-OH, iso-C15:0, and iso-C15:1G. The DNA G+C content of strain Hal144Twas 41.4 mol%. Based on the polyphasic approach, strain Hal144Trepresents a novel species of the genusMaribacter, and we propose the nameMaribacter halichondrissp. nov.. The type strain is Hal144T(= DSM 114563T= LMG 32744T).
Rice Gene Index (RGI): a comprehensive pan-genome database for comparative and functional genomics of Asian rice
Authors: Yu Zhichao , Chen Yongming , Zhou Yong , Zhang Yulu , Li Mengyuan , Ouyang Yidan , Chebotarov Dmytro , Mauleon Ramil , Zhao Hu , Xie Weibo , McNally Kenneth L. , Wing Rod A. , Guo Weilong , Zhang Jianwei
Published: February 2023

To integrate the genomic information of the rice pan-genome, we performed comparative analyses and established a user-friendly Rice Gene Index (RGI,https://riceome.hzau.edu.cn) platform with 16 platinum standard reference genomes and supplementary transcriptome data. To logically organize and scientifically the index of 744,233 genes among rice accessions, we detected 112,658 Ortholog Gene Indices, and provide ‘GeneCard’ pages to query genomic, transcriptomic, and homology information for each gene. The RGI allows users to search for relationships and comprehensive information of genes in keyword-based, sequence-based, and relationship-based ways. Furthermore, users can visualize these relationships at local and global scales corresponding to ‘Microcollinearity’ and ‘Macrocollinearity’ modules.
Signatures of criticality in efficient coding networks
Authors: Safavi Shervin , Chalk Matthew , Logothetis Nikos , Levina Anna
Published: February 2023

The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory information processing (e. g., sensitivity to input) are optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient encoding of stimuli. We consider a spike-coding network of leaky integrate-and-fire neurons with synaptic transmission delays and input noise. Previously, it was shown that the performance of such networks varies non-monotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibits signatures of criticality, namely, the distribution of avalanche sizes follows a power law. When the noise amplitude is too low or too high for efficient coding, the network appears either super-critical or sub-critical, respectively. Our work suggests that two influential, and previously disparate theories of neural processing optimization – efficient coding, and criticality – may be intimately related.
Exploring Decision-making Processes: The Impact of Acute High-Intensity Aerobic Exercise
Authors: Davranche Karen , Giraud Dorian , Hays Arnaud , Gajdos Thibault
Published: February 2023

The present study aims to investigate the impact of acute high-intensity aerobic exercise on cognitive processes related to perceptual decision-making through computational modelling. Participants completed a perceptual decision task before, after, and while exercising at high-intensity aerobic intensity (eight 5-minutes blocks at 90% of the first ventilatory threshold SV1; 86 +- 7% HRmax). Cognitive processes were assessed by determining the best-fitting parameters of a drift diffusion model (DDM) based on behavioral data (accuracy and reaction times). The results showed decreased reaction times while exercising and suggested a trend toward enhanced cognitive performance immediately following exercise. Significant changes in the main parameters of the drift-diffusion model were observed immediately post-exercise compared to pre-exercise, indicating an improvement in perceptual discrimination and more efficient non-decisional processes (perceptual encoding and motor execution), associated with a more cautious decision strategy. The impact of exercise on cognitive processes during exercise presented a different picture. The decision threshold decreased over the course of the exercise, indicating that participants became less cautious as time passed. Additionally, the time required for processes unrelated to the perceptual decision increased in the first part of exercise and diminished afterward, suggesting a nuanced and dynamic evolution of decision-making over the course of the exercise.