bluuebunny/crossref_metadata_2025 huggingface dataset:
Atomistic Modeling of Liquid-Liquid Phase Equilibrium Explains Dependence of Critical Temperature on γ-Crystallin Sequence
Authors: Qin Sanbo , Zhou Huan-Xiang
Published: April 2023

Liquid-liquid phase separation of protein solutions has regained heightened attention for its biological importance and pathogenic relevance. Coarse-grained models are limited when explaining residue-level effects on phase equilibrium. Here we report phase diagrams for γ-crystallins using atomistic modeling. The calculations were made possible by combining our FMAP method for computing chemical potentials and Brownian dynamics simulations for configurational sampling of dense protein solutions, yielding the binodal and critic temperature (Tc). We obtain a higherTcfor a known high-Tcγ-crystallin, γF, than for a low-Tcparalog, γB. The difference inTcis corroborated by a gap in second virial coefficient. Decomposition of inter-protein interactions reveals one amino-acid substitution between γB and γF, from Ser to Trp at position 130, as the major contributor to the difference inTc. This type of analysis enables us to link phase equilibrium to amino-acid sequence and to design mutations for altering phase equilibrium.
Not one, but multiple radiations underlie the biodiversity of Madagascar’s endangered lemurs
Authors: Everson Kathryn M. , Pozzi Luca , Barrett Meredith A. , Blair Mary E. , Donohue Mariah E. , Kappeler Peter M. , Kitchener Andrew C. , Lemmon Alan R. , Lemmon Emily M. , Pavón-Vázquez Carlos J. , Radespiel Ute , Randrianambinina Blanchard , Rasoloarison Rodin M. , Rasoloharijaona Solofonirina , Roos Christian , Salmona Jordi , Yoder Anne D. , Zenil-Ferguson Rosana , Zinner Dietmar , Weisrock David W.
Published: April 2023

Lemurs are a well-known example of adaptive radiation. Since colonizing Madagascar, more than 100 extant lemur species have evolved to fill the variety of ecological niches on the island. However, recent work suggests that lemurs do not exhibit one of the hallmarks of adaptive radiations: explosive speciation rates that decline over time. We test this idea using a phylogenomic dataset with broad taxonomic sampling of lemurs and their sister group, the lorisiforms of Asia and continental Africa. We find higher rates of speciation in Madagascar’s lemurs compared to lorisiforms and we confirm that lemurs did not experience an “early burst” of speciation after colonizing Madagascar. Instead, we identify three independent bursts of speciation approximately 15 million years ago that underly much of today’s lemur diversity. We demonstrate that the lemur clades with exceptionally high diversification rates have higher rates of introgression. This suggests that hybridization in these primates is not an evolutionary dead- end, but a driving force for diversification. Considering the conservation crisis affecting strepsirrhine primates, with approximately 95% of species being threatened with extinction, this phylogenomic study offers a new perspective for explaining Madagascar’s exceptional primate diversity and reveals patterns of speciation, extinction, and gene flow that will help inform future conservation decisions.
Tau Filaments from Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) adopt the CTE Fold
Authors: Qi Chao , Verheijen Bert M. , Kokubo Yasumasa , Shi Yang , Tetter Stephan , Murzin Alexey G. , Nakahara Asa , Morimoto Satoru , Vermulst Marc , Sasaki Ryogen , Aronica Eleonora , Hirokawa Yoshifumi , Oyanagi Kiyomitsu , Kakita Akiyoshi , Ryskeldi-Falcon Benjamin , Yoshida Mari , Hasegawa Masato , Scheres Sjors H.W. , Goedert Michel
Published: April 2023

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

SIGNIFICANCE

A neurodegenerative disease of unknown cause on the island of Guam and the Kii peninsula of Japan has been widely studied, because patients can suffer from the combined symptoms of motor neuron disease, parkinsonism and dementia. Abnormal filamentous inclusions made of tau protein characterise this amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) and their formation closely correlates with neurodegeneration. Here we have used electron cryo-microscopy (cryo-EM) to show that tau filaments from ALS/PDC are identical to those from chronic traumatic encephalopathy (CTE), a disease caused by repetitive head impacts or blast waves. CTE tau filaments are also found in subacute sclerosing panencephalitis, which is a rare consequence of measles infection. ALS/PDC may therefore also be caused by environmental factors.
Evolutionarily-conserved behavioral plasticity enables context-dependent performance of mating behavior inC. elegans
Authors: Susoy Vladislav , Samuel Aravinthan D.T.
Published: April 2023

Behavioral plasticity helps humans and animals to achieve their goals by adapting their behaviors to different environments. Although behavioral plasticity is ubiquitous, many innate species-specific behaviors, such as mating, are often assumed to be stereotyped and unaffected by plasticity or learning, especially in invertebrates. Here, we describe a novel case of behavioral plasticity in the nematodeC. elegans– under a different set of naturalistic conditions the male uses a unique, previously undescribed set of behavioral steps for mating. Under standard lab conditions (agar plates with bacterial food), the male performs parallel mating, a largely two-dimensional behavioral strategy where his body and tail remain flat on the surface and slide alongside the partner ‘s body from initial contact to copulation. But when placed in liquid medium, the male performs spiral mating, a distinctly three-dimensional behavioral strategy where he winds around the partner ’s body in a helical embrace. The performance of spiral mating does not require a long-term change in growing conditions but it does improve with experience. This experience-dependent improvement involves a critical period – a time window around the L4 to early adult stage, which coincides with the development of most male-specific neurons. We tested several wild isolates ofC. elegansand otherCaenorhabditisspecies and found that most were capable of parallel mating on surfaces and spiral mating in liquids. We suggest that two- and three-dimensional mating strategies inCaenorhabditisare plastic, conditionally expressed phenotypes conserved across the genus, and which can be genetically “fixed ” in some species.
Computational Mechanobiology Model Evaluating Healing of Postoperative Cavities Following Breast-Conserving Surgery
Authors: Harbin Zachary , Sohutskay David , Vanderlaan Emma , Fontaine Muira , Mendenhall Carly , Fisher Carla , Voytik-Harbin Sherry , Tepole Adrian Buganza
Published: April 2023

Breast cancer is the most commonly diagnosed cancer type worldwide. Given high survivorship, increased focus has been placed on long-term treatment outcomes and patient quality of life. While breast-conserving surgery (BCS) is the preferred treatment strategy for early-stage breast cancer, anticipated healing and breast deformation (cosmetic) outcomes weigh heavily on surgeon and patient selection between BCS and more aggressive mastectomy procedures. Unfortunately, surgical outcomes following BCS are difficult to predict, owing to the complexity of the tissue repair process and significant patient-to-patient variability. To overcome this challenge, we developed a predictive computational mechanobiological model that simulates breast healing and deformation following BCS. The coupled biochemical-biomechanical model incorporates multi-scale cell and tissue mechanics, including collagen deposition and remodeling, collagen-dependent cell migration and contractility, and tissue plastic deformation. Available human clinical data evaluating cavity contraction and histopathological data from an experimental porcine lumpectomy study were used for model calibration. The computational model was successfully fit to data by optimizing biochemical and mechanobiological parameters through the Gaussian Process. The calibrated model was then applied to define key mechanobiological parameters and relationships influencing healing and breast deformation outcomes. Variability in patient characteristics including cavity-to-breast volume percentage and breast composition were further evaluated to determine effects on cavity contraction and breast cosmetic outcomes, with simulation outcomes aligning well with previously reported human studies. The proposed model has the potential to assist surgeons and their patients in developing and discussing individualized treatment plans that lead to more satisfying post-surgical outcomes and improved quality of life.
Dynamic saccade context triggers more stable object-location binding
Authors: Lu Zitong , Golomb Julie D.
Published: April 2023

Our visual systems rapidly perceive and integrate information about object identities and locations. There is long-standing debate about how we achieve world-centered (spatiotopic) object representations across eye movements, with many studies reporting persistent retinotopic (eye-centered) effects even for higher-level object-location binding. But these studies are generally conducted in fairly static experimental contexts. Might spatiotopic object-location binding only emerge in more dynamic saccade contexts? In the present study, we investigated this using the Spatial Congruency Bias paradigm in healthy adults. In the static (single saccade) context, we found purely retinotopic binding, as before. However, robust spatiotopic binding emerged in the dynamic (multiple frequent saccades) context. We further isolated specific factors that modulate retinotopic and spatiotopic binding. Our results provide strong evidence that dynamic saccade context can trigger more stable object-location binding in ecologically-relevant spatiotopic coordinates, perhaps via a more flexible brain state which accommodates improved visual stability in the dynamic world.

Significance Statement

One of the most fundamental challenges for human behavior is how we integrate and stabilize perceptual information in our ever-changing sensory environments. In particular, we make multiple eye movements every second, constantly displacing and distorting our visual input. Yet despite receiving visual input in these disjointed, eye-centered (retinotopic) coordinates, we perceive the world as stable, based on objects’ world-centered (spatiotopic) locations. Our study provides strong evidence for a previously unstudied cue – dynamic saccade context – in triggering more stable object-location binding, which offers a novel step forward in understanding how we form a stable perception of the dynamic world. More broadly, these findings suggest the importance of considering dynamic saccade context in visual perception and cognitive neuroscience studies.
Psychedelic Concentrations of Nitrous Oxide Reduce Functional Differentiation in Frontoparietal and Somatomotor Cortical Networks
Authors: Dai Rui , Huang Zirui , Larkin Tony E. , Tarnal Vijay , Picton Paul , Vlisides Phillip E. , Janke Ellen , McKinney Amy , Hudetz Anthony G. , Harris Richard E. , Mashour George A.
Published: April 2023

Abstract

Despite the longstanding use of nitrous oxide and descriptions of its psychological effects more than a century ago, there is a paucity of neurobiological investigation of associated psychedelic experiences. Identifying the impact of nitrous oxide on functional brain networks would advance understanding and contribute to the growing body of research in psychedelic neuroscience. Based on human resting-state fMRI data acquired before and during the administration of 35% nitrous oxide, we measured the brain’s functional geometry (through analysis of cortical gradients) and temporal dynamics (through analysis of co-activation patterns). Both analyses show that nitrous oxide reduces functional differentiation in frontoparietal and somatomotor networks. Importantly, the subjective psychedelic experience induced by nitrous oxide is inversely correlated with the degree of functional differentiation. Thus, like classical psychedelics acting on 5-HT2 receptors, nitrous oxide flattens the functional geometry of the cortex and disrupts temporal dynamics in association with psychoactive effects.
Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift
Authors: Song Ge , Yuan Meng , Liu Hejun , Capozzola Tazio , Lin Ryan N. , Torres Jonathan L. , He Wan-ting , Musharrafieh Rami , Dueker Katharina , Zhou Panpan , Callaghan Sean , Mishra Nitesh , Yong Peter , Anzanello Fabio , Avillion Gabriel , Vo Anh Lina , Li Xuduo , Makhdoomi Muzamil , Feng Ziqi , Zhu Xueyong , Peng Linghang , Nemazee David , Safonova Yana , Briney Bryan , Ward Andrew B , Burton Dennis R. , Wilson Ian A. , Andrabi Raiees
Published: April 2023

Developing broad coronavirus vaccines requires identifying and understanding the molecular basis of broadly neutralizing antibody (bnAb) spike sites. In our previous work, we identified sarbecovirus spike RBD group 1 and 2 bnAbs. We have now shown that many of these bnAbs can still neutralize highly mutated SARS-CoV-2 variants, including the XBB.1.5. Structural studies revealed that group 1 bnAbs use recurrent germline encoded CDRH3 features to interact with a conserved RBD region that overlaps with class 4 bnAb site. Group 2 bnAbs recognize a less well-characterized "site V" on the RBD and destabilize spike trimer. The site V has remained largely unchanged in SARS-CoV- 2 variants and is highly conserved across diverse sarbecoviruses, making it a promising target for broad coronavirus vaccine development. Our findings suggest that targeted vaccine strategies may be needed to induce effective B cell responses to escape resistant subdominant spike RBD bnAb sites.
Identification of a new Corin atrial natriuretic peptide-converting enzyme substrate: Agouti-signaling protein (ASIP)
Authors: MacDonald Bryan T. , Elowe Nadine H. , Garvie Colin W. , Kaushik Virendar K. , Ellinor Patrick T.
Published: April 2023

Corin is a transmembrane tethered enzyme best known for processing the hormone atrial natriuretic peptide (ANP) in cardiomyocytes to control electrolyte balance and blood pressure. Loss of function mutations in Corin prevent ANP processing and lead to hypertension. Curiously, Corin loss of function variants also result in lighter coat color pigmentation in multiple species. Corin pigmentation effects are dependent on a functional Agouti locus encoding the agouti-signaling protein (ASIP) based on a genetic interaction. However, the nature of this conserved role of Corin has not been defined. Here we report that ASIP is a direct proteolytic substrate of the Corin enzyme.
Network analysis for identifying potential anti-virulence targets through whole transcriptome analysis ofPseudomonas aeruginosaandStaphylococcus aureusexposed to certain anti-pathogenic polyherbal formulations
Authors: Ruparel Feny , Shah Siddhi , Patel Jhanvi , Thakkar Nidhi , Gajera Gemini , Kothari Vijay
Published: April 2023

Transcriptome of two important pathogens,Pseudomonas aeruginosaandStaphylococcus aureusexposed to two different quorum-modulatory polyherbal formulations were subjected to network analysis to identify the most highly networked differentially expressed genes (hubs) as potential anti-virulence targets. Genes associated with denitrification and sulfur metabolism emerged as the most important targets inP. aeruginosa. Increased build-up of nitrite (NO2) inP. aeruginosaculture exposed to the polyherbal formulationPanchvalkalwas confirmed throughin vitroassay too. Generation of nitrosative stress and inducing sulfur starvation seems to be effective anti-pathogenic strategies against this notorious gram-negative pathogen. Important targets identified inS. aureuswere the transcriptional regulatorsarA, immunoglobulin-binding protein Sbi, serine proteaseSplA, thesaeR/Sresponse regulator system, and gamma-haemolysin componentshlgBandhlgC. Further validation of the potential targets identified in these pathogens is warranted through appropriatein vitroandin vivoassays in model hosts. Such validated targets can prove vital to many antibacterial drug discovery programmes globally.
Migratory pattern of zoonoticToxocara catiandT. canisin experimentally infected pigs
Authors: Poulsen Casper Sahl , Yoshida Ayako , Wellbrant Tinna Thordardottir , Leifsson Pall Skuli , Skallerup Per , Thamsborg Stig Milan , Nejsum Peter
Published: April 2023

Over a billion people are infected withToxocara canisorT. cati, the roundworms of dogs and cats. Historically,T. canishas been considered the main responsible of human toxocarosis but as serodiagnosis cannot discriminate the two species, this remains unresolved. We assessed the migratory pattern ofT. catiandT. canisin a pig model and found them to be equally infective. Overall, they had a similar migration pattern reaching multiple organs and tissues, including mesenteric lymph nodes, liver, lungs and diaphragm. We recovered larvae of both species in the brain, suggesting thatT. catialso can cause neurological toxocarosis in humans. Both species induced systemic eosinophilia and histopathological changes in lungs, livers and mesenteric lymph nodes. This study emphasizes the importance ofT. catias a zoonotic agent and the need to develop diagnostic methods that can differentiate between sources of infection in humans.
Investigating Spatiotemporal Dynamics of Cortical Activity During Language Production in the Healthy and Lesioned Brain
Authors: Mesnildrey Quentin , Aksenov Alexandre , D’Ambra Malo Renaud , Hartwigsen Gesa , Volpert Vitaly , Beuter Anne
Published: April 2023

Efficient language production requires rapid interactions between different brain areas. These interactions can be severely affected by brain lesions. However, the neurophysiological correlates of the spatiotemporal dynamics during language production are not well understood. The current pilot study explores differences in spatiotemporal cortical dynamics between five subjects with post-stroke aphasia and five control subjects. Electroencephalography was recorded during picture naming in both groups.

Average-based analyses (event-related potential (ERP), frequency-specific Global Field Power (GFP)), reveal a strong synchronization of cortical oscillations, especially within the first 600ms post-stimulus, with a time shift between participants with aphasia and control subjects. ERPs and the corresponding brain microstates indicate coordinated brain activity alternating mainly between frontal and occipital zones. This behavior can be described as standing waves between two main sources.

At the single-trial scale, traveling waves (TW) were identified from both phase and amplitude analyses. The spatiotemporal distribution of amplitude TW reveals subject-specific organization of several interconnected hubs. In patients with aphasia this spatial organization of TW reveals zones with no TW notably in the vicinity of stroke lesions.

The present results provide important hints for the hypothesis that TW contribute to the synchronization and communication between different brain areas especially by interconnecting cortical hubs. Moreover, our findings show that cortical dynamics is affected by brain lesions.

Contribution to the Field

Spatiotemporal cortical dynamics of individual trials reveals the presence of phase and amplitude traveling waves.

Exploration of traveling waves on the 2D cortical surface reveals the presence of interconnected epicenters or hubs in all subjects.

The spatiotemporal distribution of traveling waves shows a higher density in the prefrontal area for people with aphasia than for healthy subjects.

For subjects with aphasia, a sparser density of traveling waves is observed in the approximated lesion area.

Event-related potential analyses reveal a consistent alternating activity between the frontal and occipital regions.

Subjects with aphasia present a larger and/or delayed contribution in the delta range in the GFP patterns compared to control subjects.
A high-sensitivity low-nanoflow LC-MS configuration for high-throughput sample-limited proteomics
Authors: Zheng Runsheng , Matzinger Manuel , Mayer Rupert , Valenta Alec , Sun Xuefei , Mechtler Karl
Published: April 2023

This study demonstrates how optimized liquid chromatography-mass spectrometry (LC-MS) conditions combined with a 50 µm internal diameter (I.D.) column operated at 100 nL/min enables high-sensitivity and high-throughput sample-limited proteomics analysis, including single-cell proteomics (SCP). Through systematic parameter evaluation, an optimized method was developed, capable of identifying ∼3,000 protein groups from 250 pg of HeLa protein digest using a 10-min gradient in the direct injection workflow using data-independent acquisition (DIA) from a library-free search method. Further improvements reduced the cycle time from 20 to 14.4 min by employing a trap-and-elute workflow, permitting 100 runs/day with 70% MS utilization. A proof of principle study indicated thatca. 1,700 protein groups were identified from single-cell samples without a library for label-free quantification (LFQ). In conclusion, we demonstrate a high-sensitivity LC-MS/MS configuration that serves the needs for limited sample analysis, permitting 100 runs/day throughout.
Swi/Snf Chromatin Remodeling Regulates Transcriptional Interference and Gene Repression
Authors: Morse Kaitlin , Swerdlow Sarah , Ünal Elçin
Published: April 2023

Alternative transcription start sites can affect transcript isoform diversity and translation levels. In a recently described form of gene regulation, coordinated transcriptional and translational interference results in transcript isoform-dependent changes in protein expression. Specifically, a long undecoded transcript isoform (LUTI) is transcribed from a gene-distal promoter, interfering with expression of the gene-proximal promoter. While transcriptional and chromatin features associated with LUTI expression have been described, the mechanism underlying LUTI-based transcriptional interference is not well understood. Using an unbiased genetic approach followed by integrated genomic analysis, we uncovered that the Swi/Snf chromatin remodeling complex is required for co-transcriptional nucleosome remodeling that leads to LUTI-based repression. We identified genes with tandem promoters that rely on Swi/Snf function for transcriptional interference during protein folding stress, including LUTI-regulated genes. To our knowledge, this study is the first to observe Swi/Snf’s direct involvement in gene repression via acistranscriptional interference mechanism.
Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen
Authors: Lee Sandy , Zhan Huichun
Published: April 2023

Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/-and MPL-/-mice during aging. Despite severe thrombocytopenia, TPO-/-and MPL-/-mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/-and MPL-/-mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.
Receptor endocytosis orchestrates the spatiotemporal bias of β-arrestin signaling
Authors: Tóth András Dávid , Szalai Bence , Kovács Orsolya Tünde , Garger Dániel , Prokop Susanne , Balla András , Inoue Asuka , Várnai Péter , Turu Gábor , Hunyady László
Published: April 2023

The varying efficacy of biased and balanced agonists is generally explained by the stabilization of different active receptor conformations. In this study, systematic profiling of transducer activation of AT1angiotensin receptor agonists revealed that the extent and kinetics of β-arrestin binding exhibit substantial ligand-dependent differences, which however completely disappear upon the inhibition of receptor internalization. Even weak partial agonists for the β- arrestin pathway acted as full or near full agonists, if receptor endocytosis was prevented, indicating that receptor conformation is not an exclusive determinant of β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation at endosomes was much larger than it was at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway is spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shape the effects of agonists on endosomal receptor–β-arrestin binding and thus determine the extent of bias. Among others, ligand dissociation rate and G protein activity have particularly strong impact on receptor–β-arrestin interaction, and their effects are integrated at endosomes. Our results highlight that endocytosis forms a key spatiotemporal platform for biased GPCR signaling and can aid the development of more efficacious functionally-selective compounds.

One Sentence summary

Agonist-specific differences in β-arrestin recruitment are mainly determined by the ligand dissociation rate and G protein activation at the endosomes.
Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
Authors: Ratnasinghe Brian D. , Haque Neshatul , Wagenknecht Jessica B. , Jensen Davin R. , Esparza Guadalupe V. , Leverence Elise N. , Milech De Assuncao Thiago , Mathison Angela J. , Lomberk Gwen , Smith Brian C. , Volkman Brian F. , Urrutia Raul , Zimmermann Michael T.
Published: April 2023

ABSTRACT

Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation.

Key Points

Please provide 3 bullet points summarizing the manuscript’s contribution to the field (100 characters max per point)

1)

We functionally grouped 86 distinct KRAS mutations using MD scores, demonstrating scalability for genomics

2)

MD-based groups explain experimental differences and mechanistic information about mutant proteins

3)

Demonstrated added functional information from simulations for interpreting human genetic variation
A novel resistance reversion mechanism in a vancomycin-variableEnterococcus faeciumstrain
Authors: McInnes Ross S. , Snaith Ann E. , Dunn Steven J. , Papangeli Maria , Hardy Katherine J. , Hussain Abid , van Schaik Willem
Published: April 2023

Objectives

To investigate an outbreak ofEnterococcus faeciumin a hospital haematology ward and uncover the mechanism of a vancomycin resistance phenotype-genotype disparity in an isolate from this outbreak.

Methods

Whole genome shotgun sequencing was used for the phylogenetic analysis ofE. faeciumisolates (n = 39) and to identify the carriage of antibiotic resistance genes. A long-read sequencing approach was adopted to identify structural variations in the vancomycin resistance region of a vancomycin-variableE. faecium(VVE) and to uncover the resistance reversion mechanism in this isolate. RT-qPCR and RT-PCR were used to determine differences in the expression ofvanRSandvanHAXamong strains.

Results

TheE. faeciumstrains isolated in the hospital haematology ward were extensively drug resistant and highly diverse. The notable expansion of ST262 among patients was the likely driver of a VRE outbreak. A VVE isolate was identified that could rapidly revert to a vancomycin-resistant state in the presence of vancomycin. Disruption of thevanRgene in this isolate by an IS6-family element impaired its response to vancomycin. However, when the isolate was evolved to vancomycin resistance, it could constitutively express thevanHAXgenes at levels up to 36,000-fold greater than the parent isolate via co-transcription with a ribosomal RNA operon.

Conclusion

In this study, we report a VVE isolate that was isolated during a VRE outbreak. This strain was capable of rapidly reverting to a resistant phenotype through a novel mechanism involving integration ofvanHAXdownstream of a ribosomal RNA operon. During VRE outbreaks, attention should be paid to contemporaneous vancomycin-susceptible strains as these may carry silent vancomycin resistance genes that can be activated through genomic rearrangements upon exposure to vancomycin.
Rapid Synthesis of Cryo-ET Data for Training Deep Learning Models
Authors: Purnell Carson , Heebner Jessica , Swulius Michael T. , Hylton Ryan , Kabonick Seth , Grillo Michael , Grigoryev Sergei , Heberle Fred , Waxham M. Neal , Swulius Matthew T.
Published: April 2023

Deep learning excels at cryo-tomographic image restoration and segmentation tasks but is hindered by a lack of training data. Here we introduce cryo-TomoSim (CTS), a MATLAB-based software package that builds coarse-grained models of macromolecular complexes embedded in vitreous ice and then simulates transmitted electron tilt series for tomographic reconstruction. We then demonstrate the effectiveness of these simulated datasets in training different deep learning models for use on real cryotomographic reconstructions. Computer-generated ground truth datasets provide the means for training models with voxel-level precision, allowing for unprecedented denoising and precise molecular segmentation of datasets. By modeling phenomena such as a three-dimensional contrast transfer function, probabilistic detection events, and radiation-induced damage, the simulated cryo-electron tomograms can cover a large range of imaging content and conditions to optimize training sets. When paired with small amounts of training data from real tomograms, networks become incredibly accurate at segmentingin situmacromolecular assemblies across a wide range of biological contexts.

By pairing rapidly synthesized Cryo-ET data with computed ground truths, deep learning models can be trained to accurately restore and segment real tomograms of biological structures bothin vitroandin situ.
The duplication of genomes and gene regulatory networks and its potential for evolutionary adaptation and survival
Authors: Ebadi Mehrshad , Bafort Quinten , Mizrachi Eshchar , Audenaert Pieter , Simoens Pieter , Van Montagu Marc , Bonte Dries , Van de Peer Yves
Published: April 2023

The importance of whole genome duplication (WGD), or polyploidy, for evolution, is controversial. Whereas some view WGD mainly as detrimental and an evolutionary dead end, there is growing evidence that (the establishment of) polyploidy can help overcome environmental change, stressful conditions, or periods of extinction. However, despite much research, the mechanistic underpinnings of why and how polyploids might be able to outcompete or outlive non-polyploids at times of environmental upheaval remain elusive, especially for autopolyploids, in which heterosis effects are limited. On the longer term, WGD might increase both mutational and environmental robustness due to redundancy and increased genetic variation, but on the short – or even immediate – term, selective advantages of WGDs are harder to explain. Here, by duplicating artificially generated Gene Regulatory Networks (GRNs), we show that duplicated GRNs – and thus duplicated genomes – show higher signal output variation than non-duplicated GRNs. This increased variation leads to niche expansion and can provide polyploid populations with substantial advantages to survive environmental turmoil. In contrast, under stable environments, GRNs might be maladaptive to changes, a phenomenon that is exacerbated in duplicated GRNs. We believe that these results provide new insights into how genome duplication and (auto)polyploidy might help organisms to adapt quickly to novel conditions and to survive ecological uproar or even cataclysmic events.
Mapping problem-solving competencies and talent management strategies for universities
Authors: Ábrahám Zsolt , Szőgyényi Dániel , Eckert Bálint , Németh Szilárd
Published: April 2023

Purpose

The paper aims to clarify the relationship between problem-solving skills and socialization of first-year university students and propose talent management strategies for university management, course instructors and administrators. Thus, this paper identifies three student clusters among the first-year bachelor students. This paper aims to propose a talent management framework and makes recommendations for course instructors and administrators.

Design/methodology/approach

In this paper, a Simulated Work Experience is applied to collect data on problem-solving skills and demographics of first-year business students. Based on the anonymous competency and demographic data of 546 students, 3 clusters were identified with a hierarchical K-means clustering method and linked with talent management and curriculum design strategies.

Findings

The paper provides empirical insights about how the demographic background of the first-year students affects the students' problem-solving skills. This paper identifies three clusters – laggers, unpolished diamonds and drivers – and proposes a talent management framework to support the students' personal and professional development. The proposed talent management framework is based on the direction of upskilling and type of talent management incentives and outlines four distinct categories: extracurricular reward, tutoring and catching up, perform-or-punish and up-or-out systems. This paper makes suggestions to course administrators and instructors how to incorporate talent management and competency mapping aspects into the curriculum and syllabus design activities.

Research limitations/implications

The research is limited to problem-solving skills and focused only on first-year business students.

Practical implications

The paper includes practical implications for business school management, course administrators and instructors about competency mapping, talent management strategies, curriculum and syllabus design.

Originality/value

The research is based on the competency mapping of 546 first-year students at Budapest Business School. The data were collected via a Simulated Work Experience, where the students were participating in a virtual business project.
How supplier concentration impacts a buyer firm's R&D intensity: testing a mediation and moderation model
Authors: Yang Jinyu , Zhang Shanshan , Wang Zhiqiang , Zhao Xiande
Published: April 2023

Purpose

The purpose of this paper is to investigate how supplier concentration influences a buyer firm's R&D intensity. This study proposes a mediation and moderation model to test this relationship in the Chinese household appliance industry. Specifically, this study tests the mediation effect of operational slack on the relationship between supplier concentration and R&D intensity and the moderation effect of financial constraints on this relationship.

Design/methodology/approach

Drawing upon real options theory and resource dependence theory, the proposed relationships are tested with the Chinese household appliance market using financial data from listed companies over a ten-year span from 2012 to 2021. Fixed effects (within-group) panel regression models are used to test the hypotheses. In addition, the authors use the bias-corrected bootstrap method to test the mediation effect.

Findings

The authors find that supplier concentration negatively affects a buyer firm's R&D intensity and that internal operational slack mediates this relationship. Interestingly, financial constraints from the external financing organization weaken the negative relationship between the buyer firm's supplier concentration and R&D intensity.

Originality/value

Based on the argument of real options theory and resource dependence theory, this study provides novel insights into the issue of how concentration on several major suppliers may reduce buyer firms' R&D intensity. First, this study introduces operational slack as a form of internal uncertainty that mediates the supplier concentration–R&D intensity relationship. Second, this study suggests that the effect of supplier concentration on R&D intensity is contingent upon firms' financial constraints from external financial organizations, disclosing a synergetic interactive effect of supplier concentration and financial constraints on firms' R&D activities. Third, this study is conducted in the unique institutional context of China, providing meaningful insights into the relationship between supplier concentration and R&D intensity.
The role of organizational attributes on the marketing performance of Asian telecommunication companies: mediating effect of the Chief Marketing Officers’ political skill
Authors: Mustafi Mohitul Ameen Ahmed , Dong Ya-juan , Hosain Md Sajjad
Published: April 2023

Purpose

At present, for any product, smooth marketing has become a major challenge due to the novel market challenges as well as sudden and extended changes. Thus, the concerns for the marketers are essential to consider the choice of buyers and also to satisfy them. The purpose of this empirical research is to focus on the role of three organizational attributes (OA): job satisfaction (JS), organizational commitment (OC) and extrinsic motivation (EM) on the marketing performance (MP) mediated by the Chief Marketing Officers' (CMOs') political skill (CPS) in the telecommunication industries of China, Singapore, Vietnam, Malaysia, Indonesia, India, Pakistan, Bangladesh, United Arab Emirates (UAE) and Sri Lanka.

Design/methodology/approach

In this paper, based on 132 survey responses collected from CMOs, the authors conducted descriptive statistics using Statistical Package for Social Science (SPSS-25) and tested the assumed hypotheses through covariance-based structural equation modeling (CB-SEM) using AMOS software (version 25).

Findings

The authors found that JS has an insignificant role on MP while OC and EM have significant positive roles over the dependent variable. CPS has also a significant positive influence over MP. Further, the authors identified that CPS can fully mediate the relationship between JS and MP while it can partially mediate the relationship between OC and MP. On the other hand, CPS cannot mediate the relationship between EM and MP at all.

Originality/value

According to authors’ knowledge, this is one of the very limited initial attempts that have investigated the role of three important OA on the MP testing the mediating effect of CPS. The authors expect that the study outcomes will have an enormous impact on marketing academia as a torch-bearing research as well as for CMOs for formulating an effective marketing policy.
Empowering leadership: role of organizational culture of self-esteem and emotional intelligence on creativity
Authors: Ahmad Tufail , Hamid Ali Raza , Abbas Ansar , Anwar Aisha , Ekowati Dian , Fenitra Rakototoarisoa Maminirina , Suhariadi Fendy
Published: April 2023

Purpose

The changing workplace and the disruption and transformation of business processes brought on by modern technology make it difficult for a firm to maintain its existing plans. A management's ability to succeed is related to sustaining and developing its employees to be innovative workers. The idea is to empower subordinates and share authority with them, which increases efficiency.

Design/methodology/approach

In this study, it was anticipated that there is a definite relationship between leadership empowerment and workplace cultures of self-esteem, emotional intelligence and creative thinking. Data were obtained using random sample techniques to confirm the hypothesis. A total of 291 Pakistani private-sector employees were surveyed for this study.

Findings

There were positive and substantial links between empowered leadership and creativity, while emotional intelligence and organizational self-esteem have an inverse relationship. For psychological appeal and inventiveness at work, empowerment alone is sufficient. Intellectual stimulus or culture of excessively positive self-esteem may cause numerous limits at work. Hence, management should avoid situations where leaders are predisposed to developing empowering techniques.

Research limitations/implications

This study yields an additional understanding of organizational behavior literature. It was concluded from this study that empowering leaders should avoid using emotional intelligence when scaling up creative strategies. As an alternative, they should develop a culture of self-esteem through emotional intelligence.

Practical implications

Leaders may want to consider demographic values while developing empowerment strategies. It is not recommended to use emotional intelligence and empowerment simultaneously. As a result, this framework suggests a realistic and candid approach that is simple to implement.

Originality/value

Leaders make people aware of the ongoing importance of innovative processes to encourage staff to be creative. Successful leaders may use either empowering culture or leadership empowerment strategies for a more significant appeal. Self-esteem culture may provide a structure of interaction buffer against the other emotions that could counter disruption.
Technological solutions and adaptive processing tools to mitigate the impact of seasonal variations in milk composition on Cheddar cheese production—A review
Authors: Galli Bruno D , Hamed Ahmed M , Sheehan Jeremiah J , King Niall , Abdel‐Hamid Mahmoud , Romeih Ehab
Published: April 2023

Variability in milk composition and physicochemical properties impact both manufacturing process performance and the end‐use functionality of cheese. Such variability may be attributed to seasonal calving patterns, production systems, breed, weather patterns, and feed type and significantly impacts concentrations of macro‐ and microconstituents and ultimately cheese composition and quality. This article reviews technological approaches (e.g., milk standardisation protocols and calcium addition), and predictive strategies (e.g., predictive models for coagulation and curd cutting time, in‐line sensors), used to mitigate the effects of seasonal changes in milk composition and their impact on process efficacy and functionality in Cheddar cheese manufacturing.
Association of obesity under different metabolic status with adverse outcomes in patients with chronic myeloid leukemia: A retrospective cohort study
Authors: Dong Yingchun , Cheng Yiping , Feng Xiaoshan , Yuan Zinuo , Dong Hang , Zhang Yue , Han Junming , Wu Yafei , Wang Zhixiang , Zhong Xia , Fan Xiude , Zhao Jiajun
Published: April 2023

Background

Little is known about the association between abnormal metabolic obesity states and the outcomes of chronic myeloid leukemia (CML), especially in patients with obesity with different metabolic status. Here, we used the Nationwide Readmissions Database to assess the effects of metabolically defined obesity on adverse outcomes of CML.

Methods

Of the 35 460 557 (weighted) patients, we included 7931 adults with discharge diagnoses of CML from January 1, 2018 to June 30, 2018. The study population was observed until December 31, 2018 and divided into four groups based on body mass index and metabolic status. The primary outcome was the adverse outcomes of CML, including nonremission (NR)/relapse and severe mortality risk. Multivariate logistic regression analysis was performed to analyze data.

Results

Metabolically unhealthy normal weight and metabolically unhealthy obesity were all risk factors for adverse outcomes of CML compared with metabolically healthy normal weight (all p < 0.01), and a significant difference was not found in the metabolically healthy obese. Female patients with metabolically unhealthy normal weight and metabolically unhealthy obesity had 1.23‐fold and 1.40‐fold increased NR/relapse risk, while male patients did not have this risk. Moreover, patients with a higher number of metabolic risk factors or with dyslipidemia were at higher risk of adverse outcomes, regardless of obesity status.

Conclusions

Metabolic abnormalities were associated with adverse outcomes in patients with CML, irrespective of obesity status. Future treatment of patients with CML should consider the effects of obesity on their adverse outcomes under different metabolic status, especially in female patients.
Erythema nodosum caused by goserelin acetate sustained‐release: Case report and literature review
Authors: Meng Fanyu , Su Rong , Ling Li , Yan Weitian , Du Shiyu , Peng Jiangyun , Liu Weichao
Published: April 2023

Goserelin acetate is a gonadotropin‐releasing hormone analog that is commonly used in patients with prostate cancer, endometriosis, and precocious puberty. The side effects of the drug include allergic rash, flushing, excessive sweating, skin swelling at the injection site, sexual dysfunction, erectile dysfunction, and menopausal symptoms. However, erythema nodosum has so far not been reported. In this paper, we have presented the case of erythema nodosum caused by goserelin acetate and a review of the literature on its adverse effects, thus providing useful insights into clinical management and medication safety.