bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome ofPhyllanthus emblica: the medicinal plant Amla with super antioxidant properties
Authors: Mahajan Shruti , Bisht Manohar S. , Chakraborty Abhisek , Sharma Vineet K
Published: May 2023

Phyllanthus emblicaor Indian gooseberry, commonly known as amla, is an important medicinal horticultural plant used in traditional and modern medicines. It bears stone fruits with immense antioxidant properties due to being one of the richest natural sources of vitamin C and numerous flavonoids. This study presents the first genome sequencing of this species performed using 10x Genomics and Oxford Nanopore Technology. The draft genome assembly was 519 Mbp in size and consisted of 4,384 contigs, N50 of 597 Kbp, 98.4% BUSCO score and 37,858 coding sequences. This study also reports the genome-wide phylogeny of this species with 26 other plant species that resolved the phylogenetic position ofP. emblica. The presence of three ascorbate biosynthesis pathways including L-galactose, galacturonate and myo-inositol pathways was confirmed in this genome. A comprehensive comparative evolutionary genomic analysis including gene family expansion/contraction and identification of multiple signatures of adaptive evolution provided evolutionary insights into ascorbate and flavonoid biosynthesis pathways and stone fruit formation through lignin biosynthesis. The availability of this genome will be beneficial for its horticultural, medicinal, dietary, and cosmetic applications and will also help in comparative genomics analysis studies.
Deep learning-enhanced single-molecule spectrum imaging
Authors: Sha Hao , Li Haoyang , Zhang Yongbing , Hou Shangguo
Published: May 2023

Fluorescence is widely used in biological imaging and biosensing. Rich information can be revealed from the fluorescence spectrum of fluorescent molecules, such as pH, viscosity and polarity of the molecule’s environment, and distance between two FRET molecules. However, constructing the fluorescence spectrum of a single fluorescent molecule typically requires a significant number of photons, which can suffer from photobleaching and therefore limit its potential applications. Here we propose a deep learning-enhanced single-molecule spectrum imaging method (SpecGAN) for improving the single-molecule spectrum imaging efficiency. In SpecGAN, the photon flux required to extract a single-molecule fluorescence spectrum can be reduced by 100 times, which enables it two orders of magnitude higher temporal resolution compared to the conventional single-molecule spectrometer. The concept of SpecGAN was validated through numerical simulation and single Nile Red molecule spectrum imaging on support lipid bilayers (SLBs). With SpecGAN, the super-resolution spectrum image of the COS-7 membrane can be reconstructed with merely 12,000 frames of single-molecule localization images, which is almost half of the previously reported frame count for spectrally resolved super-resolution imaging. The low photon flux requirement and high temporal resolution of SpecGAN make it a promising tool for investigating the molecular spectrum dynamics related to biological functions or biomolecule interactions.
A single-cell strategy for the identification of intronic variants related to mis-splicing in pancreatic cancer
Authors: Duman Emre Taylan , Sitte Maren , Conrads Karly , Makay Adi , Ludewig Fabian , Ströbel Philipp , Ellenrieder Volker , Hessman Elisabeth , Papantonis Argyris , Salinas Gabriela
Published: May 2023

Most clinical diagnostic and genomic research setups focus almost exclusively on coding regions and essential splice sites, thereby overlooking other non-coding variants. As a result, intronic variants that can promote mis-splicing events across a range of diseases, including cancer, are yet to be systematically investigated. Such investigations would require both genomic and transcriptomic data, but there currently exist very few datasets that satisfy these requirements. We address this by developing a single-nucleus full-length RNA-sequencing approach that allows for the detection of potentially pathogenic intronic variants. We exemplify the potency of our approach by applying pancreatic cancer tumor and tumor-derived specimens and linking intronic variants to splicing dysregulation. We specifically find that prominent intron retention and pseudo-exon activation events are shared by the tumors and affect genes encoding key transcriptional regulators. Our work paves the way for the assessment and exploitation of intronic mutations as powerful prognostic markers and potential therapeutic targets in cancer.

Graphical Abstract
Histone H3.3 lysine 9 and 27 control repressive chromatin states at crypticcis-regulatory elements and bivalent promoters in mouse embryonic stem cells
Authors: Trovato Matteo , Bunina Daria , Yildiz Umut , Marx Nadine Fernandez-Novel , Uckelmann Michael , Levina Vita , Kori Yekaterina , Janeva Ana , Garcia Benjamin A. , Davidovich Chen , Zaugg Judith B. , Noh Kyung-Min
Published: May 2023

Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutated histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleashed cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupted deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal level of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states atcis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.
An Atypical E3 Ligase Module in UBR4 Mediates Destabilization of N-degron Substrates
Authors: Barnsby-Greer Lucy , Mabbitt Peter D. , Dery Marc-Andre , Squair Daniel R. , Wood Nicola T. , Lange Sven , Virdee Satpal
Published: May 2023

UBR4 is an E3 ligase (E3) of the N-degron pathway and is involved in neurodevelopment, age-associated muscular atrophy and cancer progression. The location and mechanistic classification of the E3 module within the 600 kDa protein UBR4 remains unknown. Herein, we identify and characterize, at a biochemical and structural level, a distinct E3 module within human UBR4 consisting of a novel “hemiRING” zinc finger, a helical-rich UBR Zinc-finger Interacting (UZI) subdomain, and a predicted backside interacting N-terminal helix. A structure of an E2 conjugating enzyme (E2)-E3 complex provides atomic level insight into the exquisite specificity of the hemiRING towards the E2s UBE2A/B. The UZI subdomain can be considered a component of the E3 module as it has a modest activating effect on the ubiquitin loaded E2 (E2∼Ub), which is complemented by the intrinsically high lysine reactivity of UBE2A. These findings reveal the mechanistic underpinnings of a neuronal N-degron E3 ligase, its specific recruitment of UBE2A, and highlight the underappreciated architectural diversity of cross-brace domains associated with ubiquitin E3 activity.
Rapid evolution of piRNA clusters in theDrosophila melanogasterovary
Authors: Srivastav Satyam , Feschotte Cédric , Clark Andrew G.
Published: May 2023

Animal genomes are parasitized by a horde of transposable elements (TEs) whose mutagenic activity can have catastrophic consequences. The piRNA pathway is a conserved mechanism to repress TE activity in the germline via a specialized class of small RNAs associated with effector Piwi proteins called piwi-associated RNAs (piRNAs). piRNAs are produced from discrete genomic regions called piRNA clusters (piCs). While piCs are generally enriched for TE sequences and the molecular processes by which they are transcribed and regulated are relatively well understood inDrosophila melanogaster, much less is known about the origin and evolution of piCs in this or any other species. To investigate piC evolution, we use a population genomics approach to compare piC activity and sequence composition across 8 geographically distant strains ofD. melanogasterwith high quality long-read genome assemblies. We perform extensive annotations of ovary piCs and TE content in each strain and test predictions of two proposed models of piC evolution. The‘de novo’model posits that individual TE insertions can spontaneously attain the status of a small piC to generate piRNAs silencing the entire TE family. The ‘trap’ model envisions large and evolutionary stable genomic clusters where TEs tend to accumulate and serves as a long-term “memory” of ancient TE invasions and produce a great variety of piRNAs protecting against related TEs entering the genome. It remains unclear which model best describes the evolution of piCs. Our analysis uncovers extensive variation in piC activity across strains and signatures of rapid birth and death of piCs in natural populations. Most TE families inferred to be recently or currently active show an enrichment of strain-specific insertions into large piCs, consistent with the trap model. By contrast, only a small subset of active LTR retrotransposon families is enriched for the formation of strain-specific piCs, suggesting that these families have an inherent proclivity to formde novopiCs. Thus, our findings support aspects of both‘de novo’and ‘trap’ models of piC evolution. We propose that these two models represent two extreme stages along an evolutionary continuum, which begins with the emergence of piCsde novofrom a few specific LTR retrotransposon insertions that subsequently expand by accretion of other TE insertions during evolution to form larger ‘trap’ clusters. Our study shows that piCs are evolutionarily labile and that TEs themselves are the major force driving the formation and evolution of piCs.
SeMOE allows for quantitative glycan perception and exhibits anti-cancer potentiality
Authors: Tian Xiao , Zheng Lingna , Wang Changjiang , Han Yida , Li Yujie , Cui Tongxiao , Liu Jialin , Liu Chuanming , Jia Guogeng , Yang Lujie , Zeng Chen , Ding Lijun , Wang Chu , Cheng Bo , Wang Meng , Xie Ran
Published: May 2023

Metabolic oligosaccharide engineering (MOE) is a classical chemical approach to perturb, profile and perceive glycans in physiological systems, but probes upon bioorthogonal reaction require accessibility and background signal readout makes it challenging to achieve absolute glycan quantification. Here we develop SeMOE, a selenosugar-based metabolic oligosaccharide engineering strategy that combines elemental analysis and MOE to enable the absolute quantification and mass spectrometric imaging of glycome in a concise procedure. We demonstrate that SeMOE probes allow for perception, absolute quantification and visualization of glycans in diverse biological contexts. We demonstrate that chemical reporters on conventional MOE can be integrated into a bifunctional SeMOE probe to provide multimodality signal readouts. We further show the anti-cancer potentiality of SeMOE probes. SeMOE thus provides a convenient and simplified method to “see more” of the glyco-world.
“When I talk about it, my eyes light up!” Impacts of a national laboratory internship on community college student success
Authors: Coté Laleh E. , Van Doren Seth , Zamora Astrid N. , Jaramillo Salcido Julio , Law Esther W. , Otero Munoz Gabriel , Manocha Aparna , Flood Colette L. , Baranger Anne M.
Published: May 2023

Participation in technical/research internships may improve undergraduate graduation rates and persistence in science, technology, engineering, and mathematics (STEM), yet little is known about the benefits of these activities a) for community college students, b) when hosted by national laboratories, and c) beyond the first few years after the internship. We applied Social Cognitive Career Theory (SCCT) to investigate alumni perspectives about how CCI at Lawrence Berkeley National Laboratory (LBNL) impacted their academic/career activities. We learned that alumni had low confidence and expectations of success in STEM as community college students. Participation in CCI increased their professional networks, expectations of success, and STEM skills, identity, and self-efficacy/confidence. Hispanic/Latinx alumni recalled the positive impact of mentors who prioritized personal connections, and women valued “warm” social environments. We propose several additions to the SCCT model, to better reflect the supports and barriers to STEM persistence for community college students.
Conformational stability and order of Hoogsteen base pair induced by protein binding
Authors: Kole Kanika , Gupta Aayatti Mallick , Chakrabarti Jaydeb
Published: May 2023

Several experimental studies have shown that in the presence of proteins, the Hoogsteen (HG) base pair (bp) becomes stabilized. The molecular mechanism underlying this stabilization is not well known. This leads us to use all-atom molecular dynamics simulation to examine the stability of the HG bp in duplex DNA in both the absence and presence of proteins. We use conformational thermodynamics to investigate the stability of a HG bp in duplex DNA at the molecular level. We also compute the changes in the conformational free energy and entropy of DNA when DNA adopts a HG bp in its bp sequence rather than a Watson–Crick (WC) bp in both naked DNA and protein-bound DNA complex. We observe that the HG bp and the entire DNA duplex conformation are stabilized and ordered in the presence of proteins. Sugar-phosphate, sugar-base, and sugar-pucker torsion angles play key roles in stabilizing and ordering the HG bp in the protein-bound DNA complex.
The association of a streamlined and updated stroke protocol with improved secondary prevention and outcome
Authors: Leung Almond , Fong Richard J , Mahawish Karim M
Published: May 2023

Background

Stroke recurrence rates following an index event remain high compared with the baseline population. Evidence-based stroke treatments reduce this risk.

Aims

To determine the effect of an updated and streamlined hospital stroke guideline on prescribing practices and stroke recurrence rates at 3 months.

Methods

Hospital registries were searched for ICD-10 codes for transient ischaemic attack (TIA) and ischaemic stroke between July 2019 and July 2020. Data on patient demographics, discharge documentation, and other outcomes of interest were dichotomised into pre and post-intervention.

Results

396 patients were identified. There was a significant reduction in the stroke recurrence rate at 3 months post guideline update (8.3% vs 2.2%, OR 0.24, p<0.01). There were significant improvements in prescriptions for statins (66.5% vs 81.2%, p≤0.01) and antihypertensives (40.7% vs 50.7%, p=0.05), and documentation of lipid and blood pressure targets in discharge letters. There was a trend towards greater use of dual antiplatelet therapy (25.2% vs 34.1%, p=0.057).

Conclusion

In this audit, we found an association between the guideline update and improved patient outcomes and prescribing practices. We were unable to directly attribute the reduction in stroke recurrence to any single factor. This may be a chance finding and warrants investigation in other settings.
The developmental timing of spinal touch processing alterations and its relation to ASD-associated behaviors in mouse models
Authors: Tasnim Aniqa , Alkislar Ilayda , Hakim Richard , Turecek Josef , Abdelaziz Amira , Orefice Lauren L. , Ginty David D.
Published: May 2023

Altered somatosensory reactivity is frequently observed among individuals with autism spectrum disorders (ASDs). Here, we report that while multiple mouse models of ASD exhibit aberrant somatosensory behaviors in adulthood, some models exhibit altered tactile reactivity as early as embryonic development, while in others, altered reactivity emerges later in life. Additionally, tactile over-reactivity during neonatal development is associated with anxiety-like behaviors and social interaction deficits in adulthood, whereas tactile over-reactivity that emerges later in life is not. The locus of circuit disruption dictates the timing of aberrant tactile behaviors: altered feedback or presynaptic inhibition of peripheral mechanosensory neurons leads to abnormal tactile reactivity during neonatal development, while disruptions in feedforward inhibition in the spinal cord lead to touch reactivity alterations that manifest later in life. Thus, the developmental timing of aberrant touch processing can predict the manifestation of ASD-associated behaviors in mouse models, and differential timing of sensory disturbance onset may contribute to phenotypic diversity across individuals with ASD.
NMR Resonance Assignment of the LA Motif of Human LA-Related Protein 1
Authors: Smith Benjamin C. , Silvers Robert
Published: May 2023

Human La-related protein 1 (HsLARP1) is involved in post-transcriptional regulation of certain 5’ s terminal oligopyrimidine (5’TOP) mRNAs as well as other mRNAs and binds to both the 5’TOP motif and the 3’-poly(A) tail of certain mRNAs. HsLARP1 is heavily involved in cell proliferation, cell cycle defects, and cancer, where HsLARP1 is significantly upregulated in malignant cells and tissues. Like all LARPs, HsLARP1 contains a folded RNA binding domain, the La motif (LaM). Our current understanding of post-transcriptional regulation that emanates from the intricate molecular framework of HsLARP1 is currently limited to small snapshots, obfuscating our understanding of the full picture on HsLARP1 functionality in post-transcriptional events. Here, we present the nearly complete resonance assignment of the LaM of HsLARP1, providing a significant platform for future NMR spectroscopic studies.
Interplay of macromolecular interactions during assembly of human DNA polymerase δ holoenzymes and initiation of DNA synthesis
Authors: Norris Jessica L. , Rogers Lindsey O. , Pytko Kara G. , Dannenberg Rachel L. , Perreault Samuel , Kaushik Vikas , Kuppa Sahiti , Antony Edwin , Hedglin Mark
Published: May 2023

In humans, DNA polymerase δ (Pol δ) holoenzymes, comprised of Pol δ and the processivity sliding clamp, proliferating cell nuclear antigen (PCNA), carry out DNA synthesis during lagging strand DNA replication, initiation of leading strand DNA replication, and the major DNA damage repair and tolerance pathways. Pol δ holoenzymes are assembled at primer/template (P/T) junctions and initiate DNA synthesis in a coordinated process involving the major single strand DNA-binding protein complex, replication protein A (RPA), the processivity sliding clamp loader, replication factor C (RFC), PCNA, and Pol δ. Each of these factors interact uniquely with a P/T junction and most directly engage one another. Currently, the interplay between these macromolecular interactions is largely unknown. In the present study, novel Förster Resonance Energy Transfer (FRET) assays reveal that dynamic interactions of RPA with a P/T junction during assembly of a Pol δ holoenzyme and initiation of DNA synthesis maintain RPA at a P/T junction and accommodate RFC, PCNA, and Pol δ, maximizing the efficiency of each process. Collectively, these studies significantly advance our understanding of human DNA replication and DNA repair.
Simultaneous enhancement of multiple functional properties using evolution-informed protein design
Authors: Fram Benjamin , Truebridge Ian , Su Yang , Riesselman Adam J. , Ingraham John B. , Passera Alessandro , Napier Eve , Thadani Nicole N. , Lim Samuel , Roberts Kristen , Kaur Gurleen , Stiffler Michael , Marks Debora S. , Bahl Christopher D. , Khan Amir R. , Sander Chris , Gauthier Nicholas P.
Published: May 2023

Designing optimized proteins is important for a range of practical applications. Protein design is a rapidly developing field that would benefit from approaches that enable many changes in the amino acid primary sequence, rather than a small number of mutations, while maintaining structure and enhancing function. Homologous protein sequences contain extensive information about various protein properties and activities that have emerged over billions of years of evolution. Evolutionary models of sequence co-variation, derived from a set of homologous sequences, have proven effective in a range of applications including structure determination and mutation effect prediction. In this work we apply one of these models (EVcouplings) to computationally design highly divergent variants of the model protein TEM-1 β-lactamase, and characterize these designs experimentally using multiple biochemical and biophysical assays. Nearly all designed variants were functional, including one with 84 mutations from the nearest natural homolog. Surprisingly, all functional designs had large increases in thermostability and most had a broadening of available substrates. These property enhancements occurred while maintaining a nearly identical structure to the wild type enzyme. Collectively, this work demonstrates that evolutionary models of sequence co-variation (1) are able to capture complex epistatic interactions that successfully guide large sequence departures from natural contexts, and (2) can be applied to generate functional diversity useful for many applications in protein design.
Background matching can reduce responsiveness of jumping spiders to stimuli in motion
Authors: Tan Min , Chan Jeremiah Y.O. , Yu Long , Tan Eunice J. , Li Daiqin
Published: May 2023

Motion and camouflage were previously considered to be mutually exclusive, as sudden movements can be easily detected. Background matching, for instance, is a well-known, effective camouflage strategy where the color and pattern of a stationary animal match its surrounding background. However, background matching may lose its efficacy when the animal moves, as the boundaries of the animal become more defined against its background. Recent evidence shows otherwise, as camouflaged objects can be less detectable than uncamouflaged objects even while in motion. Here, we explored if the detectability of computer-generated stimuli varies with the speed of motion, background (matching and unmatching) and size of stimuli in six species of jumping spiders (Araneae: Salticidae). Our results showed that in general, the responsiveness of all six salticid species tested decreased with increasing stimulus speed regardless of whether the stimuli were conspicuousness or camouflaged. Importantly, salticid responses to camouflaged stimuli were significantly lower compared to conspicuous stimuli. There were significant differences in motion detectability across species when the stimuli were conspicuous, suggesting differences in visual acuity in closely related species of jumping spiders. Furthermore, small stimuli elicited significantly lower responses than large stimuli across species and speeds. Our results thus suggest that background matching is effective even when stimuli are in motion, reducing the detectability of moving stimuli.

Summary Statement

Contrary to belief, stimuli in motion can remain camouflaged against their backgrounds. Using computer-generated stimuli, we show that smaller and faster stimuli against camouflaged background elicit lower responses from jumping spiders.
Bursting with potential: How sensorimotor beta bursts develop from infancy to adulthood
Authors: Rayson Holly , Szul Maciej J , El-Khoueiry Perla , Debnath Ranjan , Gautier-Martins Marine , Ferrari Pier F , Fox Nathan , Bonaiuto James J
Published: May 2023

Beta activity is thought to play a critical role in sensorimotor processes. However, little is known about how activity in this frequency band develops. Here, we investigated the developmental trajectory of sensorimotor beta activity from infancy to adulthood. We recorded electroencephalography (EEG) from adults, 12-month-olds, and 9-month-olds while they observed and executed grasping movements. We analysed ‘beta burst’ activity using a novel method that combines time-frequency decomposition and principal component analysis (PCA). We then examined the changes in burst rate and waveform motifs along the selected principal components. Our results reveal systematic changes in beta activity during action execution across development. We found a decrease in beta burst rate during movement execution in all age groups, with the greatest decrease observed in adults. Additionally, we identified four principal components that defined waveform motifs that systematically changed throughout the trial. We found that bursts with waveform shapes closer to the median waveform were not rate-modulated, whereas those with waveform shapes further from the median were differentially rate-modulated. Interestingly, the decrease in the rate of certain burst motifs occurred earlier during movement and was more lateralized in adults than in infants, suggesting that the rate modulation of specific types of beta bursts becomes increasingly refined with age.
Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in murine heart failure with preserved ejection fraction
Authors: Lanzer Jan D. , Wienecke Laura M. , Ramirez-Flores Ricardo O. , Zylla Maura M. , Hartmann Niklas , Sicklinger Florian , Schultz Jobst-Hendrick , Frey Norbert , Saez-Rodriguez Julio , Leuschner Florian
Published: May 2023

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chighmacrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.
Duplex perception reveals brainstem auditory representations are modulated by listeners’ ongoing percept for speech
Authors: Rizzi Rose , Bidelman Gavin M.
Published: May 2023

So-called duplex speech stimuli with perceptually ambiguous spectral cues to one ear and isolated low– vs. high-frequency third formant “chirp” to the opposite ear yield a coherent percept supporting their phonetic categorization. Critically, such dichotic sounds are only perceived categorically upon binaural integration. Here, we used frequency-following responses (FFRs), scalp-recorded potentials reflecting phase-locked subcortical activity, to investigate brainstem responses to fused speech percepts and to determine whether FFRs reflect binaurally integrated category-level representations. We recorded FFRs to diotic and dichotic stop-consonants (/da/, /ga/) that either did or did not require binaural fusion to properly label along with perceptually ambiguous sounds without clear phonetic identity. Behaviorally, listeners showed clear categorization of dichotic speech tokens confirming they were heard with a fused, phonetic percept. Neurally, we found FFRs were stronger for categorically perceived speech relative to category-ambiguous tokens but also differentiated phonetic categories for both diotically and dichotically presented speech sounds. Correlations between neural and behavioral data further showed FFR latency predicted the degree to which listeners labeled tokens as “da” vs. “ga”. The presence of binaurally integrated, category-level information in FFRs suggests human brainstem processing reflects a surprisingly abstract level of the speech code typically circumscribed to much later cortical processing.
Computational design of soluble functional analogues of integral membrane proteins
Authors: Goverde Casper A. , Pacesa Martin , Goldbach Nicolas , Dornfeld Lars J. , Balbi Petra E. M. , Georgeon Sandrine , Rosset Stéphane , Kapoor Srajan , Choudhury Jagrity , Dauparas Justas , Schellhaas Christian , Kozlov Simon , Baker David , Ovchinnikov Sergey , Vecchio Alex J. , Correia Bruno E.
Published: May 2023

De novodesign of complex protein folds using solely computational means remains a significant challenge. Here, we use a robust deep learning pipeline to design complex folds and soluble analogues of integral membrane proteins. Unique membrane topologies, such as those from GPCRs, are not found in the soluble proteome and we demonstrate that their structural features can be recapitulated in solution. Biophysical analyses reveal high thermal stability of the designs and experimental structures show remarkable design accuracy. The soluble analogues were functionalized with native structural motifs, standing as a proof-of-concept for bringing membrane protein functions to the soluble proteome, potentially enabling new approaches in drug discovery. In summary, we designed complex protein topologies and enriched them with functionalities from membrane proteins, with high experimental success rates, leading to ade factoexpansion of the functional soluble fold space.
Strain and temperature dependent aggregation ofCandida aurisis attenuated by inhibition of surface amyloid proteins
Authors: Malavia-Jones Dhara , Farrer Rhys A. , Stappers Mark H.T. , Edmondson Matt B. , Borman Andrew M. , Johnson Elizabeth M. , Lipke Peter N. , Gow Neil A.R.
Published: May 2023

Candida aurisis a multi-drug resistant human fungal pathogen that has become a global threat to human health due to its drug resistant phenotype, persistence in the hospital environment and propensity for patient to patient spread. Isolates display variable aggregation that may affect the relative virulence of strains. Therefore, dissection of this phenotype has gained substantial interest in recent years. We studied eight clinical isolates from four different clades (I-IV); four of which had a strongly aggregating phenotype and four of which did not. Genome analysis identified polymorphisms associated with loss of cell surface proteins were enriched in weakly-aggregating strains. Additionally, we identified down-regulation of chitin synthase and chitinase genes involved in the synthesis and dissolution of the chitinous septum. Characterisation of the cells revealed no ultrastructural defects in cytokinesis or cell separation in aggregating isolates. Strongly and weakly aggregating strains did not differ in net surface charge or in cell surface hydrophobicity. The capacity for aggregation and for adhesion to polystyrene microspheres were also not correlated. However, aggregation and extracellular matrix formation were all increased at higher growth temperatures, and treatment with the amyloid protein inhibitor Thioflavin-T markedly attenuated aggregation. Genome analysis further indicated strain specific differences in the genome content of GPI-anchored proteins including those encoding genes with the potential to form amyloid proteins. Collectively our data suggests that aggregation is a complex strain and temperature dependent phenomenon that may be linked in part to the ability to form extracellular matrix and cell surface amyloids.

HIGHLIGHTS

The amyloid inhibitor Thioflavin-T inhibitedC. aurisaggregation. Aggregating isolates do not exhibit any defects in cell separation.

Genomic differences were identified between strongly aggregating and weakly-aggregating strains ofC. auris.

Aggregation did not correlate with surface charge or hydrophobicity of yeast cells.
Reward-Bases: Dopaminergic Mechanisms for Adaptive Acquisition of Multiple Reward Types
Authors: Millidge Beren , Song Yuhang , Lak Armin , Walton Mark E. , Bogacz Rafal
Published: May 2023

Animals can adapt their preferences for different types for reward according to physiological state, such as hunger or thirst. To describe this ability, we propose a simple extension of temporal difference model that learns multiple values of each state according to different reward dimensions such as food or water. By weighting these learned values according to the current needs, behaviour may be flexibly adapted to present demands. Our model predicts that different dopamine neurons should be selective for different reward dimensions. We reanalysed data from primate dopamine neurons and observed that in addition to subjective value, dopamine neurons encode a gradient of reward dimensions; some neurons respond most to food rewards while the others respond more to fluids. Moreover, our model reproduces instant generalization to new physiological state seen in dopamine responses and in behaviour. Our results demonstrate how simple neural circuit can flexibly optimize behaviour according to animals’ needs.
Neural mechanisms underlying release-mode-specific abnormalities in dopamine neural activity in a schizophrenia-like model
Authors: Sotoyama Hidekazu
Published: May 2023

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, we demonstrate that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. We examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or NMDA), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs.

Significance

I discovered that the hypo-NMDA function occurs in midbrain dopaminergic neurons of a schizophrenia-like model instead of the cerebral cortex, which has been the focus of attention so far. This suggests that the schizophrenia glutamate hypothesis may interact with the dopamine hypothesis. Furthermore, it was elucidated that a subpopulation of dorsal raphe serotonergic neurons inhibits VTA dopaminergic neurons in the resting state, resulting in promotion of social behavior. 5HT2 receptor-mediated regulation of inhibitory inputs to the dopaminergic neurons underlies this serotonergic regulation. In the schizophrenia-like model, this regulation by 5HT2 receptors is impaired. Chronic administration of an atypical antipsychotic ameliorates this abnormality. Therefore, this result may represent a mechanism underlying the differential efficacy between atypical and typical antipsychotics.
Increasing environmental fluctuations can dampen variability of endogenously cycling populations
Authors: Kortessis Nicholas , Ponciano José Miguel , Simon Franz W. , Ferguson Jake M.
Published: May 2023

Understanding how populations respond to increasingly variable conditions is a major objective for natural resource managers attempting to forecast extinction risk. The lesson from current modeling is clear: Increasing environmental variability increases population abundance variability. We show that this paradigm fails to describe a broad class of empirically observed dynamics, namely endogenously-driven population cycles. In contrast to the dominant paradigm, these populations can exhibit reduced long-run population variance under increasing environmental variability. We hypothesize that this paradox arises from interactions between environmental stochasticity and nonlinear density dependence. Such interactions violate the oft-assumed additivity of stochastic and deterministic drivers of population fluctuations present in many models that forecast population size. We show evidence for the interaction in two canonical cyclical populations: flour beetles and Canadian Lynx. To help identify the interaction, we develop new theory to quantify the strength of these interactions by partitioning the effects of nonlinear dynamics and stochastic variation on dynamical systems. In both empirical examples, the partitioning shows that the interaction between deterministic and stochastic dynamics reduces the overall variance in population size. Our results highlight that previous predictions about extinction under environmental variability may prove inadequate to understand the effects of climate change in many populations.
ECLiPSE: A Versatile Classification Technique for Structural and Morphological Analysis of Super-Resolution Microscopy Data
Authors: Hugelier Siewert , Kim Hannah , Gyparaki Melina Theoni , Bond Charles , Tang Qing , Santiago-Ruiz Adriana Naomi , Porta Sílvia , Lakadamyali Melike
Published: May 2023

We introduce a new automated machine learning analysis pipeline to precisely classify cellular structures captured through single molecule localization microscopy, which we call ECLiPSE (Enhanced Classification of Localized Pointclouds by Shape Extraction). ECLiPSE leverages 67 comprehensive shape descriptors encompassing geometric, boundary, skeleton and other properties, the majority of which are directly extracted from the localizations to accurately characterize individual structures. We validate ECLiPSE through unsupervised and supervised classification on a dataset featuring five distinct cellular structures, achieving exceptionally high classification accuracies nearing 100%. Moreover, we demonstrate the versatility of our approach by applying it to two novel biological applications: quantifying the clearance of tau protein aggregates, a critical marker for neurodegenerative diseases, and differentiating between two distinct morphological features (morphotypes) of TAR DNA-binding protein 43 proteinopathy, potentially associated to different TDP-43 strains, each exhibiting unique seeding and spreading properties. We anticipate that this versatile approach will significantly enhance the way we study cellular structures across various biological contexts, elucidating their roles in disease development and progression.
Classifying travellers’ requirements from online reviews: an improved Kano model
Authors: Zhao Meng , Liu Mengjiao , Xu Chang , Zhang Chenxi
Published: May 2023

Purpose

This study aims to provide a method for classifying travellers’ requirements to help hoteliers understand travellers’ requirements and improve hotel services. Specifically, this study develops a strength-frequency Kano (SF-Kano) model to classify the requirements expressed by travellers in online reviews.

Design/methodology/approach

The strength and frequency of travellers’ requirements are determined through sentiment and statistical analyses of the 13,217 crawled online reviews. The proposed method considering the interaction between strength and frequency is proposed to classify the different travellers’ requirements.

Findings

This study identifies 13 travellers’ requirements by mining online reviews. According to the results of the improved Kano model, the six travellers’ requirements belong to one-dimensional requirements; two travellers’ requirements belong to must-be requirements; three travellers’ requirements belong to attractive requirements; two travellers’ requirements belong to indifferent requirements.

Research limitations/implications

Results of this research can guide hoteliers to address hotel service improvement strategies according to the types of travellers’ requirements. This study can also expand the analysis scope of hotel online reviews and provide a reference for hoteliers to understand travellers’ requirements.

Originality/value

By mining online reviews, this study proposes an SF-Kano model to classify travellers’ requirements by considering both the strength and frequency of requirements. This study uses the optimisation model to determine the classification thresholds. This process maximises travellers’ satisfaction at the lowest cost. The classification results of travellers’ requirements can help hoteliers gain a deeper understanding of travellers’ requirements and prioritise service improvements.
Macroeconomic impact of the supply shock during COVID-19 pandemic in India
Authors: Sharma Apica , Sachdeva Paras
Published: May 2023

Purpose

The study focuses on examining the impact of the supply shock on the Indian macroeconomic variables during the COVID-19 period.

Design/methodology/approach

Time-varying factor augmented vector autoregressive model has been employed to study the asymmetry in transmission of supply shock on Indian economy during pre- and post-COVID-19 times.

Findings

The authors find that with supply shock, retail food inflation outpaced in COVID-19 times. Production levels reported by IIP fell to abysmally low levels in the post-COVID-19 times when the economy stalled. The liquidity stimulus provided by the central bank led to the negative response of policy rates to the supply shocks during the COVID-19 times.

Originality/value

The study stands novel in examining the impact of COVID-19 pandemic on Indian economy through the lenses of asymmetric transmission of supply shock during pre- and post-COVID-19 times.
A systematic review of articles in PDS Partners: Bridging Research to Practice (2017–2022)
Authors: Polly Drew
Published: May 2023

Purpose

The purpose of this study is to provide a systematic review of articles published in PDS Partners: Bridging Research to Practice between 2017 and 2022.

Design/methodology/approach

This study uses a systematic review of published articles.

Findings

Findings indicate that keywords in published articles focused on partnerships, professional development, teacher education and teaching. Findings related to authorship indicated that the journal published a combination of articles authored by only individuals in postsecondary institutions, or author teams that included individuals from both postsecondary institutions and PK-12 settings. Findings also indicate that the most common NAPDS Nine Essentials in articles were Essential 4: Reflection and Innovation and Essential 2: Clinical Practice.

Research limitations/implications

Implications for this study include a need for more scholarly writing about specific NAPDS Nine Essentials as well as a potential need for more studies on student learning within PDS partnerships.

Originality/value

This is the first systematic review published about articles published in PDS Partners, which transitioned from a magazine to a peer-reviewed journal in 2018.
Alterations and clinical relevance of gut microbiota in patients with Peutz–Jeghers syndrome: A prospective study
Authors: Wang Yu Xin , Huang Hua Bing , Dong Yuan Hang , Li Zhao Shen , Liu Feng , Du Yi Qi
Published: May 2023

Objective

In this case–control study we aimed to investigate the intestinal microbiota profile of patients with Peutz‐Jeghers syndrome (PJS) and its association with polyp growth.

Methods

Thirty‐two PJS patients and 35 healthy controls were enrolled. Fecal samples of all participants were collected for gut microbiota analysis via 16S rRNA gene (regions V3–V4) sequencing. SPSS version 22.0 and R software version 3.1.0 were used for the statistical analysis.

Results

The richness was comparable, while the overall structure of the gut microbiota differed significantly between the PJS and control groups (weighted UniFrac, P = 0.001; unweighted UniFrac, P = 0.008). Significantly different abundances of two phyla, seven families, and 18 genera as well as twenty‐nine differentially enriched functional modules (false discovery rate, P < 0.05) between the two groups were identified. Morganella was positively associated with the median number of polyps (JPN; r = 0.96, P < 0.001) and number of newly discovered polyps in the jejunum between two recent endoscopic resections (JPNG; r = 0.78, P = 0.04). Desulfovibrio was positively associated with JPNG (r = 0.87, P = 0.01). Blautia was negatively associated with the median maximum size of polyps in the jejunum (JPS). Anaerostipes was negatively associated with JPN, JPNG and JPS. Clostridium XVIII and Fusicatenibacter were negatively associated with JPN and JPS, respectively.

Conclusions

We found remarkably different gut microbiota of patients with PJS compared to healthy individuals and associations between specific fecal bacteria and clinical features of PJS. These findings may provide a new perspective for the management of PJS in clinical practice.
Romania: Political Developments and Data in 2022
Authors: STAN LAVINIA , ZAHARIA RAZVAN
Published: May 2023

No elections or referenda were organized in Romania in 2022. The government was preoccupied primarily with the economic, social, and political consequences of Russia's invasion of Ukraine, which borders Romania. The ruling coalition, supported by the Social Democrats and the Liberals, was politically stable but undermined by an inability to adequately address social and economic problems (reforming the pension system, reducing inflation, and improving living standards), as well as by frequent disputes between its main political parties, and numerous revelations that prominent government members had engaged in plagiarism during their doctoral studies.