bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis of closed groove scrambling by a TMEM16 protein
Authors: Feng Zhang , Alvarenga Omar E. , Accardi Alessio
Published: August 2023

Activation of Ca2+-dependent TMEM16 scramblases induces the externalization of phosphatidylserine, a key molecule in multiple signaling processes. Current models suggest that the TMEM16s scramble lipids by deforming the membrane near a hydrophilic groove, and that Ca2+dependence arises from the different association of lipids with an open or closed groove. However, the molecular rearrangements involved in groove opening and of how lipids reorganize outside the closed groove remain unknown. Using cryogenic electron microscopy, we directly visualize how lipids associate at the closed groove of Ca2+-bound nhTMEM16 in nanodiscs. Functional experiments pinpoint the lipid-protein interaction sites critical for closed groove scrambling. Structural and functional analyses suggest groove opening entails the sequential appearance of two π-helical turns in the groove-lining TM6 helix and identify critical rearrangements. Finally, we show that the choice of scaffold protein and lipids affects the conformations of nhTMEM16 and their distribution, highlighting a key role of these factors in cryoEM structure determination.
Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice
Authors: Baker Jonathan , Ombredane Hugo , Daly Leah , Knowles Ian , Rapeport Garth , Ito Kazuhiro
Published: August 2023

Endocytosis, or internalization through endosomes is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of Phosphatidylinositol (3,5)biphosphate (PtdIns(3,5)P2), and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virusin vitroandin vivo. PIKfyve inhibitors, Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in a MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, whilst improving the cell integrity of human nasal air liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2mg/ml), when intranasally treated, exhibited significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated anti-viral effects in RSV A2 infected human nasal epitheliumin vitroand mousein vivo, with equivalent effect to that of ribavirin. AM also showed anti-viral effects against human rhinovirus and seasonal coronavirusin vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for pan-viral approach against respiratory viruses.
Acute or chronic depletion of macrophages in the dorsal root ganglia induces neuropathic pain after unilateral cervical spinal cord injury
Authors: Chhaya Soha J. , Richards Jonathan Houston , Giddings Grace A. , Detloff Megan Ryan
Published: August 2023

The inflammatory response at the spinal cord injury (SCI) epicenter and heightened macrophage presence in the dorsal root ganglia (DRG) has been well characterized after SCI and correlates with neuropathic pain. CCL2, a chemokine that acts as a macrophage chemoattractant and neuromodulator, is implicated in pain development, however, the role of the CCL2-CCR2 axis in the development of pain after SCI has not been explored. Here, we examined the role of CCL2-CCR2 signaling in macrophage recruitment to the DRG as well as the prolonged presence of macrophages in the DRG on the development and persistence of pain after SCI. Adult female Sprague-Dawley rats received a moderate, unilateral C5 contusion. Sandwich ELISA revealed that CCL2 is upregulated in the ipsilesional C7 and C8 DRGs in the first 24 hours post injury (hpi) and returns to naïve levels by 72 hpi. To prevent monocyte-derived macrophage recruitment to the DRG, additional SCI rats received vehicle or INCB3344, a CCR2 antagonist, intravenously at the time of SCI and at 24 and 48 hpi. INCB3344 administration induced transient forepaw allodynia at 7dpi in nearly all rats (88%) compared to only 33% in vehicle controls that resolves partially by 28 dpi, as measured by von Frey and mechanical conflict avoidance paradigms. As expected, qPCR analyses of whole DRG revealed that INCB3344 reduced macrophage markers and inflammatory cytokines in the ipsilesional C7 and C8 DRGs at 7 dpi compared to vehicle treated rats. By 28 dpi, there were no significant differences between INCB3344 or vehicle-treated groups, indicating that SCI-induced macrophage presence in the DRG is delayed by INCB3344 treatment. Moreover, gene expression of markers of macrophage polarity and cytokines suggest a pro-inflammatory environment in the DRG at 28dpi. DRG macrophage ablation via liposomal clodronate at 21dpi did not ameliorate hypersensitive pain behavior, though their ablation did reduce paw withdrawal thresholds in SCI rats that did not previously demonstrate pain behavior. Collectively, these data suggest that driving macrophages to a pro-reparative phenotype may be a viable and effective analgesic strategy that acts by modulating both the immune response and the experience of pain.
Conformational ensemble dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
Authors: Araya Mussie K. , Gorfe Alemayehu A.
Published: August 2023

We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. We show that conformational plasticity is a key determinant of lipid sorting by polybasic PIDRs and provide evidence for lipid sorting based on both headgroup and acyl chain structures. We further show that conformational ensemble-based lipid recognition is generalizable to all polybasic PIDRs, and that the sequence outside the polybasic domain (PBD) modulates the conformational plasticity, bilayer adsorption, and interactions of PIDRs with membrane lipids. Specifically, we found that palmitoylation, the ratio of basic to acidic residues, and the hydrophobic content of the sequence outside the PBD significantly impact the diversity of conformational substates and hence the extent of conformation-dependent lipid interactions. We thus propose that the PBD is required but not sufficient for the full realization of lipid sorting by prenylated PBD-containing membrane anchors, and that the membrane anchor is not only responsible for high affinity membrane binding but also directs the protein to the right target membrane where it participates in lipid sorting.
Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1
Authors: Meyers Margot , Cismoski Sabine , Panidapu Anoohya , Chie-Leon Barbara , Nomura Daniel K.
Published: August 2023

Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4A adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.
Label-Free Composition Analysis of Supramolecular Polymer – Nanoparticle Hydrogels by Reversed-Phase Liquid Chromatography Coupled with a Charged Aerosol Detector
Authors: Tang Shijia , Pederson Zachary , Meany Emily L. , Yen Chun-Wan , Swansiger Andrew K. , Prell James S. , Chen Bifan , Grosskopf Abigail K. , Eckman Noah , Jiang Grace , Baillet Julie , Pellett Jackson D. , Appel Eric A.
Published: August 2023

Supramolecular hydrogels formed through polymer-nanoparticle interactions are promising biocompatible materials for translational medicines. This class of hydrogels exhibits shear-thinning behavior and rapid recovery of mechanical properties following applied stresses, providing desirable attributes for formulating sprayable and injectable therapeutics. Characterization of hydrogel composition and loading of encapsulated drugs is critical to achieving desired rheological behavior as well as tunable in vitro and in vivo payload release kinetics. However, quantitation of hydrogel compositions is challenging due to material complexity, heterogeneity, high molecular weight, and the lack of chromophores. Here, we present a label-free approach to simultaneously determine hydrogel polymeric components and encapsulated payloads by coupling a reversed phase liquid chromatographic method with a charged aerosol detector (RPLC-CAD). The hydrogel studied consists of modified hydroxypropylmethylcellulose, self-assembled PEG-b-PLA nanoparticles, and a therapeutic compound, Bimatoprost. The three components were resolved and quantitated using the RPLC-CAD method with a C4 stationary phase. The method demonstrated robust performance, applicability to alternative cargos (i.e. proteins), and was suitable for composition analysis as well as for evaluating in vitro release of cargos from the hydrogel. Moreover, this method can be used to monitor polymer degradation and material stability, which can be further elucidated by coupling the RPLC method with high resolution mass spectrometry and a Fourier-transform based deconvolution algorithm. To our knowledge, this is the first RPLC-CAD method for characterizing the critical quality attributes of supramolecular hydrogels. We envision this analytical strategy could be generalized to characterize other classes of supramolecular hydrogels, establish structure-property relationships, and provide rational design guidance in hydrogel drug product development.
Aminomutation catalyzed by CO2self-sufficient cascade amino acid decarboxylases
Authors: Song Zhan , Li Yuan , Li Yunjie , Cui Xiangwei , Zhong Jian-Jiang , Zhang Yi-Heng P. J.
Published: August 2023

Molecular editing of an amino group from α-position of amino acids to its β-position is of scientific interest and could be economically appealing. Here we reconstructed anin vitrobiotransformation pathway composed of two cascade decarboxylases, i.e., aspartate β-decarboxylase and aspartate α-decarboxylase, and implemented molecular editing to change α-alanine into β-alanine. In it, we discovered a new reaction of aspartate β-decarboxylase that can fix CO2directly. This cascade enzymatic pathway enabled an aminomutation reaction with 100% carbon atom economy. This work presented the first CO2-fixing biological reaction catalyzed by the amino acid decarboxylases and demonstrated a new means for the molecular editing of α-amino acids.
The defensome of complex bacterial communities
Authors: Beavogui Angelina , Lacroix Auriane , Wiart Nicolas , Poulain Julie , Delmont Tom O. , Paoli Lucas , Wincker Patrick , Oliveira Pedro H.
Published: August 2023

Bacteria have developed various defense mechanisms to avoid infection and killing in response to the fast evolution and turnover of viruses and other genetic parasites. Such pan-immune system (ordefensome) encompasses a growing number of defense lines that include well-studied innate and adaptive systems such as restriction-modification, CRISPR-Cas and abortive infection, but also newly found ones whose mechanisms are still poorly understood. While the abundance and distribution of defense systems is well-known in complete and culturable genomes, there is a void in our understanding of their diversity and richness in complex microbial communities. Here we performed a large-scale in-depth analysis of the defensomes of 7,759 high-quality bacterial population genomes reconstructed from soil, marine, and human gut environments. We observed a wide variation in the frequency and nature of the defensome among large phyla, which correlated with lifestyle, genome size, habitat, and geographic background. The defensome’s genetic mobility, its clustering in defense islands, and genetic variability was found to be system-specific and shaped by the bacterial environment. Hence, our results provide a detailed picture of the multiple immune barriers present in environmentally distinct bacterial communities and set the stage for subsequent identification of novel and ingenious strategies of diversification among uncultivated microbes.
PRDM16 co-operates with LHX2 to shape the human brain
Authors: Suresh Varun , Bhattacharya Bidisha , Tshuva Rami Yair , Danan Gotthold Miri , Olender Tsviya , Bose Mahima , Pradhan Saurabh J. , Ben Zeev Bruria , Smith Richard Scott , Tole Shubha , Galande Sanjeev , Harwell Corey , Baizabal José-Manuel , Reiner Orly
Published: August 2023

PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.
Overexpression of tomatoSlBBX16andSlBBX17impacts fruit development and gibberellin metabolism
Authors: Dusi Valentina , Pennisi Federica , Fortini Daniela , Atarés Alejandro , Wenkel Stephan , Molesini Barbara , Pandolfini Tiziana
Published: August 2023

BBXs are B-Box zinc finger proteins that can act as transcription factors and regulators of protein complexes. Several BBX proteins play important roles in plant development. TwoArabidopsis thalianamicroProteins belonging to the BBX family, named miP1a and miP1b, homotypically interact with and modulate the activity of other BBX proteins, including CONSTANS, which transcriptionally activates the florigen,FLOWERING LOCUS T. In tomato, the closest homologs of miP1a and miP1b are the microProteinsSlBBX16 andSlBBX17. To deepen our understanding of the role of tomato microProteins in flowering, we constitutively expressedSlBBX16/17 inArabidopsisand tomato and examined possible interacting partners. Overexpression of the two tomato microProteins inArabidopsiscaused a delay in the flowering transition; however, the effect was weaker than that observed inArabidopsisplants overexpressing the native miP1a/b. In tomato, overexpression ofSlBBX17prolonged the flowering period; this effect was accompanied by downregulation of the flowering inhibitorsSelf Pruning(SP) andSP5G.SlBBX16 andSlBBX17 are able to hetero-oligomerize with TCMP-2, a cystine-knot peptide involved in flowering pattern and fruit development in tomato. Increasing the expression of both tomato microProteins also caused alterations in fruit development: overexpression ofSlBBX17resulted in a diminished number and size of ripe fruits as compared to WT plants, while overexpression ofSlBBX16caused delayed fruit production up to the breaker stage. These effects were associated with changes in the expression of genes regulating gibberellin content.
Worms on the Cape: an integrative survey of polydorid infestation in wild and cultivated oysters (Crassostrea virginica) from Massachusetts, USA
Authors: Davinack Andrew A. , Strong Margaret , Brennessel Barbara
Published: August 2023

Polydorid infestations pose a significant challenge to shellfish aquaculture by impacting marketability and profitability of farms. In this study, we investigated the prevalence, intensity, identity and biogeography of shell-boring worms infecting both farmed and wild oysters (Crassostrea virginica) from three sites in Wellfleet Harbor, Massachusetts – an economically important shellfishing region in the northeastern United States. DNA barcoding revealed thatPolydora websteriwas the sole culprit responsible for infecting oysters from all three sites, reaching maximum prevalence (100% infection) and intensity (mean intensity: 38.63) in the Herring River. The oysters in the Herring River are subjected to restricted tidal flow due to the presence of a physical barrier (dike), and this could be responsible for the high infestation levels ofP. websteriobserved in this population. In addition, a population genetic analysis incorporating COI sequence data from WellfleetP. websteriin addition to newly published sequences from the Black Sea and the Sea of Azov found very low levels of genetic differentiation across several intercontinental populations (0.000 – 0.399), which is likely being driven by multiple introductory events such as oyster importations. These findings are discussed in relation to the future of shellfish aquaculture in the United States.
Age-associated failure of efficient cardiac proteostatic adaptations to chronic cAMP-stress is associated with accelerated heart aging
Authors: Perino Maria Grazia , Barrera Miguel Calvo-Rubio , Riordon Daniel R. , Agnetti Giulio , Parveen Admira , Morrell Christopher H. , Ahmet Ismayil , Chakir Khalid , Tarasova Yelena S. , Qu Jia-Hua , Tarasov Kirill V , Lyashkov Alexey E. , Lukyanenko Yevgeniya O. , Kadioglu Hikmet , Ranek Mark , deCabo Rafael , Lakatta Edward G.
Published: August 2023

Dysregulated proteostasis, leading to accumulation of misfolded proteins, electron-dense aggregates (lipofuscin, LF), preamyloid oligomers (PAOs), and proteotoxic stress is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic adenosine monophosphate (cAMP)-dependent stress change with aging in mice harboring marked, cardiac-specific over-expression of adenylyl cyclase VIII (TGAC8). We assessed protein quality control (PQC) mechanisms: ubiquitin proteasome system (UPS), autophagic flux via macroautophagy, and mitophagy in left ventricles (LVs) of TGAC8and wild type littermates (WT) at 3-4 months and at 17-21 months of age. At 3-4 months of age TGAC8mice exhibited markers of increased autophagic flux, measured by levels of microtubule-associated protein 1 light chain 3 (LC3), p62, and their phospho-forms in TGAC8LV; cathepsin L1 activity was also significantly increased. In addition, canonical mitophagy signaling was enhanced, as receptors PARKIN, p62S405and p62S351were all upregulated, confirming a more efficient proteostasis in TGAC8at 3-4 months vs WT. In advanced age, however, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity and an unbalanced autophagic flux (accelerated for markers such as LC3A in the context of a sloweroverallflux), leading to an increase in the accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions). Although both canonical (PARKIN, p62S405and p62S351receptors) and non-canonical (FKBP8 receptor) mitophagy signaling were upregulated in advanced age in TGAC8, mitophagy was markedly impaired and mitochondrial dysfunction increased. Accumulation of LF bodies, of brownish-to-black pigments, and of LC3+and p62+-inclusions of aberrant sizes, of desmin cardiac preamyloid oligomers (PAOs) and of cleaved desmin, tagged for ubiquitination, were all increased in TGAC8compared to young TGAC8. In contrast, the rate of protein synthesis and levels of soluble aggregates were reduced in aged vs young TGAC8, a sign of “normal” aging. Thus, increased proteostatic mechanisms maintain cardiac health in TGAC8in youth (3-4 months), but long-term exposure to chronic cardiac stress, imposed by sustained activation of the AC/cAMP/PKA/Ca2+signaling axis, results in severely dysregulated proteostasis in TGAC8vs WT mice, associated with proteostatic insufficiency and increased cardiomyopathy that leads to accelerated cardiac aging.

GRAPHICAL ABSTRACT
Does pickup service quality explain BOPIS users' store relationship performance? The moderating role of users' service experience consciousness
Authors: Natarajan Thamaraiselvan , Veera Raghavan Deepak Ramanan
Published: August 2023

Purpose

Building on Stimulus-Organism-Response theory, the current study examines the influence of pickup service quality in buy-online pickup in-store service (BOPIS) on users' perceived relationship investment with the mediating role of users' perceived experience quality and relationship proneness. This research also demonstrates the subsequent impact of BOPIS users' perceived relationship investment on their relationship performance indicators, like their cross-buying behaviors (breadth), frequency of their purchase (depth) and longevity of their relationship (length) with the store. The moderating role of BOPIS users' service experience consciousness in a few proposed relationships was tested.

Design/methodology/approach

The research is descriptive, quantitative and cross-sectional investigation. The study employed a purposive sampling technique. It was conducted using data collected using a validated self-administered questionnaire from 786 Indian omnichannel shoppers who have used BOPIS services in the past. The proposed conceptual model was tested using Partial Least Squares-Structural Equation Modeling.

Findings

The results indicate that BOPIS users' perceived experience quality and relationship proneness positively mediate pickup service quality and perceived relationship investment. The users' perceived relationship investment subsequently significantly positively impacts different dimensions of their relationship performance with the store (breadth, depth and length). Additionally, BOPIS users' service experience consciousness has a significant negative moderating effect on the direct relationship between pickup service quality and different dimensions of relationship performance.

Research limitations/implications

The study is conducted in the Indian population, where omnichannel retailing is still nascent.

Originality/value

This study addresses the need to investigate the relationship performance indicators of BOPIS users, like their cross-buying behaviors(breadth), frequency of their purchase(depth) and longevity of their relationship(length) with the store. This study is the first to show that pickup service quality might explain the relationship performance of BOPIS users through their perceived experience quality, relationship proneness and relationship investments. The moderating role of BOPIS users' service experience consciousness in a few proposed relationships was also tested for the first time.
Three‐axis borehole gravity monitoring for CO2 storage using machine learning coupled to fluid flow simulator
Authors: Alyousuf Taqi , Li Yaoguo , Krahenbuhl Richard , Grana Dario
Published: August 2023

The field of geophysics faces the daunting task of monitoring complex reservoir dynamics and imaging carbon dioxide storage up to several decades into the future. This presents numerous challenges, including sensitivity to parameter changes, resolution of obtained results and the cost of long‐term deployment. To effectively store CO2 subsurface, it is necessary to monitor and account for the injected CO2. The gravity method provides several advantages for CO2 monitoring, as changes in fluid saturation correspond directly and uniquely to observed density changes. Three‐axis borehole gravity has demonstrated significant promise as a next‐generation tool for reliably monitoring reservoir dynamics across a range of depths and sizes. However, the gravity inverse problem is highly ill‐posed, necessitating regularization that incorporates prior knowledge. To address this issue, we propose using a feed‐forward neural network, a machine learning method, to invert time‐lapse three‐axis borehole gravity data and monitor CO2 movement within a reservoir. By training the neural network on models that analyse changes in density and corresponding gravity responses resulting from perturbations made to the reservoir model, we can create scenarios that train the algorithm to identify unexpected CO2 migration in addition to the normal movement of CO2. Our method is demonstrated using reservoir models for the Johansen formation in offshore Norway. We convert reservoir saturation models into density changes and generate their corresponding three‐axis gravity data in a set of boreholes. Our results show that the developed machine learning inversion algorithm has high reliability and resolution for imaging density change associated with CO2 plumes, as demonstrated in the Johansen reservoir models utilized by the simulator. We also investigate machine learning inversion using regularization parameters and show that it is robust, with a strong tolerance for higher levels of noise. Our study demonstrates that the developed machine learning algorithm is a powerful tool for inverting three‐axis borehole gravity data and monitoring the migration and long‐term storage of injected CO2.
How artificial intelligence is reshaping the autonomy and boundary work of radiologists. A qualitative study
Authors: Lombi Linda , Rossero Eleonora
Published: August 2023

The application of artificial intelligence (AI) in medical practice is spreading, especially in technologically dense fields such as radiology, which could consequently undergo profound transformations in the near future. This article aims to qualitatively explore the potential influence of AI technologies on the professional identity of radiologists. Drawing on 12 in‐depth interviews with a subgroup of radiologists who participated in a larger study, this article investigated (1) whether radiologists perceived AI as a threat to their decision‐making autonomy; and (2) how radiologists perceived the future of their profession compared to other health‐care professions. The findings revealed that while AI did not generally affect radiologists’ decision‐making autonomy, it threatened their professional and epistemic authority. Two discursive strategies were identified to explain these findings. The first strategy emphasised radiologists’ specific expertise and knowledge that extends beyond interpreting images, a task performed with high accuracy by AI machines. The second strategy underscored the fostering of radiologists’ professional prestige through developing expertise in using AI technologies, a skill that would distinguish them from other clinicians who did not pose this knowledge. This study identifies AI machines as status objects and useful tools in performing boundary work in and around the radiological profession.
Identification of an odorant receptor responding to sex pheromones in Spodoptera frugiperda extends the novel type‐I PR lineage in moths
Authors: Zhang Sai , Jacquin‐Joly Emmanuelle , Montagné Nicolas , Liu Fang , Liu Yang , Wang Guirong
Published: August 2023

In moths, pheromone receptors (PRs) are crucial for intraspecific sexual communication between males and females. Moth PRs are considered as an ideal model for studying the evolution of insect PRs, and a large number of PRs have been identified and functionally characterized in different moth species. Moth PRs were initially thought to fall into a single monophyletic clade in the odorant receptor (OR) family, but recent studies have shown that ORs in another lineage also bind type‐I sex pheromones, which indicates that type‐I PRs have multiple independent origins in the Lepidoptera. In this study, we investigated whether ORs of the pest moth Spodoptera frugiperda belonging to clades closely related to this novel PR lineage may also have the capacity to bind type‐I pheromones and serve as male PRs. Among the 7 ORs tested, only 1 (SfruOR23) exhibited a male‐biased expression pattern. Importantly, in vitro functional characterization showed that SfruOR23 could bind several type‐I sex pheromone compounds with Z‐9‐tetradecenal (Z9‐14:Ald), a minor component found in female sex pheromone glands, as the optimal ligand. In addition, SfruOR23 also showed weak responses to plant volatile organic compounds. Altogether, we characterized an S. frugiperda PR positioned in a lineage closely related to the novel PR clade, indicating that the type‐I PR lineage can be extended in moths.
Pre‐ and post‐treatment FDG PET‐CT as a predictor of patient outcomes in anal squamous cell carcinoma: A systematic review and meta‐analysis
Authors: Mac Curtain Benjamin M , Qian Wanyang , Bell Jack , O'Mahony Aaron , Temperly Hugo C , Ng Zi Qin
Published: August 2023

Anal squamous cell carcinoma (ASCC) has a generally acceptable outlook in terms of survival. 18‐fluorodeoxyglucose‐positron emission tomography/computer tomography (FDG PET‐CT) is not recommended for routine monitoring post‐ASCC treatment. We examine herein if FDG PET‐CT has a use in the prognostic evaluation of patients with ASCC, what FDG PET‐CT metrics are of value and if a pre‐ or post‐chemo/radiotherapy scan is more prognostic of outcomes. PubMed, EMBASE and Cochrane Central Registry of Controlled Trials were comprehensively searched until 3 May, 2023. A modified Newcastle Ottawa scale was used to assess for study bias. We present our systematic review alongside pooled hazard ratios (HR) for maximum standardised uptake values (SUV) as a predictor of overall survival (OS) and progression‐free survival (PFS). Seven studies including 523 patients were included in our systematic review. Current evidence suggests that SUV maximum and median, metabolic tumour volume, total lesion glycolysis and complete and partial metabolic response may be prognostic when considering overall or progression‐free survival (OS)/(PFS) along with local recurrence (LR). Pooled HR from two included studies indicate SUV max is prognostic of OS, HR 1.179, CI (1.039–1.338), P = 0.011 and PFS 1.176, CI (1.076–1.285), P < 0.01. FDG PET‐CT may have a role to play in the prognostic evaluation of ASCC patients. Current evidence suggests post‐treatment scanning may hold superior prognostic value at this time.
Learning from others' experience: Social fear conditioning deficits in patients with severe alcohol use disorder
Authors: Bakkali Nahid , Ott Laurent , Triquet Claire , Cottencin Olivier , Grynberg Delphine
Published: August 2023

Background

Alcohol use disorder (AUD) is a significant public health problem. A better understanding of the psychosocial factors contributing to AUD is important for developing public health policy. The purpose of this study was to identify social mechanisms involved in AUD and, more specifically, to determine whether vicarious learning deficits are related to the disorder. A secondary objective was to evaluate the role of empathy in social fear conditioning.

Methods

Patients with severe AUD (n = 30) and healthy participants (n = 30) performed a social fear learning (SFL) task. The task assesses how an association between a stimulus and an aversive consequence is acquired through social means. Specifically, participants observed a person receiving an electric shock (unconditioned stimulus; US) that was associated (conditioned stimulus; CS+) or not (CS−) with a neutral CS. The skin conductance response was used to measure the effect of learning.

Results

Individuals with severe AUD showed a deficit in SFL, indicating that they had difficulty learning from another's negative experience. Patients also evaluated the emotional experience as less unpleasant than healthy participants.

Conclusions

This study is the first to show that patients with severe AUD have social learning deficits. The findings suggest that these individuals do not learn from another's negative experience. At a fundamental level, the findings demonstrate the importance of understanding the role of social mechanisms in AUD. At a clinical level, the study highlights the potential for using social learning enhancement to prevent relapse in individuals with severe AUD.
Factors associated with entry to residential care in frail older inpatients
Authors: Misquitta Karen , Reid Natasha , Hubbard Ruth E. , Gordon Emily H.
Published: August 2023

Objective

To examine factors that may influence the risk of discharge to a residential aged care facility (RACF) in a population of frail older inpatients.

Methods

We analysed data from 5846 inpatients aged over 60 years from 27 hospitals in Queensland, Australia, admitted from independent living and referred for geriatric consultation. Patients underwent an interRAI Acute Care Comprehensive Geriatric Assessment by trained nurses. Frailty was assessed using a 52‐item frailty index (FI). Risk/protective factors were determined a priori. Logistic regression assessed the relationship between factors and discharge destination, adjusted for FI, age, sex and hospital. Frailty × risk/protective factor interactions were performed.

Results

Patients had a mean (SD) age of 79.7 (8.2) years and a mean (SD) FI of 0.44 (0.14). Twenty‐nine per cent (n = 1678) of patients were discharged to an RACF. Each 0.1 increment in FI increased the risk of discharge to an RACF by 54% (OR 1.54, 95% CI 1.40–1.68, p < 0.01). Being married or in a de facto relationship had protective effects up to an FI of 0.7, whereas behavioural and psychological symptoms of dementia (BPSD) increased the risk of RACF discharge up to an FI of 0.7. Female sex, faecal incontinence and living alone did not influence the relationship between frailty and discharge destination.

Conclusions

The association between frailty and discharge to RACF has previously been recognised but here we found that risk and protective factors can influence this association. Whether early identification and management of mutable factors can reduce discharge to RACF should be addressed in future studies.
Climate Cascades: IOs and the Prioritization of Climate Action
Authors: Clark Richard , Zucker Noah
Published: August 2023

International organizations (IOs) are rapidly reorienting around climate change, despite powerful principal states having divergent preferences on the issue. When and why do IOs prioritize climate change? We argue that they do so as a result of an endogenous process of staff learning and rotation. IO staff surveil and implement programs in target states. When working in climate‐vulnerable countries, they come to see climate change as an issue warranting aggressive action. As these staff are rotated and promoted, interest in climate diffuses outwards and upwards through the institution. To test this theory, we introduce original data tracking the International Monetary Fund's attention to climate change and the career paths of key staff. We complement this with interviews of International Monetary Fund personnel. We find support for our theory.
Bureaucratic Structure and Compliance with International Agreements
Authors: Carcelli Shannon P.
Published: August 2023

Why do some states comply with international agreements while others flout them? In this article, I introduce a previously unconsidered explanation: bureaucratic structure. I develop a rational choice model examining the impact of bureaucratic structure on compliance, suggesting that the existence of several distinct bureaucracies can mute compliance with an international agreement by insulating some bureaucrats from pressure to comply. I examine this theory through newly coded data on a 2001 OECD agreement designed to decrease the percentage of aid that is “tied” to donor‐state products and services—a practice that is popular among special interests but which decreases foreign aid's effectiveness. I find that non–development‐oriented bureaucracies, such as departments of interior, labor, and energy, were significantly less likely to comply with the agreement than traditional development bureaucracies. This aggregates to the state level as well, where states with many aid agencies were less compliant than states with a streamlined bureaucracy.
Exploiting nanopore sequencing for characterization and grading of IDH‐mutant gliomas
Authors: Wongsurawat Thidathip , Jenjaroenpun Piroon , Anekwiang Panatna , Arigul Tantip , Thongrattana Wichayapat , Jamshidi‐Parsian Azemat , Boysen Gunnar , Suriyaphol Prapat , Suktitipat Bhoom , Srirabheebhat Prajak , Cheunsuchon Pornsuk , Tanboon Jantima , Nookaew Intawat , Sathornsumetee Sith
Published: August 2023

The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin‐dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to codeletion of 1p/19q to characterize IDH‐mutant gliomas. Here, we demonstrated the use of a nanopore‐based copy‐number variation sequencing (nCNV‐seq) approach to simultaneously identify deletions of CDKN2A/B and 1p/19q. The nCNV‐seq approach was initially evaluated on three distinct glioma cell lines and then applied to 19 IDH‐mutant gliomas (8 astrocytomas and 11 oligodendrogliomas) from patients. The whole‐arm 1p/19q codeletion was detected in all oligodendrogliomas with high concordance among nCNV‐seq, FISH, DNA methylation profiling, and whole‐genome sequencing. For the CDKN2A/B deletion, nCNV‐seq detected the loss in both astrocytoma and oligodendroglioma, with strong correlation with the CNV profiles derived from whole‐genome sequencing (Pearson correlation (r) = 0.95, P < 2.2 × 10−16 to r = 0.99, P < 2.2 × 10−16) and methylome profiling. Furthermore, nCNV‐seq can differentiate between homozygous and hemizygous deletions of CDKN2A/B. Taken together, nCNV‐seq holds promise as a new, alternative approach for a rapid and simultaneous detection of the molecular signatures of IDH‐mutant gliomas without capital expenditure for a sequencer.
Infantile onset encephalomyopathy, retinopathy, optic atrophy, and mitochondrial DNA depletion associated with a novel pathogenic DHX16 variant
Authors: Hautakangas Milla‐Riikka , Widgren Paula , Korpelainen Paavo , Kangas Salla M. , Komulainen Tuomas , Vieira Päivi , Rahikkala Elisa , Pylkäs Katri , Tuominen Hannu , Kokkonen Hannaleena , Miinalainen Ilkka , Nadaf Javad , Majewski Jacek , Hinttala Reetta , Uusimaa Johanna
Published: August 2023

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH‐box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient‐derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease.
Role of ultra‐high definition endoscopy (endomicroscopy and endocytoscopy) and real‐time histologic examination in inflammatory bowel disease: Scoping review
Authors: Pal Partha , Ramchandani Mohan , Patel Rajendra , Banerjee Rupa , Kanaganti Swathi , Gupta Rajesh , Tandan Manu , Reddy Duvvuru Nageshwar
Published: August 2023

Objectives

Confocal laser endomicroscopy (CLE) and endocytoscopy (EC) are ultra‐high definition (HD) imaging modalities that enable real‐time histological assessment. Although existent for nearly two decades, their role in current clinical decision making in inflammatory bowel disease management is not well defined.

Methods

We searched PubMed using keywords (“confocal” OR “CLE” OR “endocytoscopy”) AND (“IBD” OR “inflammatory bowel” OR “Crohn*” OR “Crohn's” OR “colitis ulcerosa” OR “ulcerative colitis”) between 2005 and March 2023. We identified 52 studies for detailed review.

Results

Confocal laser endomicroscopy was useful in real‐time assessment of histologic inflammation and dysplasia characterization in both ulcerative colitis (UC) and Crohn's disease. Although CLE was associated with higher per‐biopsy yield for UC‐associated neoplasia (UCAN), the benefit was offset by higher procedure time, frequent equipment failure, and conflicting results on incremental yield over chromoendoscopy. Assessment of barrier dysfunction by CLE did not correlate with disease/endoscopic activity but could predict major adverse outcomes. The implications of residual CLE abnormalities in endoscopic remission remain uncertain. Ex vivo binding of labeled biologics can help in predicting biologic response in UC. EC can discriminate mucosal inflammatory cells by morphology and allows assessment of histologic activity. EC combined with pit pattern was better than pit pattern alone for UCAN. Artificial intelligence‐assisted EC in UCAN needs further study.

Conclusion

Ultra‐HD imaging in inflammatory bowel disease can be useful in assessment of UCAN, barrier dysfunction, predicting histologic remission, and biologic response. Future controlled studies are warranted to define the role of these novel technologies in clinical decision making.
Views of children with diabetes from underserved communities, and their families on diabetes, glycaemic control and healthcare provision: A qualitative evidence synthesis
Authors: Moore Theresa H. , Dawson Sarah , Wheeler Jessica , Hamilton‐Shield Julian , Barrett Timothy G. , Redwood Sabi , Litchfield Ian , Greenfield Sheila M. , Searle Aidan ,   the Diversity in Diabetes (DID) Consortium Members
Published: August 2023

Aims

Children and young people with diabetes (CYPD) from socio‐economically deprived and/or ethnic minority groups tend to have poorer glucose control and greater risk of diabetes‐related complications. In this systematic review of qualitative evidence (qualitative evidence synthesis, QES), we aimed to explore the experiences and views of clinical encounters in diabetes care from the perspectives of CYPD and their family/carers from underserved communities and healthcare professionals in diabetes care.

Methods

We searched 6 databases to March 2022 with extensive search terms, and used a thematic synthesis following methods of Thomas and Harden.

Results

We identified 7 studies and described 11 descriptive themes based on primary and secondary constructs. From these, three “analytical themes” were developed. (1) “Alienation of CYPD” relates to their social identity and interaction with peers, family and health service practitioners in the context of diabetes self‐ and family/carer management and is impacted by communication in the clinical encounter. (2) “Empowerment of CYPD and family/carers” explores families' understanding of risks and consequences of diabetes and taking responsibility for self‐ and family/carer management in the context of their socio‐cultural background. (3) “Integration of diabetes (into self and family)” focuses on the ability to integrate diabetes self‐management into the daily lives of CYPD and family/carers beyond the clinical consultation.

Conclusions

The analytical themes are interdependent and provide a conceptual framework from which to explore and strengthen the therapeutic alliance in clinical encounters and to foster greater concordance with treatment plans. Communicating the biomedical aspects of managing diabetes in the clinical encounter is important, but should be balanced with addressing socio‐emotional factors important to CYPD and family/carers.
Native fish abundance and habitat selection changes in the presence of nonnative piscivores
Authors: Jenney Christopher J. , Bauder Javan M. , Bonar Scott A.
Published: August 2023

We compared abundance patterns and developed resource selection models for imperilled native southwestern (USA) fishes in the presence and absence of Black Bass (Micropterus spp.) to evaluate how fishes alter their selection for habitats when sympatric with a nonnative piscivore. We collected data using snorkel surveys and in‐stream habitat sampling in Fossil Creek (AZ), upstream (native fish only) and downstream (native and nonnative fish) of a fish barrier. The abundance of all Roundtail Chub (Gila robusta), small (≤127 mm total length [TL]; vulnerable to predation) Sonora Sucker (Catostomus insignis) and Speckled Dace (Rhinichthys osculus) was significantly reduced, but the abundance of both small and large (>127 mm TL; invulnerable to predation) Desert Sucker (Catostomus clarkii) was similar in sampling reaches with and without Black Bass. When sympatric with Black Bass, small Roundtail Chub increased their selection for riffles by 2.57 times and small Desert Sucker reduce their selection for pools by 6.90 times while also selecting for faster flow velocity and finer substrates in lotic mesohabitats. Large native fishes altered selection least, notwithstanding an increased selection for canopy cover in sampling reaches with Black Bass. Observed shifts in resource selection are consistent with predator avoidance strategies. Our study highlights the behavioural consequences of nonnative piscivores on native fish communities and stresses the importance of maintaining lotic mesohabitats as potential refugia for vulnerable native fishes when nonnative piscivores are present.