bluuebunny/crossref_metadata_2025 huggingface dataset:
TRAF6 signaling in T cells is crucial for the pathogenicity of experimental autoimmune encephalomyelitis
Authors: Kamiyama Naganori , Saechue Benjawan , Sachi Nozomi , Dewayani Astri , Chalalai Thanyakorn , Ozaka Sotaro , Ariki Shimpei , Soga Yasuhiro , Kagoshima Yomei , Ekronarongchai Supanuch , Hidano Shinya , Kobayashi Takashi
Published: December 2023

Multiple sclerosis (MS) is an incurable chronic autoimmune disease affecting the central nervous system (CNS). Although IL-17-producing helper T (Th17) cells are thought to be one of the exacerbating factors in MS, the underlying pathogenic mechanism is incompletely understood. TNF receptor-associated factor 6 (TRAF6) deficient T cells exhibited enhanced Th17 cell differentiation, however, the physiological relevance of TRAF6 in T cells remains unknown. Here, we induced experimental autoimmune encephalomyelitis (EAE) in T cell-specific TRAF6 deficient (TRAF6ΔT) mice to investigate the role of TRAF6 in T cells during the course of MS using an EAE model. Although Th17 cell differentiation was enhanced in TRAF6ΔT mice, mutant mice were resistant to EAE. In contrast, TRAF6 loss did not affect regulatory T-cell differentiation. Consistent with the severity of EAE, a small number of infiltrating T cells and a small area of demyelination were observed in the CNS of TRAF6ΔT mice. Moreover, myelin oligodendrocyte glycoprotein-induced IL-17 production in TRAF6-deficient T cells was significantly suppressed. We further confirmed lower levels of CD69 and granulocyte-macrophage colony-stimulating factor in Th17 cells of TRAF6ΔT mice than in wild-type mice. In contrast, the expression of IL-10 and cytotoxic T-lymphocyte-associated protein 4 in T cells was significantly elevated in the absence of TRAF6 because of enhanced T-cell receptor signaling. Collectively, TRAF6 signaling in T cells contributes to the pathogenesis of EAE by regulating the pathogenicity and autoantigen reactivity of Th17 cells.
GRB 201015A: from seconds to months of optical monitoring and supernova discovery
Authors: Belkin S , Pozanenko A S , Minaev P Y , Pankov N S , Volnova A A , Rossi A , Stratta G , Benetti S , Palazzi E , Moskvitin A S , Burhonov O , Rumyantsev V V , Klunko E V , Inasaridze R Ya , Reva I V , Kim V , Jelinek M , Kann D A , Volvach A E , Volvach L N , Xu D , Zhu Z , Fu S , Mkrtchyan A A
Published: December 2023

We present full photometric coverage and spectroscopic data for soft gamma-ray burst GRB 201015A with a redshift z = 0.426. Our data span a time range of 85 d following the detection of GRB. These observations revealed an underlying supernova SN 201015A with a maximum at 8.54 ± 1.48 d (rest frame) and an optical peak absolute magnitude $-19.45_{-0.47}^{+0.85}$ mag. The SN stands out clearly, since the contribution of the afterglow at this time is not dominant, which made it possible to determine SN’s parameters. A comparison of these parameters reveals that the SN 201015A is the earliest (the minimum Tmax) known SN associated with GRBs. Spectroscopic observations during the SN decay stage showed broad lines, indicating a large photospheric velocity, and identified this SN as a Type Ic-BL. Thus, the SN 201015A associated with the GRB 201015A becomes the 27th SN/GRB confirmed by both photometric and spectroscopic observations. Using the results of spectral analysis based on the available data of Fermi-GBM experiment, the parameters Ep,i = 20.0 ± 8.5 keV and Eiso = (1.1 ± 0.2) × 1050 erg were obtained. According to the position of the burst on the Ep,i–Eiso correlation, GRB 201015A was classified as a type II (long) GRB, which was also confirmed by the T90,i–EH diagram.
Long-term and Landmark Analysis of Transcatheter versus Surgical Aortic-Valve Replacement in Severe Aortic Stenosis
Authors: Zhang Xiaowen , Kang Lina , Wang Lian , Wang Kun , Xu Wei , Xu Biao , Zhang Xinlin
Published: December 2023

Background

Previous reports of long-term outcomes of TAVR focus on higher risk patients and suggest potential temporal changes. The indications of TAVR have expanded to low-risk patients. We aimed to evaluate the long-term and temporal performances of transcatheter aortic valve replacement (TAVR) compared to surgical aortic valve replacement (SAVR).

Methods

Randomized controlled trials reporting outcomes with at least 1-year follow-up were included. The primary outcome was the composite of all-cause death or disabling stroke.

Results

We included 8 trials with 8,749 patients. TAVR was associated with a higher risk of long-term (5-year) primary outcome compared to SAVR among higher-risk (odds ratio [OR], 1.25; 95% CI, 1.07–1.47) but not lower-risk participants (1.0 [0.77–1.29]). However, a significant temporal interaction was detected in both risk profiles. TAVR with balloon-expandable valves was associated with a higher risk of long-term primary outcome compared to SAVR (1.38 [1.2–1.6]), whereas no statistical difference was found with self-expanding valves (1.03 [0.89–1.19]). There was a significant interaction between the two valve systems, and a temporal interaction was detected in both systems. Overall landmark analysis revealed a lower risk in TAVR within the initial 30 days (0.76 [0.6, 0.96]), comparable between 30 days to 2 years (1.04 [0.85, 1.28]), and higher beyond 2 years (1.36 [1.15– 1.61]). Analysis for all-cause death generated largely similar results.

Conclusions

TAVR was associated with a higher long-term risk of primary outcome compared to SAVR in higher-risk patients and with balloon-expandable valves. However, a characteristic temporal interaction was documented in all subgroups. Future studies are warranted to test these findings.
Learning the fitness dynamics of pathogens from phylogenies
Authors: Lefrancq Noémie , Duret Loréna , Bouchez Valérie , Brisse Sylvain , Parkhill Julian , Salje Henrik
Published: December 2023

The dynamics of pathogen genetic diversity, including the emergence of lineages with increased fitness, is a foundational concept of disease ecology with key public health implications. However, the identification of distinct lineages and estimation of associated fitness remain challenging, and are rarely done outside densely sampled systems. Here, we present a scalable framework that summarizes changes in population composition in phylogenies, allowing for the automatic detection of lineages based on shared fitness and evolutionary relationships. We apply our approach to a broad set of viruses and bacteria (SARS-CoV-2, H3N2 influenza,Bordetella pertussisandMycobacterium tuberculosis)and identify previously undiscovered lineages, as well as specific amino acid changes linked to fitness changes, the findings of which are robust to uneven and limited observation. This widely-applicable framework provides an avenue to monitor evolution in real-time to support public health action and explore fundamental drivers of pathogen fitness.

One sentence summary

Using an agnostic framework we shed light on changes in population composition in phylogenetic trees, allowing for the automatic detection of circulating lineages and estimation of fitness dynamics.
Dengue Virus Serotype 2 Cosmopolitan C Genotype Reemerges with a New Subclade in Southwest Region of Bangladesh
Authors: Setu Md. Ali Ahasan , Das Prosanto Kumar , Ahammed Toukir , Saha Shuvo , Hasan Adib , Kumar P K Shishir , Das Samiran , Ahamed Tanvir , Hossain KM Amran , Al-Emran Hassan M. , Hossain M. Anwar , Jahid Iqbal Kabir
Published: December 2023

In 2023, the Dengue virus (DENV) outbreak infected over 0.3 million cases and 1500 deaths in Bangladesh. Although the the serotype and genotype data were unavailable. Our study conducted serotyping and genomic surveillance in four districts of Southwest Bangladesh between September and October 2023. The surveillance data from 2019 to 2023 extracted from the Directorate General of Health Services in Bangladesh indicated a significant increase of Dengue infections in 2023, particularly during September-November. The two-layered hypothesis examination confirmed that, despite endemic months, 2023 dengue outbreak had a higher morbidity rate compared to previous years (2019-2022) in Southwest of Bangladesh. Serotyping and E gene sequence analysis of 25 randomly selected positive samples reveals that DENV-2 was the sole serotype circulating in this region during the study period. Genomic analysis exposed a new subclade of DENV-2, classified under Cosmopolitan genotype within C clade, distinct from previous years Bangladeshi variants until 2022. This subclade, possibly migrating from India, might be emerged during COVID-19 pandemic years and exhibited higher morbidity rates, thus challenging our existing mitigation strategies. This investigation provides valuable insights for public health interventions and underscores the importance of continuous genomic surveillance in managing Dengue outbreaks.
Single-cell transcriptomics reveals cellular hierarchies and aberrant CTS contraction-mediated premature hair regression in androgenetic alopecia
Authors: Li Guo , Yang Li , Duan Shixin , Chen Mengting , Zhang Yujin , Liu Fangfen , Tang Yan , Wang Yunying , Li Jiayun , Xu San , Wu Zheng , Wang Ben , Zhao Zhixiang , Shi Wei , Xie Hongfu , Deng Zhili , Li Ji
Published: December 2023

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.
Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network
Authors: Chen Yibo , Chien Jonathan , Dai Bing , Lin Dayu , Chen Zhe Sage
Published: December 2023

Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.
High spatiotemporal resolution radial encoding single vessel fMRI
Authors: Jiang Yuanyuan , Pais-Roldán Patricia , Pohmann Rolf , Yu Xin
Published: December 2023

High-field preclinical functional MRI (fMRI) has enabled the high spatial resolution mapping of vessel-specific hemodynamic responses, i.e. single-vessel fMRI. In contrast to investigating neuronal sources of the fMRI signal, single vessel fMRI focuses on elucidating its vascular origin, which can be readily implemented to identify vascular changes relevant to vascular dementia or cognitive impairment. However, the limited spatial and temporal resolution of fMRI has hindered hemodynamic mapping of intracortical microvessels. Here, we implemented the radial encoding MRI scheme to measure BOLD signals of individual vessels penetrating the rat somatosensory cortex. Radial encoding MRI is employed to map cortical activation with a focal field of view (FOV), allowing vessel-specific functional mapping with 50×50 µm in-plane resolution at 1 to 2 Hz sampling rate. Besides detecting refined hemodynamic responses of intracortical micro-venules, the radial encoding-based single-vessel fMRI enables the differentiation of the intravascular and extravascular effects from the draining venules.
Vision rescue via chemically engineered endogenous retinal ganglion cells
Authors: Shoaib Rana Muhammad , Sandrosyan Aregnazan , Mahato Biraj
Published: December 2023

Loss of retinal ganglion cells (RGCs) is the final common end point for many optic neuropathies, ultimately leading to irreversible vision loss. Endogenous RGC regeneration from Müller cells presents a promising approach to treat these diseases, but mammalian retinas lack regenerative capacity. Here, we report a small molecule cocktail that causes endogenous Müller cell proliferation, migration, and specification to newly generated chemically induced RGCs (CiRGCs) in NMDA injured mice retina. Notably, regenerated CiRGCs extend axons towards optic nerve, and rescue vision post-NMDA treatment. Moreover, we successfully reprogrammed human primary Müller glia and fibroblasts into CiRGCs using this chemical-only approach, as evidenced by RGC-specific gene expression and chromatin signature. Additionally, we show that interaction between SOX4 and NF-kB determine CiRGC fate from Müller cells. We anticipate endogenous CiRGCs would have therapeutic potential in rescuing vision for optic nerve diseases.
TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43
Authors: Godoy-Corchuelo Juan M. , Ali Zeinab , Brito Armas Jose M. , Martins-Bach Aurea B. , García-Toledo Irene , Fernández-Beltrán Luis C. , López-Carbonero Juan I. , Bascuñana Pablo , Spring Shoshana , Jimenez-Coca Irene , Muñoz de Bustillo Alfaro Ramón A. , Sánchez-Barrena Maria J. , Nair Remya R. , Nieman Brian J. , Lerch Jason P. , Miller Karla L. , Ozdinler Hande P , Fisher Elizabeth M.C. , Cunningham Thomas J. , Acevedo-Arozena Abraham , Corrochano Silvia
Published: December 2023

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as “TDP-43 proteinopathies”. Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenousTardbpgene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find thatTardbpM323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an idealin vivomodel system to study the complex biology of TDP-43.
The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain
Authors: Fitzsimons Lindsey A. , Staurengo-Ferrari Larissa , Bogen Oliver , Araldi Dioneia , Bonet Ivan J. M. , Jordan Ethan E. , Levine Jon D. , Tucker Kerry L.
Published: December 2023

The primary cilium, a 1-3 μm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targetingIft88, a primary cilium-specific intra-flagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss ofIft88mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E2, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein,Ift52.Ift52 siRNA results in loss ofIft52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia byIft88knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.
Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction
Authors: Choe Mangyu , Titov Denis V.
Published: December 2023

Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the Integrated Stress Response induced by ATP synthase inhibition in mammalian cells.
Is there a neural common factor for visual illusions?
Authors: Jastrzębowska Maya A. , Ozkirli Ayberk , Cretenoud Aline F. , Draganski Bogdan , Herzog Michael H.
Published: December 2023

It is tempting to map interindividual variability in human perception to variability in brain structure or neural activity. Indeed, it has been shown that susceptibility to size illusions correlates with the size of primary visual cortex V1. Yet contrary to common belief, illusions correlate only weakly at the perceptual level, raising the question of how they can correlate with a localized neural measure. In addition, mounting evidence suggests that there is substantial interindividual variability not only in neural function and anatomy but also in the mapping between the two, which further challenges the findings of a neural common factor for illusions. To better understand these questions, here, we re-evaluated previous studies by correlating illusion strengths in a battery of 13 illusions with the size of visual areas and population receptive field sizes. We did not find significant correlations either at the perceptual level or between illusion susceptibility and visual functional neuroanatomy.
Numerical Simulation of Transdermal Delivery of Drug Nanocarriers Using Solid Microneedles
Authors: Newell Ben , Zhan Wenbo
Published: December 2023

Solid microneedles can successfully puncture the stratum corneum and thus enable the drugs to migrate from the adhesive patch to the viable skin tissues for therapy. The treatment in different skin layers can vary greatly. However, how to improve its effectiveness remains less understood. In this study, numerical simulation is employed to predict the transport and disposition of drugs in each skin layer and blood using a skin model rebuilt from the real skin anatomical structure. The therapeutic effect is assessed by exposure to drugs over time. Results reveal the dominance of diffusion in determining the transport of nanosized drug carriers and free drugs in viable skin tissues. Delivery outcomes are highly sensitive to drug delivery system properties. Increasing the nanocarrier partition coefficient or diffusion coefficient in the skin can successfully enhance the treatment in entire skin tissue and blood. The enhancement can also be obtained by reducing the microneedle spacing or patch thickness. However, several properties should be optimised individually with respect to the target site’s location, including the microneedle length, diffusion coefficient of nanocarriers in the skin, drug release rate and nanocarrier vascular permeability. Drug concentrations in the blood can be effectively increased when administered to skin areas rich in capillaries; whereas, the treatment in the skin tissues slightly would reduce simultaneously. Furthermore, delivery results are insensitive to changes in lymphatic function and the properties of free drugs introduced by the medicated patch. These findings can be used to improve transdermal drug delivery for better treatment.
Sex change every year: A unique reproductive strategy of the stony coral,Fimbriaphyllia(Euphyllia)ancora
Authors: Shikina Shinya , Tsai Pin-Hsuan , Chiu Yi-Ling , Chang Ching-Fong
Published: December 2023

The present study documents a unique reproductive strategy of the colonial stony coral,Fimbriaphyllia ancora,during observations spanning 8 years. Of 26 colonies monitored at Nanwan Bay, southern Taiwan, about 70% changed their sexes every year, i.e., colonies that were males two years ago became females last year, and changed back to males this year. Apparently, the remaining 30% were permanently male or female. Sex-change and non-sex-change colonies were growing in close proximity or even side-by-side, suggesting that this sex change phenomenon is not driven by environmental factors. No significant differences were found in colony size between sex-change and non-sex-change colonies, suggesting that the sex change strategy may be related to intrinsic factors, e.g., age or genetics. Histological analysis showed that female-to-male sex change occurs 4-5 months after spawning, whereas male-to-female sex change occurs 0-3 months after sperm release. We propose that this unique strategy may increase success of sexual reproduction of sessile, colonial corals.
Computationally guided insights into substrate recognition and specificity of Alg1
Authors: Yu Cheng , Long Fangyuan , Li Ruijie , Ding Yi
Published: December 2023

The assembly of N-linked glycans for the N-glycosylation, which is an important protein modification process, starts with the consecutive synthesis of the dolichol-linked oligosaccharide (DLO) precursor in the endoplasmic reticulum (ER). Asparagine-linked glycosylation protein 1 (Alg1) is the first mannosyltransferase (MTase) in DLO synthesis, which transfers a mannose residue from the sugar donor GDP-mannose (GDP-Man) to the substrate dolichol pyrophosphate-GlcNAc2 (Dol-PP-GlcNAc2) to form a β-1,4 glycosidic bond. However, little is known about its process of substrate recognition and the mechanism for its substrate specificity. Here, the models of large-scale systems in solution and membrane environments were built, revealing the substrate recognition and specificity mechanism of Alg1 based on extensive all-atom microsecond molecular dynamics (MD) simulations. In this study, the unique non-natural donor recognition ofScAlg1 and its mechanisms was reported. Further, the cooperation of the hydrophobic region and lysine in substrate recognition was revealed for bothScAlg1 andHsAlg1. Moreover, the functional roles of these sites were confirmed via mutant activity assays invitro. Additionally, the substrate binding process of Alg1 was simulated, elucidating the effect of dolichol on substrate specificity. This work reports the substrate recognition of Alg1 and reveals mechanisms for its sugar donor and substrate selectivity, which could further aid in mechanistic studies of the DLO biosynthetic process and drug development targeting Alg1.
Constitutive and conditional epitope-tagging of endogenous G protein coupled receptors inDrosophila
Authors: Bonanno Shivan L. , Sanfilippo Piero , Eamani Aditya , Sampson Maureen M. , Binu Kandagedon , Li Kenneth , Burns Giselle D. , Makar Marylyn E. , Zipursky S. Lawrence , Krantz David E.
Published: December 2023

To visualize the cellular and subcellular localization of neuromodulatory G-protein coupled receptors (GPCRs) inDrosophila, we implement a molecular strategy recently used to add epitope tags to ionotropic receptors at their endogenous loci. Leveraging evolutionary conservation to identify sites more likely to permit insertion of a tag, we generated constitutive and conditional tagged alleles forDrosophila5-HT1A, 5-HT2A, 5-HT2B, Octβ1R, Octβ2R, two isoforms of OAMB, and mGluR. The conditional alleles allow for the restricted expression of tagged receptor in specific cell types, an option not available for any previous reagents to label these proteins. We show that 5-HT1A and 5-HT2B localize to the mushroom bodies and central complex respectively, as predicted by their roles in sleep. By contrast, the unexpected enrichment of Octβ1R in the central complex and of 5-HT1A and 5-HT2A to nerve terminals in lobular columnar cells in the visual system suggest new hypotheses about their function at these sites. Using an additional tagged allele of the serotonin transporter, a marker of serotonergic tracts, we demonstrate diverse spatial relationships between postsynaptic 5-HT receptors and presynaptic 5-HT neurons, consistent with the importance of both synaptic and volume transmission. Finally, we use the conditional allele of 5-HT1A to show that it localizes to distinct sites within the mushroom bodies as both a postsynaptic receptor in Kenyon cells and a presynaptic autoreceptor.

Significance Statement

InDrosophila, despite remarkable advances in both connectomic and genomic studies, antibodies to many aminergic GPCRs are not available. We have overcome this obstacle using evolutionary conservation to identify loci in GPCRs amenable to epitope-tagging, and CRISPR/Cas9 genome editing to generated eight novel lines. This method also may be applied to other GPCRs and allows cell-specific expression of the tagged locus. We have used the tagged alleles we generated to address several questions that remain poorly understood. These include the relationship between pre- and post-synaptic sites that express the same receptor, and the use of relatively distant targets by pre-synaptic release sites that may employ volume transmission as well as standard synaptic signaling.
Homeostatic Dysregulation of Systemic CD8+T Cell Compartment in Lung Cancer Patients
Authors: Lee Sung-Woo , Yun Ju Sik , Kim Young Ju , Kim Hee-Ok , Cho Hyun-Ju , Park Cheol-Kyu , Oh In-Jae , Cho Jae-Ho
Published: December 2023

Cancer adapts various resistance mechanisms to counteract CD8+T cell attacks. While this suppression of antigen-specific CD8+T cells is common within the tumor microenvironment, little is known about how tumors affect CD8+T cells systemically. Here we show a new link between tumor-associated homeostatic dysregulation and uncontrolled differentiation of peripheral blood CD8+T cells. These CD8+T cells exhibited progressive alterations indicative of diminished quiescence, increased spontaneous activation, and more-differentiated proliferation-incompetent effector cells. This phenomenon was not limited to tumor-reactive cells but broadly applicable to non-specific cells, correlating with poor clinical responses to immune checkpoint inhibitor therapy. These findings provide a new mechanism by which cancer impairs CD8+T cells by dysregulating the homeostasis of systemic CD8+T cell populations.

One-Sentence Summary

Cancer-associated homeostatic dysregulation accelerates uncontrolled differentiation of systemic CD8+T cells.
Pharmacological modulation of dopamine receptors reveals distinct brain-wide networks associated with learning and motivation in non-human primates
Authors: Fujimoto Atsushi , Elorette Catherine , Fujimoto Satoka H. , Fleysher Lazar , Rudebeck Peter H. , Russ Brian E.
Published: December 2023

The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How modulation of these receptors influences learning and motivation by altering intrinsic brain-wide networks remains unclear. Here we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) slowed probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in cortico-cortical and fronto-striatal connections. By contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparisons between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA manipulation, respectively. Thus, we reveal distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors.

Significance Statement

D1 and D2 receptors are heavily implicated in cognitive and motivational processes, as well as in a number of psychiatric disorders. Despite this, little is known about how selective manipulation of these different receptors impacts cognition through changing activity across brain-wide intrinsic networks. Here, we examined the acute behavioral and brain-wide effects of D1 and D2 receptor-selective antagonists, SCH-23390 and haloperidol, in macaques performing a probabilistic learning task. SCH administration diminished, and haloperidol improved, animals’ task performance. Mirroring these effects on behavior, SCH reduced, and haloperidol increased, the resting-state functional connectivity across brain-wide networks, most notably in the cortico-striatal areas. Thus, our results highlight the opposing effects of D1 and D2 receptor modulation on the brain and behavior.
Sorted stem/progenitor epithelial cells of pubertal bovine mammary gland present limited potential to reconstitute an organised mammary epithelium after transplantation
Authors: Finot Laurence , Hue-Beauvais Cathy , Aujean Etienne , Provost Fabienne Le , Chanat Eric
Published: December 2023

The development and maintenance of mammary gland tissue depend on the proliferation and differentiation of mammary stem and progenitor cells. Here, we investigated populations of mammary epithelial cells that are potential candidates for bovine mammary gland development using xenotransplantation into mice cleared mammary fat pad. Transplanted mammary explants from 17-month-old Holstein heifers developed outgrowths exhibiting the archetypal morphology and molecular marker distributions of the bovine gland. Xenotransplantation of sorted mammary epithelial cells (CD49fpos) into bovinised fat pads using inactivated bovine fibroblasts resulted in outgrowth developments with 50% take rate, but these lacked the ductal or alveolar epithelial structures of the normal mammary gland. Similar results were obtained with xenografts of candidate bovine mammary epithelial stem cells (CD49fhighCD24pos) or epithelial cells of the basal lineage (CD49fhighCD24neg) which also developed as clumps of cells surrounded by stromal stretches within the mouse adipose tissue. These results provide further evidence for the existence of cells with self-renewing capacities in the bovine mammary gland. Sorted cells, however, showed compromised regenerative potential for epithelial morphogenesis. Further work is therefore needed to identify mammary stem/progenitor cells with full regenerative capabilities for biogenesis of normal mammary gland structure, with milk-secreting function.
Heterogeneous potential of human airway basal cells: Holoclone-stem cell identification in a clinical-grade system
Authors: Davide Adamo , Giuseppe Genna Vincenzo , Giulia Galaverni , Chiara Chiavelli , Alessia Merra , Fabio Lepore , Federica Boraldi , Daniela Quaglino , Jessica Evangelista , Filippo Lococo , Graziella Pellegrini
Published: December 2023

The clinical results of tissue engineering approaches aimed at treating extensive tracheal or bronchial defects highlighted some impactful limitations, among which stand out the inability to regenerate a functional and self-renewing airway epithelium onto the bioengineered graft. This outcome is often caused by culture conditions unable to sustain the long-term proliferative and differentiative potential of primary airway epithelial cells, resulting in progressive stem cell exhaustion. Here, we examined the capacity of a clinical-grade culture system to safely and efficiently support thein vitroexpansion of primary human tracheal and bronchial epithelial cells, regenerating a functional and fully differentiated airway epithelium. Moreover, we identified and characterized airway epithelial stem cells, unravelling the mechanisms that underlie tracheobronchial epithelium renewal. Finally, we suggested possible parameters to be employed as quality controls during critical stages of the tissue engineering process, thereby maximizing the likelihood of success of the treatment and prioritizing patients’ safety, crucial prerequisites before embarking on other clinical applications.

GRAPHICAL ABSTRACT
Liquid-liquid Phase Separation of Alpha-synuclein Increases the Structural Variability of Fibrils Formed during Amyloid Aggregation
Authors: Ziaunys Mantas , Sulskis Darius , Veiveris Dominykas , Kopustas Aurimas , Snieckute Ruta , Mikalauskaite Kamile , Sakalauskas Andrius , Tutkus Marijonas , Smirnovas Vytautas
Published: December 2023

Protein liquid-liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process of amyloid fibril formation, serving as an intermediate step between the native protein transition into their aggregated state. The formation of fibrils via LLPS has been demonstrated for a number of proteins related to neurodegenerative disorders, as well as other amyloidoses. Despite the surge in amyloid-related LLPS studies, the influence of protein condensate formation on the end-point fibril characteristics is still far from fully understood. In this work, we compare alpha-synuclein aggregation under conditions, which promote or negate its LLPS and examine the differences between the formed aggregates. We show that alpha-synuclein phase separation generates a wide variety of assemblies with distinct secondary structures and morphologies. The LLPS-induced structures also possess higher levels of toxicity to cells, indicating that biomolecular condensate formation may be a critical step in the appearance of disease-related fibril variants.
Cultural variations in conceptualization of excessive drinking among young adults in Denmark, Estonia and Italy
Authors: Rolando Sara , Cuomo Gaia , Allaste Airi-Alina , Fabricius Venus Athena Vangsgaard , Kolind Torsten , Läänemets Merlin
Published: December 2023

Purpose

This paper aims to investigate the cultural meanings of excessive drinking in three different countries with different levels of alcohol use chosen as case studies of wider geographies representing Northern (Denmark), Southern (Italy) and Eastern (Estonia) Europe.

Design/methodology/approach

Data were collected according to the Reception Analytical Group Interview method, using video clips as stimuli to enhance comparability. Eight online focus groups were organized in each country for a total number of 128 participants. Symbolic boundaries defining what drinking patterns are socially acceptable were then analysed to look at cross-national variations.

Findings

Results show how different conceptualizations of excessive drinking persist, although a convergence process among drinking patterns is also observed, which suggests that differences mainly depend on meanings and values attributed to intoxication. These are both rooted in the traditional drinking cultures and affected by ongoing social and economic change processes.

Research limitations/implications

Because of the chosen research approach, the research results may lack generalizability, even at country level, as there are differences also within the same drinking culture; however, addressing these differences was beyond the scope of the present study, which aimed to contribute to understanding persisting differences in European drinking culture despite different drivers seem to act for globalization of drinking habits.

Practical implications

The paper includes implications for the development of tailored and effective prevention messages, considering rooted attitudes and cultural values attached to drinking and drunkenness in different European geographies, which are also related to conceptualizations of risks and pleasure.

Originality/value

This paper fulfils an identified need to understand persisting differences in alcohol-related behaviours and outcome in different European countries emerging from quantitative data.
Employee psychological ownership and work attitudes
Authors: Rapti Andriana , Rayton Bruce A. , Yalabik Zeynep Yesim
Published: December 2023

Purpose

This study aims to explain the link between employee psychological ownership (EPO) and work engagement (WE). The authors conceptualize EPO as a combination of various personal resources, i.e. self-efficacy, self-identity, accountability, belongingness and territoriality, and expected it to positively contribute to WE.

Design/methodology/approach

The authors analyze survey data from employees of a public service organization in Greece and verify key findings using a two-wave cross-sectional survey design targeting a heterogeneous population of employees in the United States of America.

Findings

The findings indicate that EPO is positively related to WE and job satisfaction mediates the relationship between EPO and WE. Furthermore, the authors' results support the discriminant validity between promotive EPO, preventative EPO (territoriality), WE and job satisfaction.

Originality/value

The present study provides a deeper understanding of EPO, as it is explained in the theoretical foundations of the job demands-resources model (JD-R) model and helps us understand how EPO can affect WE.
How can facilities management benefit from offices becoming more user-centred?
Authors: Einola Kiia Aurora , Remes Laura , Dooley Kenneth
Published: December 2023

Purpose

This study aims to explore an emerging collection of smart building technologies, known as smart workplace solutions (SWS), in the context of facilities management (FM).

Design/methodology/approach

This study is based on semi-structured interviews with facility managers in Finland, Norway and Sweden who have deployed SWSs in their organizations. SWS features, based on empirical data from a previous study, were also used to further analyse the interviews.

Findings

It analyses the benefits that SWSs bring from the facility management point of view. It is clear that the impetus for change and for deploying SWS in the context of FM is primarily driven by cost savings related to reductions in office space.

Research limitations/implications

This research has been conducted with a focus on office buildings only. However, other building types can learn from the benefits that facility managers receive in the area of user-centred smart buildings.

Practical implications

SWSs are often seen as employee experience solutions that are only related to “soft” elements such as collaboration, innovation and learning. Understanding the FM business case can help make a more practical case for their deployment.

Originality/value

SWSs are an emerging area, and this study has collected data from facility managers who use them daily.
Inside out. Social media videos and destination branding. Neuromarketing using EEG technique
Authors: Shahzad Muhammad Faisal , Yuan Jingbo , Arif Farrah , Waheed Abdul
Published: December 2023

Purpose

This study aims to investigate the effectiveness of two types of social media videos used for destination image development: induced/commercial-oriented content and organic content (where content is made without commercial interest, such as vlogs classified as user-generated content).

Design/methodology/approach

Experimental research using “Emotive EEG” (electroencephalogram) in a controlled environment was conducted with 30 participants (20 males, 10 females), age range 18 to 26. Emotive EEG recording was performed while the participants watched both types of video clips. Test results for both groups indicate that induced content is preferred over organic content.

Findings

This study opens up future research avenues where neuromarketing’s “Marketer Friendly” EEG equipment can be applied to the customer selection process.

Originality/value

Marketing analysts can gauge the interest and response of customers on different types of social media video content for destination marketing based on the findings of this study.
ANTi-microhistory of social innovation: humanistic education at Robert Owen’s New Harmony experiment
Authors: Roberts Foster B. , Novicevic Milorad M. , Humphreys John H.
Published: December 2023

Purpose

The purpose of this study is to present ANTi-microhistory of social innovation in education within Robert Owen’s communal experiment at New Harmony, Indiana. The authors zoom out in the historical context of social innovation before zooming into the New Harmony case.

Design/methodology/approach

The authors used ANTi-microhistory approach to unpack the controversy around social innovation using the five-step procedure recently proposed by Mills et al. (2022), a version of the five-step procedure originally proposed by Tureta et al. (2021).

Findings

The authors found that the educational leaders of the New Harmony community preceded proponents of innovation, such as Drucker (1957) and Fairweather (1967), who viewed education as a form of social innovation.

Originality/value

The authors contribute to the history of social innovation in education by exploring the New Harmony community’s education society to uncover the enactment of sustainable social innovation and the origin story of humanistic management education.
Analysis and mapping of research on barriers to mental health service utilization in minority and underserved groups (1993-2022)
Authors: Sweileh Waleed
Published: December 2023

Purpose

This paper aims to investigate research activity on barriers for minority and underserved groups to access and use mental health services.

Design/methodology/approach

Using Scopus, relevant articles published from 1993 to 2022 were collected. The final list included 122 articles.

Findings

Research hotspots included cultural and ethnic barriers, obstacles encountered by LGBTQ+ individuals, challenges faced by refugees and immigrants, limited access in rural areas and barriers affecting special populations. The top 10 cited articles focused on language barriers, cultural stigma, gender-specific challenges and systemic obstacles. New research avenues included the role of technology in overcoming barriers to access mental health services.

Practical implications

Policymakers and practitioners can use this knowledge to develop targeted interventions, enhance cultural competence, reduce stigma, improve rural access and provide LGBTQ+-affirming care, ultimately promoting equitable mental health care.

Social implications

This research underscores the importance of addressing mental health service barriers for equity and social justice. Neglecting these disparities can worsen mental health, increase health-care costs, reduce productivity and lead to higher social welfare expenses, perpetuating disadvantages.

Originality/value

This paper's uniqueness lies in its comprehensive analysis of barriers and facilitators to mental health service utilization among minority and underserved groups. It serves as a basis for developing evidence-based strategies to improve service accessibility and enhance the well-being of marginalized communities.
Insights into proteolysis, textural evolution, microstructural changes and sensory attributes of white brined cheese from frozen‐stored caprine milk
Authors: Kljajevic Nemanja V. , Miloradovic Zorana N. , Miocinovic Jelena B. , Pavlovic Vladimir B. , Tomic Nikola S. , Jovanovic Snezana T.
Published: December 2023

Long‐term frozen storage of caprine milk is an important way of overcoming seasonal production. White brined cheese, matured for 56 days, was made from frozen‐stored caprine milk. Several properties of experimental and control cheese variants were investigated throughout the maturation period: physico‐chemical, sensory, proteolytic (by urea‐PAGE electrophoresis), texture attributes, microstructure (by scanning electron microscopy). Most of investigated properties were influenced by frozen storage and maturation period, but differences were less pronounced on the 56th day of maturation. Moreover, sensory analysis showed that both cheese variants were well accepted by consumers.
Editorial: Gastroenterologists should definitely draw closer attention to psychosocial comorbidities
Authors: Pittet Valerie , Restellini Sophie
Published: December 2023

LINKED CONTENT

This article is linked to Riggott et al paper. To view this article, visit https://doi.org/10.1111/apt.17735
Letter: Are we forgetting the importance of steatosis in steatotic liver disease? Authors' reply
Authors: Kuo Selena Z. , Loomba Rohit
Published: December 2023

LINKED CONTENT

This article is linked to Kuo et al papers. To view these articles, visit https://doi.org/10.1111/apt.17637 and https://doi.org/10.1111/apt.17759