bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Higher-Dose Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial
Authors:   The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators, Naggie Susanna
Published: September 2023

Background

The impact of fluvoxamine in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) remains uncertain. Our objective was to assess the effectiveness of fluvoxamine 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19.

Methods

The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days. Participants were randomized to receive fluvoxamine 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days or to placebo. The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell.

Results

Among participants who were randomized and received study drug, the median age was 50 years (IQR 40-60), 66% were female, 45% identified as Hispanic/Latino, and 77% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09; P(efficacy) = 0.4]). Additionally, unadjusted, median time to sustained recovery was 10 days (95% CI 10-11) in both the intervention and placebo group. No deaths were reported. Thirty-five participants reported healthcare utilization events (a prioridefined as death, hospitalization, emergency department/urgent care visit); 14 in the fluvoxamine group compared with 21 in the placebo group (HR 0.69; 95% CrI 0.27–1.21; P(efficacy)=0.86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo).

Conclusions

Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms.

Trial Registration

ClinicalTrials.gov(NCT04885530).
Tissue-scale dynamic mapping of Hematopoietic Stem Cells and supportive niche cells in the fetal liver
Authors: Helbling Patrick M. , Vijaykumar Anjali , Gomariz Alvaro , Zerkatje Thomas , Zielińska Karolina A. , Loosli Kathrin , Isringhausen Stephan , Nagasawa Takashi , Roeder Ingo , Manz Markus G. , Yokomizo Tomomasa , Nombela-Arrieta César
Published: September 2023

The fetal liver (FL) plays a fundamental role in the ontogeny of the hematopoietic system, by transiently providing a fertile microenvironment for the maturation, proliferation and expansion of fetal hematopoietic progenitors, as well as definitive hematopoietic stem cells (HSCs). Nonetheless, the cellular make up and identity of HSC niches in the FL remain poorly described. Here we employed a combination of 3D quantitative microscopy, bulk mRNA-seq, flow cytometry and cell-specific reporter models, to dissect the spatiotemporal dynamics of putative niche cells and HSCs in the FL microenvironment. We find that at peak stages of FL hematopoiesis, pro-hematopoietic cytokines are promiscuously expressed by endothelial, mesenchymal cells and most prominently by hepatoblasts. These multicellular consortia of parenchymal/stromal cells are spatially predominant in the FL, thus providing unrestricted access to supportive factors throughout the entire tissue. Accordingly, in these early phases HSCs are found scattered across the parenchyma not displaying obvious spatial biases within the broad microanatomy of the FL, but exhibiting clustering behaviors. This highly conducive microenvironment is transient and gets rapidly remodeled through hepatoblast differentiation and sterile inflammatory signaling, leading to the downregulation of hematopoietic factors and the contraction of supportive niches, which temporarily coincide with the exit of HSCs towards emergent BM tissues.
Growth factor-induced desialylation for the fast control of endocytosis
Authors: MacDonald Ewan , Forrester Alison , Valades-Cruz Cesar A. , Madsen Thomas D. , Hetmanski Joseph H. R. , Dransart Estelle , Ng Yeap , Godbole Rashmi , Shp Ananthan Akhil , Leconte Ludovic , Chambon Valérie , Ghosh Debarpan , Pinet Alexis , Bhatia Dhiraj , Lombard Bérangère , Loew Damarys , Larson Martin R. , Leffler Hakon , Lefeber Dirk J. , Clausen Henrik , Caswell Patrick , Shafaq-Zadah Massiullah , Mayor Satyajit , Weigert Roberto , Wunder Christian , Johannes Ludger
Published: September 2023

It is commonly assumed that the glycan makeup of glycoproteins that reach the cell surface is final and static. Here, we challenge this notion by the discovery of a molecular switch that induces acute and reversible changes of glycans on the plasma membrane. We demonstrate that within minutes, the epidermal growth factor triggers the galectin-driven endocytosis of cell surface glycoproteins, such as integrins, that are key regulators of cell adhesion and migration. The onset of this process, mediated by the Na+/H+antiporter NHE-1 and the neuraminidases Neu1/3, requires the pH-triggered enzymatic removal of sialic acids whose presence otherwise prevents galectin binding. Desialylated glycoproteins are then retrogradely transported to the Golgi apparatus where their glycan makeup is reset, and their function is repurposed to regulate EGF-dependent invasive cell migration. Glycosylation at the cell surface thereby emerges as a dynamic and reversible regulatory post-translational modification that controls a highly adaptable trafficking pathway.
Serial attentional resource allocation during parallel feature value tracking
Authors: Merkel Christian , Burgmann Luise , Bartsch Mandy V. , Schoenfeld Mircea A. , Hopf Jens-Max
Published: September 2023

The visual system has evolved the ability to track features like color and orientation in parallel. This property aligns with the specialization of processing these feature dimensions in the visual cortex. But what if we ask to track changing feature-values within the same feature dimension? Parallel tracking would then have to share the same cortical representation, which would set strong limitations on tracking performance. We address this question by measuring the precision of color representations when human observers track the color of two superimposed dot clouds that simultaneously change color along independent trajectories in color-space. We find (1) that tracking precision is highly imbalanced between streams. (2) Tracking precision changes over time by alternating between streams at a rate of ∼1Hz. These observations suggest that, while parallel color tracking is possible, it is highly limited, essentially allowing for only one color-stream to be tracked with precision at a given time.
Fast updating feedback from piriform cortex to the olfactory bulb relays multimodal reward contingency signals during rule-reversal
Authors: Trejo Diego Hernandez , Ciuparu Andrei , da Silva Pedro Garcia , Velasquez Cristina M. , Rebouillat Benjamin , Gross Michael D. , Davis Martin B. , Muresan Raul C. , Albeanu Dinu F.
Published: September 2023

While animals readily adjust their behavior to adapt to relevant changes in the environment, the neural pathways enabling these changes remain largely unknown. Here, using multiphoton imaging, we investigated whether feedback from the piriform cortex to the olfactory bulb supports such behavioral flexibility. To this end, we engaged head-fixed mice in a multimodal rule-reversal task guided by olfactory and auditory cues. Both odor and, surprisingly, the sound cues triggered cortical bulbar feedback responses which preceded the behavioral report. Responses to the same sensory cue were strongly modulated upon changes in stimulus-reward contingency (rule reversals). The re-shaping of individual bouton responses occurred within seconds of the rule-reversal events and was correlated with changes in the behavior. Optogenetic perturbation of cortical feedback within the bulb disrupted the behavioral performance. Our results indicate that the piriform-to-olfactory bulb feedback carries reward contingency signals and is rapidly re-formatted according to changes in the behavioral context.
HIV co-infection is associated with reducedMycobacterium tuberculosistransmissibility in sub-Saharan Africa
Authors: Windels Etthel M. , Wampande Eddie M. , Joloba Moses L. , Boom W. Henry , Goig Galo A. , Cox Helen , Hella Jerry , Borrell Sonia , Gagneux Sebastien , Brites Daniela , Stadler Tanja
Published: September 2023

Persons living with HIV are known to be at increased risk of developing tuberculosis (TB) disease upon infection withMycobacterium tuberculosis(Mtb). However, it has remained unclear how HIV co-infection affects subsequentMtbtransmission from these patients. Here, we customized a Bayesian phylodynamic framework to estimate the effects of HIV co-infection on theMtbtransmission dynamics from sequence data. We applied our model to fourMtbgenomic datasets collected in sub-Saharan African countries with a generalized HIV epidemic. Our results confirm that HIV co-infection is a strong risk factor for developing active TB. Additionally, we demonstrate that HIV co-infection is associated with a reduced effective reproductive number for TB. Stratifying the population by CD4+ T-cell count yielded similar results, suggesting that, in this context, CD4+ T-cell count is not a better predictor ofMtbtransmissibility than HIV infection status. Together, our genome-based analyses complement observational household studies, and firmly establish the negative association between HIV co-infection andMtbtransmissibility.

Author summary

Many sub-Saharan African countries have seen a considerable rise in TB incidence since the introduction of HIV, suggesting a strong interaction between HIV and TB epidemics. HIV infection is recognized as an important risk factor for developing TB, but the contribution of HIV-infected TB patients to furtherMtbtransmission is poorly understood. In this study, we analyzed four sets ofMtbgenomic sequences collected in different countries, including sequences from HIV-negative and HIV-positive TB patients. We applied a phylodynamic model to these sequences, aimed at inferring transmission dynamics within and between different host populations. While our findings support that HIV is a strong risk factor for TB, we show that HIV-positive TB patients generate a significantly lower number of secondary TB cases than HIV-negative patients. This suggests that HIV-positive patients often act as sinks inMtbtransmission chains, while HIV-negative patients are a major source of transmission.
Behaviorally irrelevant feature matching increases neural and behavioral working memory readout
Authors: Karabay Aytaç , Wolff Michael J. , Ruuskanen Veera , Akyürek Elkan G.
Published: September 2023

There is an ongoing debate about whether working memory (WM) maintenance relies on persistent activity and/or short-term synaptic plasticity. This is a challenging question, because neuroimaging techniques in cognitive neuroscience measure activity only. Recently, neural perturbation techniques have been developed to tackle this issue, such as visual impulse perturbation or “pinging”, which reveals (un)attended WM content during maintenance. There are contrasting explanations of how pinging reveals WM content, which is central to the debate. Pinging could reveal mnemonic representations by perturbing content-specific networks or by increasing the neural signal-to-noise ratio of active neural states. Here we tested the extent to which the neural impulse response is patterned by the WM network, by presenting two different impulse stimuli. If the impulse interacts with WM networks, the WM-specific impulse response should be enhanced by physical overlap between the initial memory item and the subsequent external perturbation stimulus. This prediction was tested in a working memory task by matching or mismatching task-irrelevant spatial frequencies between memory items and impulse stimuli, as well as probes. Matching probe spatial frequency with memory items resulted in faster behavioral response times and matching impulse spatial frequency with memory items increased the specificity of the neural impulse response as measured from EEG. Matching spatial frequencies did neither result in globally stronger neural responses nor in a larger decrease in trial-to-trial variability compared to mismatching spatial frequencies. The improved neural and behavioural readout of irrelevant feature matching provide evidence that impulse perturbation interacts directly with the memory representations.
Streptococcus mutansinhibits the growth ofEnterococcusvia the non-ribosomal cyclic peptide mutanobactin
Authors: Robertson Ethan B. , Willett Julia L. E.
Published: September 2023

Enterococcus faecalisis a Gram-positive commensal bacterium in the gastrointestinal tract and an opportunistic pathogen. Enterococci are a leading cause of nosocomial infections, treatment of which is complicated by intrinsic and acquired antibiotic resistance mechanisms. Additionally,E. faecalishas been associated with various oral diseases, and it is frequently implicated in the failure of endodontic treatment. For establishment and persistence in a microbial community,E. faecalismust successfully compete against other bacteria. Streptococcal species play an important role in the establishment of the oral microbiome and co-exist withEnterococcusin the small intestine, yet the nature of interactions betweenE. faecalisand oral streptococci remains unclear. Here, we describe a mechanism by whichStreptococcus mutansinhibits the growth ofE. faecalisand other Gram-positive pathogens through the production of mutanobactin, a cyclic lipopeptide. Mutanobactin is produced by a polyketide synthase–nonribosomal peptide synthetase hybrid system encoded by themublocus. Mutanobactin-producingS. mutansinhibits planktonic and biofilm growth ofE. faecalisand is also active against otherEnterococcusspecies andStaphylococcus aureus. Mutanobactin damages the cell envelope ofE. faecalis, similar to other lipopeptide antibiotics like daptomycin.E. faecalisresistance to mutanobactin is mediated by the virulence factor gelatinase, a secreted metalloprotease. Our results highlight the anti-biofilm potential of the microbial natural product mutanobactin, provide insight into howE. faecalisinteracts with other organisms in the human microbiome, and demonstrate the importance of studyingE. faecalisdynamics within polymicrobial communities.

Significance

Entercoccus faecalisis a leading cause of hospital-acquired infections, treatment of which is complicated by virulence factors, biofilm formation, and antibiotic resistance. Here, we demonstrate the antibiotic and anti-biofilm activity of mutanobactin, a cyclic lipopeptide produced byStreptococcus mutans, againstEnterococcusandStaphylococcusspp., including vancomycin-resistant Enterococci (VRE). Similar to other lipopeptides, mutanobactin damages the bacterial cell envelope.E. faecalismay overcome antagonism from mutanobactin through production of gelatinase, a secreted protease and prevalent virulence factor. Our results demonstrate the antibiotic and anti-biofilm potential of mutanobactin and highlight the role of bacterial proteases in resistance to bacteria- and host-derived antimicrobial compounds.
Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus
Authors: Lee Jimin , Zepeda Samantha K. , Park Young-Jun , Taylor Ashley L. , Quispe Joel , Stewart Cameron , Leaf Elizabeth M. , Treichel Catherine , Corti Davide , King Neil P. , Starr Tyler N. , Veesler David
Published: September 2023

AlthoughRhinolophusbats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad ACE2 usage and that RBD mutations further expand receptor promiscuity and enable human ACE2 utilization. We determined a cryoEM structure of the PRD-0038 RBD bound toR. alcyoneACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryoEM and monoclonal antibody reactivity revealed its distinct antigenicity relative to SARS-CoV-2 and identified PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicited greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared to SARS-CoV-2 S due to broader antigenic targeting, motivating the inclusion of clade 3 antigens in next-generation vaccines for enhanced resilience to viral evolution.
Hyperexcitability in humanMECP2null neuronal networks manifests as calcium-dependent reverberating super bursts
Authors: Pradeepan Kartik S , McCready Fraser P , Wei Wei , Khaki Milad , Zhang Wenbo , Salter Michael W , Ellis James , Martinez-Trujillo Julio
Published: September 2023

Rett syndrome (RTT) patients show abnormal developmental trajectories including loss of language and repetitive hand movements but also have signs of cortical hyperexcitability such as seizures. RTT is predominantly caused by mutations inMECP2and can be modelled in vitro using human stem cell-derived neurons.MECP2null excitatory neurons are smaller in soma size and have reduced synaptic connectivity but are also hyperexcitable, due to higher input resistance, which increases the chance to evoke action potentials with a given depolarized current. Few studies examine how single neuron activity integrates into neuronal networks during human development. Paradoxically, networks ofMECP2null neurons show a decrease in the frequency of bursting patterns consistent with synaptic hypoconnectivity, but no hyperexcitable network events have been reported. Here, we show thatMECP2null neurons have an increase in the frequency of a network event described as reverberating super bursts (RSBs) relative to isogenic controls. RSBs can be mistakenly called as a single long duration burst by standard burst detection algorithms. However, close examination revealed an initial large amplitude network burst followed by high frequency repetitive low amplitude mini-bursts. Using a custom burst detection algorithm, we unfolded the multi-burst structure of RSBs revealing thatMECP2null networks increased the total number of bursts relative to isogenic controls. Application of the Ca2+chelator EGTA-AM selectively eliminated RSBs and rescued the network burst phenotype relative to the isogenic controls. Our results indicate that during early development,MECP2null neurons are hyperexcitable and produce hyperexcitable networks. This may predispose them to the emergence of hyper-synchronic states that potentially translate into seizures. Network hyperexcitability is dependent on asynchronous neurotransmitter release driven by pre-synaptic Ca2+and can be rescued by EGTA-AM to restore typical network dynamics.

HIGHLIGHTS

Reverberating super-bursts (RSBs) follow a stereotypic form of a large initial network burst followed by several smaller amplitude high-frequency mini-bursts.

RSBs occur more often inMECP2null excitatory networks.

MECP2null excitatory networks with increased RSBs show a hyperexcitable network burst phenotype relative to isogenic controls.

The calcium chelator, EGTA-AM, decreases RSBs and rescues the dynamics ofMECP2null hyperexcitable networks.
The Interactome of DUX4 Reveals Multiple Activation Pathways
Authors: Slavin Moriya , Zohar Keren , Claus Clothilde , Schneidman-Duhovny Dina , Linial Michal , Coppée Frédérique , Kalisman Nir
Published: September 2023

The ectopic expression of the DUX4 protein in muscle cells is the underlying cause of Facioscapulohumeral Muscular Dystrophy (FSHD). DUX4 is a potent transcription factor that activates a large number of genes in a dysregulated manner, but the direct protein interactions involved in this activation are only partially known. Here, we tailored an affinity purification and mass spectrometry (AP-MS) analysis to the unique features and functions of DUX4, to provide a more complete view of its interactome. We also obtained and verified all-atom models for two of the major interactions by employing cross-linking and mass spectrometry (CL-MS), computational modeling, and guided mutation studies. We find that DUX4 interacts strongly with two homologous transcription activators, PTOV1 and MED25, in addition to the previously characterized CBP/p300. The interaction with the PTOV1/MED25 domain involves the wrapping of the last thirty residues of the DUX4 activation region around the domain in a very extensive interface. Hence, DUX4 has the capacity to both open the chromatin and directly recruit the Mediator complex. DUX4 also binds to all members of the RFPL4 family, which are among the strongest genes it activates. These interactions are mediated through a hitherto unrecognized motif in the DUX4 disordered linker region. This feedback mechanism suggests that DUX4 may be inhibited by its own activation products, and explains its typical pulsed expression profile. We also found SIX1 and the AP-2 complex as strong DUX4 C-terminal interactors. A separate analysis of interactions involving the N-terminal of DUX4 revealed enrichment of proteins that are involved in DNA repair following double-strand breaks. Overall, these findings reveal new activation pathways for DUX4, which may be modulated in future strategies to control its toxicity. This study also showcases the synergy between CL-MS and deep-learning based modeling for the structural elucidation of challenging protein-protein interactions.
The Microtubule Severing Protein UNC-45A Counteracts the Microtubule Straightening Effects of Taxol
Authors: Hoshino Asumi , Clemente Valentino , Shetty Mihir , Castle Brian , Odde David , Bazzaro Martina
Published: September 2023

UNC-45A is the only known ATP-independent microtubule (MT) severing protein. Thus, it severs MTs via a novel mechanism.In vitroand in cells UNC-45A-mediated MT severing is preceded by the appearance of MT bends. While MTs are stiff biological polymers, in cells, they often curve, and the result of this curving can be breaking off. The contribution of MT severing proteins on MT lattice curvature is largely undefined. Here we show that UNC-45A curves MTs. Usingin vitrobiophysical reconstitution and TIRF microscopy analysis, we show that UNC-45A is enriched in the areas where MTs are curved versus the areas where MTs are straight. In cells, we show that UNC-45A overexpression increases MT curvature and its depletion has the opposite effect. We also show that this effect occurs is independent of actomyosin contractility. Lastly, we show for the first time that in cells, Paclitaxel straightens MTs, and that UNC-45A can counteracts the MT straightening effects of the drug.Significance:Our findings reveal for the first time that UNC-45A increases MT curvature. This hints that UNC-45A-mediated MT severing could be due to the worsening of MT curvature and provide a mechanistic understanding of how this MT-severing protein may act. UNC-45A is the only MT severing protein expressed in human cancers, including paclitaxel-resistant ovarian cancer. Our finding that UNC-45A counteracts the paclitaxel-straightening effects of MTs in cells suggests an additional mechanism through which cancer cells escape drug treatment.
A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite
Authors: Huang Lei , Liu Pengpeng , Du Yong , Bazan J. Fernando , Pan Dongning , Chen Qingbo , Lee Alexandra , Rao Kola Vijaya Sudhakara , Wolfe Scot , Wang Yong-Xu
Published: September 2023

The endocrine control of food intake remains incompletely understood, and whether the leptin receptor (LepR)-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here, we identify an appetite-stimulating factor - ASRA - that represents a peripheral signal of energy deficit and orthosterically antagonizes LepR signaling. Asra encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver. ASRA associates with autophagy vesicles and its secretion is enhanced by energy deficiency. In vivo, fasting and cold stimulate Asra expression and increase its protein concentration in cerebrospinal fluid. Asra overexpression attenuates LepR signaling, leading to elevated blood glucose and development of severe hyperphagic obesity. Conversely, either adipose- or liver-specific Asra knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, resistance to high-fat diet-induced obesity, and blunted cold-evoked feeding response. Mechanistically, ASRA acts as a high affinity antagonist of LepR. AlphaFold2-multimer prediction and mutational studies suggest that a core segment of ASRA binds to the immunoglobin-like domain of LepR, similar to the 'site 3' recognition of the A-B loop of leptin. While administration of recombinant wild-type ASRA protein promotes food intake and increases blood glucose in a LepR signaling-dependent manner, point mutation within ASRA that disrupts LepR-binding results in a loss of these effects. Our studies reveal a previously unknown endocrine mechanism in appetite regulation and have important implications for our understanding of leptin resistance.
Cerebellar granule cell migration and folia development requires Mllt11/Af1q/Tcf7c
Authors: Blommers Marley , Stanton-Turcotte Danielle , Witt Emily A. , Heidari Mohsen , Iulianella Angelo
Published: September 2023

The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. Here we report a role Mllt11/Af1q/Tcf7c (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both tangential and radial migration of GCs. Loss ofMllt11led to an accumulation of GC precursors in the Rhombic Lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with Non-muscle Myosin IIB (NMIIB) and regulates its expression. We propose the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.
Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology
Authors: Han Feng , Lee JiaQie , Chen Xi , Ziontz Jacob , Ward Tyler , Landau Susan M , Baker Suzanne L , Harrison Theresa M , Jagust William J ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

Abstract

Amyloid-β (Aβ) and tau deposition constitute Alzheimer’s disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aβ-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aβ, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.

One Sentence Summary

Resting-state global brain activity affects tau deposition through the potential involvement of a glymphatic clearance function.
A simulation-based approach for estimating the time-dependent reproduction number from temporally aggregated disease incidence time series data
Authors: Ogi-Gittins I , Hart WS , Song J , Nash RK , Polonsky J , Cori A , Hill EM , Thompson RN
Published: September 2023

Tracking pathogen transmissibility during infectious disease outbreaks is essential for assessing the effectiveness of public health measures and planning future control strategies. A key measure of transmissibility is the time-dependent reproduction number, which has been estimated in real-time during outbreaks of a range of pathogens from disease incidence time series data. While commonly used approaches for estimating the time-dependent reproduction number can be reliable when disease incidence is recorded frequently, such incidence data are often aggregated temporally (for example, numbers of cases may be reported weekly rather than daily). As we show, commonly used methods for estimating transmissibility can be unreliable when the timescale of transmission is shorter than the timescale of data recording. To address this, here we develop a simulation-based approach involving Approximate Bayesian Computation for estimating the time-dependent reproduction number from temporally aggregated disease incidence time series data. We first use a simulated dataset representative of a situation in which daily disease incidence data are unavailable and only weekly summary values are reported, demonstrating that our method provides accurate estimates of the time-dependent reproduction number under those circumstances. We then apply our method to two previous outbreak datasets consisting of weekly influenza case numbers from 2019-20 and 2022-23 in Wales (in the United Kingdom). Our simple-to-use approach allows more accurate estimates of time-dependent reproduction numbers to be obtained during future infectious disease outbreaks.
Phosphoproteomics reveals content and signaling differences between neonatal and adult platelets
Authors: Thom Christopher S , Davenport Patricia , Fazelinia Hossein , Liu Zhi-Jian , Zhang Haorui , Ding Hua , Roof Jennifer , Spruce Lynn A , Ischiropoulos Harry , Sola-Visner Martha
Published: September 2023

Background and Objective

Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets.

Methods

We isolated resting umbilical cord blood-derived platelets from healthy full term neonates (n=9) and resting blood platelets from healthy adults (n=7), and compared protein and phosphoprotein contents using data independent acquisition mass spectrometry.

Results

We identified 4745 platelet proteins with high confidence across all samples. Adult and neonatal platelets clustered separately by principal component analysis. Adult platelets were significantly enriched for immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched for ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched for phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched for phosphorylated proteins involved in insulin growth factor signaling.

Conclusions

Using state-of-the-art mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation compared with adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of a molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.
Alstrom syndrome proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop in Drosophila
Authors: Brunet Marine , Thomas Joelle , Lapart Jean-Andre , Krüttli Léo , Laporte Marine , Riparbelli Maria Giovanna , Callaini Giuliano , Durand Benedicte , Morel Veronique
Published: September 2023

Centrioles play a central role in cell division by recruiting pericentriolar material (PCM) to form the centrosome. Alterations in centriole number or function lead to various diseases including cancer or microcephaly. Centriole duplication is a highly conserved mechanism in eukaryotes. Here, we show that the two Drosophila orthologs of the Alstrom syndrome protein 1 (Alms1a and Alms1b) are unexpected novel players of centriole duplication in fly. Using Ultrastructure Expansion Microscopy, we reveal that Alms1a is a PCM protein that is loaded proximally on centrioles at the onset of procentriole formation whereas Alms1b caps the base of mature centrioles. We demonstrate that chronic loss of Alms1 proteins affects PCM maturation, whereas their acute loss completely disrupts procentriole formation before Sas-6 cartwheel assembly. We establish that Alms1 proteins are required for the amplification of the Plk4-Ana2 pool at the duplication site and the subsequent Sas-6 recruitment. Thus, Alms1 proteins are novel critical but highly buffered regulators of PCM and cartwheel assembly in flies.
Crossmodal correspondence of natural amplitude modulations
Authors: Lemus Luis , Morán Isaac , Melchor Jonathan , Figueroa Tonatiuh , Matta Miguel , Cabrera Elizabeth
Published: September 2023

Crossmodal correspondence is the ability to recognize objects from different sensory modalities to be similar. Here, we investigated the capacity of humans to perform crossmodal discriminations between visual, acoustic, and tactile stimuli modulated in amplitudes of low-pass filtered envelopes obtained from natural sounds. We found that the perception of crossmodal correspondence emerged from the number of amplitude prominences in each stimulus rather than from temporal variations. Therefore, we propose saliency as the supramodal trade coin of temporal modulations.
Reinforcement learning during locomotion
Authors: Wood Jonathan M , Kim Hyosub E , Morton Susanne M
Published: September 2023

When learning a new motor skill, people often must use trial and error to discover which movement is best. In the reinforcement learning framework, this concept is known as exploration and has been observed as increased movement variability in motor tasks. For locomotor tasks, however, increased variability decreases upright stability. As such, exploration during gait may jeopardize balance and safety, making reinforcement learning less effective. Therefore, we set out to determine if humans could acquire and retain a novel locomotor pattern using reinforcement learning alone. Young healthy male and female humans walked on a treadmill and were provided with binary reward feedback (success or failure only) to learn a novel stepping pattern. We also recruited a comparison group who walked with the same novel stepping pattern but did so by correcting for target error, induced by providing real time veridical visual feedback of steps and a target. In two experiments, we compared learning, motor variability, and two forms of motor memories between the groups. We found that individuals in the binary reward group did, in fact, acquire the new walking pattern by exploring (increased variability). Additionally, while reinforcement learning did not increase implicit motor memories, it resulted in more accurate explicit motor memories compared to the target error group. Overall, these results demonstrate that humans can acquire new walking patterns with reinforcement learning and retain much of the learning over 24 hours.

Significance Statement

Humans can learn some novel movements by independently discovering the actions that lead to success. This discovery process, exploration, requires increased motor variability to determine the best movement. However, in bipedal locomotion especially, increasing motor variability decreases stability, heightening the risk of negative outcomes such as a trip, injury, or fall. Despite this stability constraint, the current study shows that individuals do use exploration to find the most rewarding walking patterns. This form of learning led to improved explicit retention but not implicit aftereffects. Thus, the reinforcement learning framework can explain findings across a wide range of motor and cognitive tasks, including locomotion.
Explaining Deep Learning-Based Representations of Resting State Functional Connectivity Data: Focusing on Interpreting Nonlinear Patterns in Autism Spectrum Disorder
Authors: Kim Young-geun , Ravid Orren , Zhang Xinyuan , Kim Yoojean , Neria Yuval , Lee Seonjoo , He Xiaofu , Zhu Xi
Published: September 2023

Background

Resting state Functional Magnetic Resonance Imaging fMRI (rs-fMRI) has been used to study brain function in psychiatric disorders, yielding insight into brain organization. However, the high dimensionality of the rs-fMRI data presents challenges, and requires dimensionality reduction before applying machine learning techniques. Neural networks, specifically variational autoencoders (VAEs), have been instrumental in extracting low-dimensional latent representations of resting state functional connectivity patterns, addressing the complex nonlinear structure of rs-fMRI. However, interpreting those latent representations remains a challenge. This paper aims to address this gap by creating explainable VAE models and testing their utility using rs-fMRI data in autism spectrum disorder (ASD).

Methods

One-thousand one hundred and fifty participants (601 HC and 549 patients with ASD) were included in the analysis. We extracted functional connectivity correlation matrices from the preprocessed rs-fMRI data using Power atlas with 264 ROIs. Then VAEs were trained in an unsupervised fashion. Lastly, we introduce our latent contribution scores to explain the relationship between estimated representations and the original rs-fMRI brain measures.

Results

We quantified the latent contribution scores for the ASD and control groups at the network level. We found that both ASD and control groups share the top network connectivity that contribute to all estimated latent components. For example, latent 0 was driven by resting state functional connectivity patterns (rsFC) within ventral attention network in both the ASD and control. However, significant differences in the latent contribution scores between the ASD and control groups were discovered within the ventral attention network in latent 0 and the sensory/somatomotor network in latent 2.

Conclusion

This study introduced latent contribution scores to interpret nonlinear patterns identified by VAEs. These scores effectively capture changes in each observed rsFC features as estimated latent representation changes, enabling an explainable deep learning model to better understand the underlying neural mechanism of ASD.
Stem cell proliferation and differentiation during larval metamorphosis of the model tapewormHymenolepis microstoma
Authors: Montagne Jimena , Preza Matías , Koziol Uriel
Published: September 2023

Tapeworm larvae cause important diseases in humans and domestic animals. During infection, the first larval stage undergoes a metamorphosis where tissues are formedde novofrom a population of stem cells called germinative cells. This process is difficult to study for human pathogens, as these larvae are infectious and difficult to maintain in the laboratory. In this work, we analyzed cell proliferation and differentiation during larval metamorphosis in the model tapewormHymenolepis microstoma, byin vivolabelling of proliferating cells with the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU), tracing their differentiation with a suite of specific molecular markers for different cell types. Proliferating cells are very abundant and fast-cycling during early metamorphosis: the total number of cells duplicates every ten hours, and the length of G2 is only 75 minutes. New tegumental, muscle and nerve cells differentiate from this pool of proliferating germinative cells, and these processes are very fast, as differentiation markers for neurons and muscle cells appear within 24 hours after exiting the cell cycle, and fusion of new cells to the tegumental syncytium can be detected after only 4 hours. Tegumental and muscle cells appear from early stages of metamorphosis (24 to 48 hours post-infection); in contrast, most markers for differentiating neurons appear later, and the detection of synapsin and neuropeptides correlates with scolex retraction. Finally, we identified populations of proliferating cells that express conserved genes associated with neuronal progenitors and precursors, suggesting the existence of tissue-specific lineages among germinative cells. These results provide for the first time a comprehensive view of the development of new tissues during tapeworm larval metamorphosis, providing a framework for similar studies in human and veterinary pathogens.
Contracts and Finality of Signature: The Coys of Kensington Case
Authors: Pathak Akhileshwar
Published: September 2023

Customers often sign lengthy offer documents, running in several pages, without reading them or understanding their contents. Later, they discover the contract has exclusion clauses or unfavourable terms. Are the terms binding on the person? The case explores the UK High Court judgement in Coys of Kensington Automobiles Limited v Tiziana Pugliese, which is on the theme of the signing of an offer form. The case explores themes frequently encountered in forms, including the following: The font size is small and terms not conspicuous. The form refers to more terms without enclosing them. The applicant is not fully familiar with the language.
Good Food Served Quietly: The Mime Restaurants (A)
Authors: Khokle Pradyumana , Kulkarni Vaibhavi
Published: September 2023

The case captures the origin and initial years of two restaurants Mirchi & Mime and Madeira & Mime, which exclusively employed Speech and Hearing Impaired persons (SHI) as servers (often called “waiters” in India). It documents how the restaurants were set up, captures significant incidents during this initial period and the impact of these incidents on the working of the restaurants. Further, it describes the challenge of opening a fine dining restaurant and a gastropub staffed exclusively by SHI persons as servers. The case narrates the reactions and impact on the SHIs and their families, co-workers within the outlets and the customers visiting these outlets. Finally, the case lists the recognition received by the organisation and outlines plans for the immediate future.
Facilities management and clients satisfaction nexus in hotels in secondary cities in Ghana: A study of selected hotels in Wa
Authors: Alhassan Tahiru , Kidido Joseph Kwaku
Published: September 2023

Purpose

This study aims to assess how the provision of facilities management (FM) services influences customer satisfaction in hotels in secondary cities. This study focussed on customer satisfaction in relation to specific FM services such as cleaning, maintenance, security, internet/information technology and air conditioner servicing.

Design/methodology/approach

The study used a case study design. Simple random and purposive sampling methods were used to select the hotels and the respondents. The study used a survey based on the SERVQUAL model to collect data from 136 respondents. Six hotel managers were also interviewed.

Findings

There were disparities in customer satisfaction across the various hotel categories based on the assessment indicators used. Thus, customer satisfaction with FM services was not influenced by hotel ratings. On the calibre of staff handling FM activities, none of the hotels had a professional facilities manager. The hotel managers were in charge of FM activities, which affected the provision of FM services. Generally, customers in all the selected hotels were not satisfied with the quality of FM services. Specifically, the overall mean gap score was very low (−3.20), which meant that customers’ expectations far exceeded their perceptions, hence, their dissatisfaction. Tangible(s) of services were customers’ least appreciated (−1.04) dimension. This meant that hotels did not pay much attention to the physical (place) aspect of their FM activities. This should engage the attention of hospitality industry regulators and policymakers, given the current global health crisis caused by Covid-19 and its variance.

Originality/value

The study demonstrates customer satisfaction with FM services in hotels in secondary cities. Practically, hotels can become very competitive if they consider the findings of the study to provide effective customer-oriented FM services.
Measuring customer satisfaction in electronic commerce: the impact of e-service quality and user experience
Authors: Mamakou Xenia J. , Zaharias Panagiotis , Milesi Maria
Published: September 2023

Purpose

The purpose of this study is to explore the interplay between electronic service quality, user experience (UX) and overall customer satisfaction. Additionally, it aims to assess the suitability of E-S-QUAL and UX metrics within the cultural context of Greece.

Design/methodology/approach

Data were collected from 310 Internet users based on their last online purchase from an e-retail website. To evaluate the conceptual model, the authors used partial least squares structural equation modeling (PLS-SEM).

Findings

The findings of this study validate the scales' reliability and validity in the realm of electronic commerce (e-commerce) in Greece. The findings also emphasize the favorable association between e-service quality and UX with overall satisfaction, while indicating that e-service quality plays a partial mediating role in the relationship between UX and customer satisfaction.

Originality/value

The authors' study enhances the existing theory by introducing a new multi-dimensional conceptual framework that illuminates the relative importance of the dimensions within the scales. Additionally, it offers valuable insights into the impacts of e-service quality and UX on overall satisfaction, providing managers and practitioners with a tool to evaluate the quality of their electronic services and make necessary adjustments to meet the needs of their customers.