bluuebunny/crossref_metadata_2025 huggingface dataset:
Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal
Authors: Simon Rhiana C. , Fleming Weston T. , Senthilkumar Pranav , Briones Brandy A. , Ishii Kentaro K. , Hjort Madelyn M. , Martin Madison M. , Hashikawa Koichi , Sanders Andrea D. , Golden Sam A. , Stuber Garret D.
Published: January 2024

Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (Nts; LS-Ntsneurons) were selectively activated by naloxone. Using two-photon calcium imaging andex vivoelectrophysiology, we next demonstrate that LS-Ntsneurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Ntsneurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Ntsneurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.
A call for a unified and multimodal definition of cellular identity in the enteric nervous system
Authors: Majd Homa , Cesiulis Andrius , Samuel Ryan M , Richter Mikayla N , Elder Nicholas , Guyer Richard A , Hao Marlene M. , Stamp Lincon A. , Goldstein Allan M , Fattahi Faranak
Published: January 2024

The enteric nervous system (ENS) is a tantalizing frontier in neuroscience. With the recent emergence of single cell transcriptomic technologies, this rare and poorly understood tissue has begun to be better characterized in recent years. A precise functional mapping of enteric neuron diversity is critical for understanding ENS biology and enteric neuropathies. Nonetheless, this pursuit has faced considerable technical challenges. By leveraging different methods to compare available primary mouse and human ENS datasets, we underscore the urgent need for careful identity annotation, achieved through the harmonization and advancements of wet lab and computational techniques. We took different approaches including differential gene expression, module scoring, co-expression and correlation analysis, unbiased biological function hierarchical clustering, data integration and label transfer to compare and contrast functional annotations of several independently reported ENS datasets. These analyses highlight substantial discrepancies stemming from an overreliance on transcriptomics data without adequate validation in tissues. To achieve a comprehensive understanding of enteric neuron identity and their functional context, it is imperative to expand tissue sources and incorporate innovative technologies such as multiplexed imaging, electrophysiology, spatial transcriptomics, as well as comprehensive profiling of epigenome, proteome, and metabolome. Harnessing human pluripotent stem cell (hPSC) models provides unique opportunities for delineating lineage trees of the human ENS, and offers unparalleled advantages, including their scalability and compatibility with genetic manipulation and unbiased screens. We encourage a paradigm shift in our comprehension of cellular complexity and function in the ENS by calling for large-scale collaborative efforts and research investments.
Generational differences in physical health and disability in the United States and Europe
Authors: Gimeno Laura , Goisis Alice , Dowd Jennifer B. , Ploubidis George B.
Published: January 2024

Objectives

Declines in mortality have typically been associated with improvements in physical health across generations. While life expectancy in most high-income countries continues to increase, there is evidence that younger generations, particularly in the United States (US), are less healthy than previous generations at the same age. We compared generational trends in physical health in the US, England, and continental Europe to explore whether other regions have experienced a similar pattern of worsening health across cohorts.

Methods

Using data from nationally representative studies of adults aged ≥50 years from the US (Health and Retirement Study,n=26,939), England (English Longitudinal Study of Ageing,n=14,992) and 11 continental European countries (Survey of Health, Ageing and Retirement in Europe,n=72,595), we estimated differences in the age-adjusted prevalence of self-reported chronic disease and disability and observer-measured health indicators across pseudo-birth cohorts (born <1925, 1925-1935, 1936-1945, 1946-1954, 1955-1959).

Results

Age-adjusted prevalence of doctor-diagnosed chronic disease increased across cohorts in all regions. Trends in disability prevalence were more regionally varied. Still, in both the US and Europe, we observed a structural break in disability trends, with declines observed in pre-war cohorts slowing, stalling, or reversing for cohorts born since 1945.

Discussion

In all regions, we found evidence for worsening health across cohorts, particularly for those born since 1945. While more chronic disease in younger cohorts need not necessarily translate to worse quality of life or higher rates of functional limitation, there is some suggestion that worsening chronic disease morbidity may be spilling over into worsening disability.
Routine Labs in Hospital Patients: Iatrogenic Anemia and Missed Acute Kidney Injury
Authors: Dean Dawson
Published: January 2024

Guidelines recommend avoiding unnecessary laboratory tests to minimize risks of anemia in hospitalized patients as well as reduce costs. Avoiding routine labs, however, may introduce new risks of missing conditions that do not have physical exam or history findings, such as Acute Kidney Injury. This study analyzes retrospective data for routine laboratory results and simulates different strategies for skipping labs. It estimates potential benefits from avoiding iatrogenic anemia as well as costs from increased risk of Acute Kidney Injury. In a simplified estimate of pure dollar costs, the costs of daily labs appear to significantly outweigh the costs of missing Acute Kidney Injury, but there are costs to skipping routine labs.
Early developmental milestone clusters of autistic children based on electronic health records
Authors: Ben-Sasson Ayelet , Guedalia Joshua , Ilan Keren , Shefer Galit , Cohen Roe , Gabis Lidia V
Published: January 2024

ASD children vary in symptoms, co-morbidities and response to interventions. This study aimed to identify clusters of ASD children with a distinct pattern of attaining early developmental milestones. Clustering of 5,836 ASD children was based on attainment of 43 gross motor, fine motor, language and social developmental milestones in the first three years of life as recorded in baby wellness visits.

K-means cluster analysis detected 4 Early Developmental Milestone (EDM) clusters: typical (n=1,686); mild (n=1,691); moderate (n=2,265); and severe (n=194). Most prominent cluster differences were in the language domain. The severe cluster showed earlier and greater developmental delay across domains, unique early gross motor delays, and more were born preterm via cesarian section. Moderate cluster had poor language development prominently in the second year of life, later fine motor delays. Mild cluster had language delays in the third year of life. The typical cluster mostly passed milestones. EDM clusters differed demographically, with higher socioeconomic status in typical cluster and lowest in severe cluster. Moderate cluster had more immigrant and non-Jewish mothers followed by the mild cluster. The rates of parental concerns and provider developmental referrals were significantly higher in the severe, followed by the moderate, mild, and typical EDM clusters.

ASD children’s language and motor delay in the first three years can be grouped by common magnitude and onset profiles as distinct groups that may link to specific etiologies (like prematurity or genetics) and to specific intervention programs. Early ASD screening should be tailored to these different developmental profiles.
The Dearth of Representation in FDA Approved Drug Trials
Authors: Ibilibor Christine , Armbruster Shannon , Parker Rell , Yu Jia-Ray , Barros Andrew
Published: January 2024

The generalizability of data derived from randomized controlled trials is of paramount importance given their utility in the Food & Drug Administration (FDA) drug approval process. An essential part of this process is the inclusion of reliably reported gender, race and ethnicity data in trials that lead to FDA drug approval. Despite previous mandates by the FDA andClinicaltrials.gov, gender and race-specific data remains under reported. We reviewed 100 most recently approved FDA medications, and abstracted the clinical trial data fromClinicaltrials.govthat supported their approval. We then compared these FDA approved trials to non-FDA approved trials from the same year and of similar size. We found that 40% of the FDA trials were missing race/ethnicity information, while 24% of these trials did not include gender information. We demonstrate that there remains a significant amount of missing gender and racial/ethnic data in trials that lead to FDA-approved medications.
Cohort profile: a multicenter European study of acute respiratory infections: the MERMAIDS-ARI 2.0 cohort study
Authors: de Hoog Marieke L.A. , Prat-Aymerich Cristina , Troeman Darren P.R. , Lee James , Ieven Greet , Horby Peter , Leus Frank , Bonten Marc J. M. , Goossens Herman J.A. , Bruijning-Verhagen Patricia C.J.L.
Published: January 2024

Purpose

Multi-centre EuRopean study of MAjor Infectious Disease Syndromes – Acute Respiratory Infections (MERMAIDS-ARI) cohort study is a European prospective cohort study. It was originally launched in 2016 as MERMAIDS-ARI to study acute respiratory infections. When the COVID-19 pandemic hit, the study re-started inclusion under an amended protocol as MERMAIDS-ARI 2.0 focusing on SARS-CoV-2. The objectives of this study were to describe the disease spectrum, clinical features, and outcomes of SARS-CoV-2 infections in hospital care, to determine relevant risk factors and the assess prevalence and within hospital spread compared to other respiratory infections. An important second objective was to establish an extensive biobank supplemented with detailed clinical data to be able to address future virological, immunological, and clinical research questions.

Methods

Patients with either 1) ARI presenting to hospital care during the SARS-CoV-2 epidemic (including both COVID-19 and non-COVID-19 patients) or 2) confirmed COVID-19 infection, but with atypical presentation (non-ARI) or with nosocomial acquisition were included. Clinical data and biological samples were collected on enrolment day and repeatedly thereafter until discharge. A subset of COVID-19 patients was also followed up to 12 months post-discharge to study clinical recovery and long-term sequelae.

Findings to date

In total 297 patients from 8 countries and 11 sites were recruited between June 2020 and September 2021. We reached high sample completeness for most sample types (>97% for single samples and >86% for serial samples). 294 (99.0%) patients were admitted to hospital with SARS-CoV-2. The population primarily consists of patients (median age 61 years) of Caucasian ethnicity, with the majority being male (62.0%) and having ≥1 comorbidities (67.3%). The median hospital stay was 10 days, and most patients (87.5%) received treatment with systemic corticosteroids and respiratory support (81.4%). A total of 64 (21.7%) patients were admitted to the Intensive Care Unit (ICU), and 6.5% died during hospitalization. Long-term follow-up of 94 patients revealed that most individuals resumed their regular activities and work within three months, with improvements observed in mobility and personal care over time. Instances of severe and extreme pain and anxiety were rarely reported (≤1.1%).

Conclusion

This pan-European study offers a valuable resource for conducting in-depth virological, immunological, and pathophysiological investigations pertaining to SARS-CoV-2.
The transgenerational consequences of paternal social isolation and predation exposure in threespined sticklebacks
Authors: Hellmann Jennifer , Rogers Michaela
Published: January 2024

Parents routinely encounter stress in the ecological environment that can affect offspring development (transgenerational plasticity: TGP); however, parents’ interactions with conspecifics may alter how parents respond to ecological stressors.

During social buffering, the presence of conspecifics can reduce the response to or increase the speed of recovery from a stressor. This may have cascading effects on offspring if conspecifics can mitigate parental responses to ecological stress in ways that blunt the transmission of stress-induced transgenerational effects.

Here, we simultaneously manipulated both paternal social isolation and experience with predation risk prior to fertilization in threespined stickleback (Gasterosteus aculeatus). We generated offspring via in-vitro fertilization to allow us to isolate paternal effects mediated via sperm alone (i.e., in the absence of paternal care). If social buffering mitigates TGP induced by paternal exposure to predation risk, then we expect the transgenerational effects of predation exposure to be weaker when a conspecific is present compared to when the father is isolated.

Offspring of predator-exposed fathers showed reduced anxiety-like behavior and tended to be captured faster by the predator. Fathers who were socially isolated also had offspring that were captured faster by a live predator, suggesting that paternal social isolation may have maladaptive effects on how offspring respond to ecological stressors. Despite additive effects of paternal social isolation and paternal predation risk, we found no evidence of an interaction between these paternal treatments, suggesting that the presence of a conspecific did not buffer fathers and/or offspring from the effects of predation risk.

Our results suggest that socially-induced stress is an important, yet underappreciated, mediator of TGP and can elicit transgenerational effects even in species that do not form permanent social groups. Future studies should therefore consider how the parental social environment can affect both within and trans-generational responses to ecological stressors.
Few-shot pattern detection by transient boosting of somato-dendritic coupling
Authors: Sivori Gaston , Fukai Tomoki
Published: January 2024

Neurons are thought to detect salient patterns amidst noise in continuous information streams, but their rapidity tends to be overlooked. Consequently, theoretical neuron models lack key mechanistic features that are suggested to underlie biological neuron rapid learning of input patterns. To unravel these features, we propose a class of models endowed with biologically-plausible predictive learning rules. In these models, an error signal propagates somatic spiking activity to dendrites, facilitating unsupervised learning of repeatedly coactivated presynaptic-neuron communities. Spike-triggered transient boosting of dendritic coupling bestows plausibility and improves the signal-to-noise ratio of learning dramatically. We demonstrate that our plasticity rule enables neurons to swiftly establish a behavioral timescale reward-place association in spatial navigation tasks and showcase how cell assemblies pre-configured in recurrent networks learn multiple patterns within a few repetitions robustly. Our results shed light on the self-supervising function of backpropagating action potentials for pattern learning and its acceleration by pre-existing cell assemblies.
Does early-stage Alzheimer’s disease affect the dynamics of motor adaptation?
Authors: Sutter K , Oostwoud Wijdenes L , van Beers RJ , Claassen JAHR , Kessels RPC , Medendorp WP
Published: January 2024

Alzheimer’s disease (AD) is characterized by an initial decline in declarative memory, while non-declarative memory processing remains relatively intact. Error-based motor adaptation is traditionally seen as a form of non-declarative memory, but recent findings suggest that it involves both fast, declarative and slow, non-declarative adaptive processes. If the declarative memory system shares resources with the fast process in motor adaptation, it can be hypothesized that the fast, but not the slow, process is disturbed in AD patients. To test this, we studied 20 early-stage AD patients and 21 age-matched controls of both sexes using a reach adaptation paradigm that relies on spontaneous recovery after sequential exposure to opposing force fields. Adaptation was measured using error clamps and expressed as an adaptation index (AI). Although patients with AD showed slightly lower adaptation to the force field than the controls, both groups demonstrated effects of spontaneous recovery. The time course of the AI was fitted by a hierarchical Bayesian two-state model in which each dynamic state is characterized by a retention and learning rate. Compared to controls, the retention rate of the fast process was the only parameter that was significantly different (lower) in the AD patients, confirming that the memory of the declarative, fast process is disturbed by AD. The slow adaptive process was virtually unaffected. Since the slow process learns only weakly from error, our results provide neurocomputational evidence for the clinical practice of errorless learning of everyday tasks in people with dementia.
Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis
Authors: Ionescu Rosana-Bristena , Nicaise Alexandra M. , Reisz Julie A. , Williams Eleanor C. , Prasad Pranathi , Dzieciatkowska Monika , Stephenson Daniel , Cubero Marta Suarez , Pirvan Liviu , Willis Cory M. , Peruzzotti-Jametti Luca , Fossati Valentina , Edenhofer Frank , Leonardi Tommaso , Frezza Christian , Mohorianu Irina , D’Alessandro Angelo , Pluchino Stefano
Published: January 2024

Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear.

By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotypein vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of cholesteryl ester-enriched lipid droplets. An HMG-CoA reductase-mediated lipogenic state was found to induce secretion of the SASP in PMS iNSC conditioned media via transcriptional regulation by cholesterol-dependent transcription factors. SASP from PMS iNSCs induced neurotoxicity. Chemical targeting of HMG-CoA reductase using the cholesterol-lowering drug simvastatin (SV) prevented SASP release and resulting neurotoxicity.

Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.
Heterodimerization of Endolysin Isoforms During Bacterial Infection by Staphylococcal Phage φ2638A
Authors: Zinsli Léa V. , Sobieraj Anna M. , Ernst Patrick , Meile Susanne , Kilcher Samuel , Iseli Cedric , Keller Anja , Dreier Birgit , Mittl Peer R. E. , Plückthun Andreas , Loessner Martin J. , Schmelcher Mathias , Dunne Matthew
Published: January 2024

Abstract

Bacteriophage endolysins targeting Gram-positive bacteria typically feature a modular architecture of one or more enzymatically active domains (EADs) and cell wall binding domains (CBDs). Several endolysins also feature internal translational start sites (iTSSs) that produce short variant (SV) isoforms alongside the full-length (FL) endolysin. While the lytic activity of endolysins and their isoforms has been extensively studied as exogenous agents, the purpose behind producing the SV isoform during the phage infection cycle remains to be explored. In this study, we used staphylococcal phage φ2638A as a model to determine the interplay between its full-length endolysin, Ply2638A, and its SV isoform during phage infection. X-ray crystallography structures and AlphaFold-generated models enabled elucidation of individual functions of the M23 endopeptidase, central amidase, and SH3b domains of Ply2638A. Production of the SV isoform (amidase and SH3b) was confirmed during phage infection and shown to form a heterodimer complex with Ply2638A via inter-amidase domain interactions. Using genetically engineered phage variants, we show that production of both isoforms provides an advantage during phage infection as phages producing only one isoform presented impaired lytic activity, which could be partly restored through recombinant protein complementation of the missing isoform. Importantly, when applied as an antimicrobial protein againstStaphylococcus aureusin culture, the activity of Ply2638A remained constant regardless of SV isoform complementation. Drawing from our findings, we propose that SV isoform production provides its biological advantage upon endolysin entry to the periplasmic space to ensure optimal peptidoglycan degradation prior to cell wall lysis and progeny phage release.
Coordinated social interactions are supported by integrated neural representations
Authors: Formica Silvia , Brass Marcel
Published: January 2024

Joint actions are defined as coordinated interactions of two or more agents towards a shared goal, often requiring different and complementary individual contributions. However, how humans can successfully act together without the interfering effects of observing incongruent movements is still largely unknown. It has been proposed that interpersonal predictive processes are at play to allow the formation of a Dyadic Motor Plan, encompassing both agents’ shares. Yet, direct empirical support for such an integrated motor plan is still limited. In this study, we aimed at testing the properties of these anticipated representations. We collected EEG data while human participants (N = 36; 27 females) drew shapes simultaneously to a virtual partner, in two social contexts: either they had to synchronize and act jointly, or they performed the movements alongside, but independently. We adopted a multivariate approach to show that the social context influenced how the upcoming action of the partner is anticipated during the interval preceding the movement. We found evidence that acting jointly induces an encoding of the partner’s action that is strongly intertwined with the participant’s action, supporting the hypothesis of an integrative motor plan in joint but not in parallel actions.
In-depth characterisation of a selection of gut commensal bacteria reveals their functional capacities to metabolise dietary carbohydrates with prebiotic potential
Authors: Bedu-Ferrari Cassandre , Biscarrat Paul , Pepke Frederic , Vati Sarah , Chaudemanche Cyril , Castelli Florence , Chollet Céline , Rué Olivier , Hennequet-Antier Christelle , Langella Philippe , Cherbuy Claire
Published: January 2024

The microbial utilisation of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex microbial communities, a prebiotic implies the selective utilisation of specific substrate, relying on the metabolic capacities of targeted microbes. In this study, we investigated the metabolic capacities of 17 commensal bacteria of the human gut microbiome toward dietary carbohydrates with prebiotic potential. First,in vitroexperiments allowed the classification of bacterial growth and fermentation profiles in response to various carbon sources, including agave inulin, corn fiber, polydextrose and citrus pectin. The influence of phylogenetic affiliation appeared to statistically outweigh carbon sources in determining the degrees of carbohydrate utilisation. Secondly, we narrowed our focus on six commensal bacteria representative of theBacteroidetesandFirmicutesphyla to perform an untargeted HR-LC/MS metabolomic analysis.Bacteroides xylanisolvens,Bacteroides thetaiotaomicron,Bacteroides intestinalis,Subdoligranulum variabile,Roseburia intestinalisandEubacterium rectaleexhibited distinct metabolomic profiles in response to different carbon sources. The relative abundance of bacterial metabolites was significantly influenced by dietary carbohydrates, with these effects being strain-specific and/or carbohydrate-specific. Particularly, the findings indicated an elevation in short-chain fatty acids and other metabolites, including succinate, gamma-aminobutyric acid, and nicotinic acid. These metabolites were associated with putative health benefits. Finally, an RNA-Seq transcriptomic approach provided deeper insights into the underlying mechanisms of carbohydrate metabolisation. Restricting our focus on four commensal bacteria, includingB. xylanisolvens,B. thetaiotaomicron, S. variabileandR. intestinalis, carbon sources did significantly modulate the level of bacterial genes related to the enzymatic machinery involved in the metabolisation of dietary carbohydrates. This study provides a holistic view of the molecular strategies induced during the dynamic interplay between dietary carbohydrates with prebiotic potential and gut commensal bacteria.
Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer
Authors: Hillis Alissandra L. , Martin Timothy D. , Manchester Haley E. , Hogstrom Jenny M. , Zhang Na , Lecky Emmalyn , Kozlova Nina , Persky Nicole S. , Root David E. , Brown Myles , Cichowski Karen , Elledge Stephen J. , Muranen Taru , Fruman David A. , Barry Simon T. , Clohessy John G. , Madsen Ralitsa R. , Toker Alex
Published: January 2024

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. We identified cholesterol homeostasis as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicityin vitro, in mouse TNBC xenografts and in patient-derived, estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single agent or combination treatment with AKT inhibitor and pitavastatin. This was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. Our work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.
Amygdalo-nigral inputs target dopaminergic and GABAergic neurons in the primate: a view from dendrites and soma
Authors: Fudge JL , Kelly EA , Love TM
Published: January 2024

The central nucleus (CeN) of the amygdala is an important afferent to the DA system that mediates motivated learning. We previously found that CeN terminals in nonhuman primates primarily overlap the elongated lateral VTA (parabrachial pigmented nucleus, PBP, A10), and retrorubral field(A8) subregion. Here, we examined CeN afferent contacts on cell somata and proximal dendrites of DA and GABA neurons, and distal dendrites of each, using confocal and electron microscopy (EM) methods, respectively. At the soma/proximal dendrites, the proportion of TH+ and GAD1+ cells receiving at least one CeN afferent contact was surprisingly similar (TH = 0.55: GAD1=0.55 in PBP; TH = 0.56; GAD1 =0.51 in A8), with the vast majority of contacted TH+ and GAD1+ soma/proximal dendrites received 1-2 contacts. Similar numbers of tracer-labeled terminals also contacted TH-positive and GAD1-positive small dendrites and/or spines (39% of all contacted dendrites were either TH- or GAD1-labeled). Overall, axon terminals had more symmetric (putative inhibitory) axonal contacts with no difference in the relative distribution in the PBP versus A8, or onto TH+ versus GAD1+ dendrites/spines in either region. The striking uniformity in the amygdalonigral projection across the PBP-A8 terminal field suggests that neither neurotransmitter phenotype nor midbrain location dictates likelihood of a terminal contact. We discuss how this afferent uniformity can play out in recently discovered differences in DA:GABA cell densities between the PBP and A8, and affect specific outputs.

Significance statement

The amygdala’s central nucleus (CeN) channels salient cues to influence both appetitive and aversive responses via DA outputs. In higher species, the broad CeN terminal field overlaps the parabrachial pigmented nucleus (‘lateral A10’) and the retrorubral field (A8). We quantified terminal contacts in each region on DA and GABAergic soma/proximal dendrites and small distal dendrites. There was striking uniformity in contacts on DA and GABAergic cells, regardless of soma and dendritic compartment, in both regions. Most contacts were symmetric (putative inhibitory) with little change in the ratio of inhibitory to excitatory contacts by region.

We conclude that post-synaptic shifts in DA-GABA ratios are key to understanding how these relatively uniform inputs can produce diverse effects on outputs.
Gamma protocadherins in vascular endothelial cells inhibit Klf2/4 to promote atherosclerosis
Authors: Joshi Divyesh , Coon Brian G. , Chakraborty Raja , Deng Hanqiang , Fernandez-Tussy Pablo , Meredith Emily , Traylor James G. , Orr Anthony Wayne , Fernandez-Hernando Carlos , Schwartz Martin A.
Published: January 2024

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide1. Laminar shear stress (LSS) from blood flow in straight regions of arteries protects against ASCVD by upregulating the Klf2/4 anti-inflammatory program in endothelial cells (ECs)2–8. Conversely, disturbed shear stress (DSS) at curves or branches predisposes these regions to plaque formation9,10. We previously reported a whole genome CRISPR knockout screen11that identified novel inducers of Klf2/4. Here we report suppressors of Klf2/4 and characterize one candidate, protocadherin gamma A9 (Pcdhga9), a member of the clustered protocadherin gene family12. Pcdhg deletion increases Klf2/4 levels in vitro and in vivo and suppresses inflammatory activation of ECs. Pcdhg suppresses Klf2/4 by inhibiting the Notch pathway via physical interaction of cleaved Notch1 intracellular domain (NICD Val1744) with nuclear Pcdhg C-terminal constant domain (CCD). Pcdhg inhibition by EC knockout (KO) or blocking antibody protects from atherosclerosis. Pcdhg is elevated in the arteries of human atherosclerosis. This study identifies a novel fundamental mechanism of EC resilience and therapeutic target for treating inflammatory vascular disease.
Regularly spaced tyrosines in EBF1 mediate BRG1 recruitment and formation of nuclear subdiffractive clusters
Authors: Zolotarev Nikolay , Wang Yuanting , Du Manyu , Bayer Marc , Grosschedl Anna , Cisse Ibrahim , Grosschedl Rudolf
Published: January 2024

B lineage priming by pioneer transcription factor EBF1 requires the function of an intrinsically disordered region (IDR). Here, we examine the role of regularly spaced tyrosines in the IDR as potential determinants of IDR function and activity of EBF1. We found that four Y > A mutations in EBF1 reduced the formation of condensates in vitro and subdiffractive clusters in vivo. Notably, Y > A mutant EBF1 was inefficient in promoting B cell differentiation and showed impaired chromatin binding, recruitment of BRG1, and activation of specific target genes. Thus, regularly spaced tyrosines in the IDR contribute to the biophysical and functional properties of EBF1.
Enhancement of high-order harmonic generation in graphene by mid-infrared and terahertz fields
Authors: Mao Wenwen , Rubio Angel , Sato Shunsuke A.
Published: January 2024

We theoretically investigate high-order harmonic generation (HHG) in graphene under mid-infrared (MIR) and terahertz (THz) fields based on a quantum master equation. Numerical simulations show that MIR-induced HHG in graphene can be enhanced by a factor of 10 for fifth harmonic and a factor of 25 for seventh harmonic under a THz field with a peak strength of 0.5 MV/cm by optimizing the relative angle between the MIR and THz fields. To identify the origin of this enhancement, we compare the fully dynamical calculations with a simple thermodynamic model and a nonequilibrium population model. The analysis shows that the enhancement of the high-order harmonics mainly results from a coherent coupling between MIR- and THz-induced transitions that goes beyond a simple THz-induced population contribution.

Published by the American Physical Society
2024
Optimized nuclear energy density functionals including long-range pion contributions
Authors: Zurek L. , Bogner S. K. , Furnstahl R. J. , Navarro Pérez R. , Schunck N. , Schwenk A.
Published: January 2024

Nuclear energy density functionals successfully reproduce properties of nuclei across almost the entire nuclear chart. However, nearly all available functionals are phenomenological in nature and lack a rigorous connection to systematically improvable nuclear forces. This issue might be solved with an energy density functional obtained from first principles. As an intermediate step towards this goal we construct the GUDE family of functionals that is obtained from a hybrid scheme consisting of long-range pion-exchange contributions derived from chiral effective field theory at the Hartree-Fock level and a phenomenological Skyrme part. When including pion contributions beyond next-to-leading order in the chiral expansion, we find significant improvements over a reference Skyrme functional constructed following the same protocol. We analyze the importance of different pion contributions and identify which terms drive the observed improvements. Since pions are incorporated without adding further optimization parameters to the functionals, the improvements can be attributed to the functional form of these terms. Our work therefore suggests that the considered chiral contributions constitute useful ingredients for true energy density functionals.

Published by the American Physical Society
2024
Decipher the width of the
X(3872)
via the QCD sum rules
Authors: Wang Zhi-Gang
Published: January 2024

In this work, we take the X(3872) as the hidden-charm tetraquark state with both isospin I=0 and I=1 components, then investigate the strong decays X(3872)→J/ψπ+π−, J/ψω,

χ

c

1

π

0

, D*0D¯0, and D0D¯0π0 with the QCD sum rules. We take account of all the Feynman diagrams, and acquire four QCD sum rules based on rigorous quark-hadron duality. We obtain the total decay width about 1 MeV, which is in excellent agreement with the experiment data ΓX=1.19±0.21  MeV from the PDG, it is the first time to reproduce the tiny width of the X(3872) via the QCD sum rules, which supports assigning the X(3872) as the hidden-charm tetraquark state with the JPC=1++.

Published by the American Physical Society
2024
Broken symmetry and fractionalized flux strings in a staggered
U(1)
pure gauge theory
Authors: Banerjee A. , Banerjee D. , Kanwar G. , Mariani A. , Rindlisbacher T. , Wiese U.-J.
Published: January 2024

Inspired by self-adjoint extensions of the electric field operator in the Hamiltonian formalism, we extend the Wilsonian framework of Abelian lattice gauge theory by introducing a modified action parametrized by an angle α, where the ordinary Wilson theory corresponds to α=0. Choosing instead α=π (the “staggered” case) gives the only other theory in the family which preserves all symmetries of the original model at the microscopic level. We study the case of 3D U(1) pure gauge theory, simulating the staggered case of this model numerically in its dual formulation. We find evidence of a continuum limit with a spontaneously broken Z2 single-site translational symmetry, in contrast to the ordinary theory. Moreover, the confining string fractionalizes into multiple strands which separate spatial regions in distinct ground states of the broken symmetry.

Published by the American Physical Society
2024
Trion Photoluminescence and Trion Stability in Atomically Thin Semiconductors
Authors: Perea-Causin Raul , Brem Samuel , Schmidt Ole , Malic Ermin
Published: January 2024

The optical response of doped monolayer semiconductors is governed by trions, i.e. photoexcited electron-hole pairs bound to doping charges. While their photoluminescence (PL) signatures have been identified in experiments, a microscopic model consistently capturing bright and dark trion peaks is still lacking. In this work, we derive a generalized trion PL formula on a quantum-mechanical footing, considering direct and phonon-assisted recombination mechanisms. We show the trion energy landscape in WSe2 by solving the trion Schrödinger equation. We reveal that the mass imbalance between equal charges results in less stable trions exhibiting a small binding energy and, interestingly, a large energetic offset from exciton peaks in PL spectra. Furthermore, we compute the temperature-dependent PL spectra for n- and p-doped monolayers and predict yet unobserved signatures originating from trions with an electron at the Λ point. Our work presents an important step toward a microscopic understanding of the internal structure of trions determining their stability and optical fingerprint.

Published by the American Physical Society
2024
Experimental characterization of multimode photon-subtracted twin beams
Authors: Thapliyal Kishore , Peřina Jan , Haderka Ondřej , Michálek Václav , Machulka Radek
Published: January 2024

States obtained from multimode twin beams by symmetric as well as asymmetric photon subtraction are experimentally investigated. Using the joint photocount distributions measured by an intensified CCD camera, their joint photon-number distributions are reconstructed. Mean photon numbers, Fano factors, and noise-reduction parameters are determined for the group of states reached by subtracting up to four photocounts in each beam. Photon subtraction is monitored using the nonclassicality depths and joint quasidistributions of integrated intensities of the emerging states. The non-Gaussianity of the obtained states is also determined. The states reached by coherent photon subtraction are also analyzed. The investigations represent an important step towards the use of photon-subtracted twin beams in sub-shot-noise metrology and imaging.

Published by the American Physical Society
2024
Royal Melbourne hospital family violence training framework 2018–2021
Authors: Fisher Caroline A. , Gill Helen , Galbraith Georgina , Sheridan Simone , Morris Emily , Bray Laura , Handley Emma , Withiel Toni D.
Published: January 2024

Family violence is a significant social and public health problem. In 2015 a Royal Commission into Family Violence was established in Victoria, Australia, following a number of family violence deaths that received a high coverage in the media. The commission findings were released in 2016. These emphasised the significant physical and psychological harm that is caused by family violence, and that this has wide ranging community impacts. Among the Commission's 227 recommendations a number pertained specifically to improving the response of the healthcare system, with a whole-of-hospital model for responding to family violence recommend-ed for all public hospitals.

Royal Melbourne Hospital (RMH) received a state government grant as part of the SHRFV project. RMH was formally partnered with Tweddle Child and Family Health Service and Dental Health Services Victoria, and also worked with associated service NorthWestern Mental Health, as part of the project. This document outlines the RMH Family Violence Training Framework, a whole-of-hospital transformation change project designed to implement Recommendation 95 from the Royal Commission. All funded services were encouraged to adapt the SHRFV project model to suit the local environment of their health service. This document outlines the RMH approach. RMH specifically focused on using an evidence based research and evaluation framework with a focus on in-depth training, underpinned by a clinical champions network.
Rethinking buildings. Should buildings simply be enclosures that house different functions?
Authors: Kurul1 Esra , Sibilla Maurizio
Published: January 2024

This document presents BasES, which is a tool kit disseminated as an open educational resource. BasES is focused on the topic of buildings-as-energy services, promoting the knowledge integration to envisage buildings as components of future distributed renewable and interactive energy systems (DRIs). BasES will allow users of exploring and analysing DRIs' emergent properties at the local level, developing, and implementing the tool kit proposed. The specific objective concerns the use of the tool kit in the organisation of a technology support net (TSN) for buildings-as-a-service. TSN is composed of a multitude of actors, who often have different perspectives and scopes, but they are called to work collaboratively in order to establish work rules, requisite skills, work contents, standards and measures, culture and organisational patterns with regard to the emergent systems. Buildings-as-a-service is a completely new topic, and thus, an appropriate TSN is needed urgently. Our tool kit (i.e. Buildings-as-Energy-Services; BasES) will be a ground-breaking cognitive apparatus for involving stakeholders in knowledge transfer and integration processes. Thus, a new generation of product-service systems will be promoted. BasES is expected to configure a multi-stakeholder co-designed UK roadmap on socio-technical innovation in DRIs transition.
Responsible leadership as whole-person learning and organisational development in practice
Authors: Duckenfield Vanessa
Published: January 2024

Putting relationships at the heart of what we do.
Coproduction, public sector innovation and governance: a systematic literature review
Authors: Baretta Julia Viezzer , Hoffmann Micheline Gaia , Militao Luciana , Farias Josivania Silva
Published: January 2024

Purpose

The purpose of this study is examined whether coproduction appears spontaneously in the literature on public sector innovation and governance, the citizens’ role in coproduction and the implication of citizens’ participation in the governance of innovation networks.

Design/methodology/approach

The review complied with preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol. The search was performed in the Ebsco, Scopus and WOS databases. The authors analyzed 47 papers published from 2017 to 2022. Thematic and content analysis were adopted, supported by MAXQDA.

Findings

The papers recognize the importance of the citizens in public innovation. However, only 20% discuss coproduction, evidencing the predominance of governance concepts related to interorganizational collaborations – but not necessarily to citizen engagement. The authors also verified the existence of polysemy regarding the concept of governance associated with public innovation, predominating the term “collaborative governance.”

Research limitations/implications

The small emphasis on “co-production” may result from the search strategy, which deliberately did not include it as a descriptor, considering the research purpose. One can consider this choice a limitation.

Practical implications

Considering collaborative governance as a governing arrangement where public agencies directly engage nonstate stakeholders in a collective decision-making process that is formal, consensus-oriented and deliberative (Ansell and Gash, 2007), the forum where the citizen is supposed to be engaged should be initiated by public agencies or institutions and formally organized, as suggested by Österberg and Qvist (2020) and Campomori and Casula (2022). These notions can be useful for public managers concerning their role and how the forums structure should be to promote collaboration and the presence of innovation assets needed to make the process fruitful (Crosby et al., 2017).

Originality/value

Despite the collaborative nature of public innovation, the need for adequate governance characteristics, and the importance of citizens in the innovative process, most studies generically address collaborative relationships, focusing on interorganizational collaboration, with little focus on specific actors such as citizens in the governance of public innovation. Thus, it is assumed that the literature that discusses public innovation and governance includes the discussion of coproduction. The originality and contribution of this study is to verify this assumption.