bluuebunny/crossref_metadata_2025_split huggingface dataset:
A circuit-based approach to repair hypersexuality in Parkinson’s disease
Authors: Mata-Marín David , Pineda-Pardo José Ángel , Michiels Mario , Pagge Cristina , Ammann Claudia , Martínez-Fernández Raúl , Molina José Antonio , Vela-Desojo Lydia , Alonso-Frech Fernando , Obeso Ignacio 
Published: January 2022

AbstractOne common neuropsychiatric complication in patients with Parkinson’s disease treated with dopamine replacement therapy is impulse control disorders. A proportion of patients under dopamine agonist exhibit excessive desire towards appetitive cues accompanied by lost control over behaviour in forms of pathological gambling, hypersexuality or binge eating. The balance between enhanced desire towards sexual cues and cognitive control changes has been hypothesized to be biased toward the former in individuals with hypersexuality and impulse control disorders. Yet, some studies report no behavioural differences in cognitive control differences between impulsive patients and general Parkinson’s disease, suggesting possible functional changes along the mesocorticolimbic cortico-subcortical circuitry. Here, we provide evidence for this hypothesis by comparing the neurobiological substrate of sexual disturbance over response inhibition associated to medication states in Parkinson’s disease patients with a specific subtype of impulse control disorders (i.e., hypersexuality).We assessed the impact of sexual cues on response inhibition using a novel erotic stop signal task inside an fMRI. A total of 50 participants were included divided in 16 hypersexual and 17 non-hypersexual Parkinson’s disease patients and 17 healthy controls. Task-related activations, functional and anatomical connectivity models were performed. Additionally, a separate sample of 20 hypersexual Parkinson’s disease patients received excitatory neuromodulation (sham-controlled) over the pre-supplementary motor area (based on fMRI group-based results) aiming to improve response inhibition when exposed to sexual cues.Compared with their non-hypersexual peers, medication perturbed response inhibition upon presentation of sexual cues in patients with hypersexuality, recruiting a network involving caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex. Dynamic causal modelling revealed distinct best models to account for cortico-subcortical interactions with reduced task-related inputs in pre-supplementary motor area and descending connectivity to caudate in hypersexual compared to non- hypersexual Parkinson’s disease patients (while medicated). This was sustained by enhanced fractional anisotropy and reduced mean diffusivity in the pre-supplementary motor area-caudate pathway. Importantly, stimulation over the pre-supplementary motor area improved response inhibition when exposed to sexual cues in hypersexual Parkinson’s disease.We identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual behaviours in Parkinson’s disease induced by medication, with recovery options by applying neuromodulation.
Comparison of vaccine effectiveness against the Omicron (B.1.1.529) variant in patients receiving haemodialysis
Authors: Spensley Katrina , Gleeson Sarah , Martin Paul , Thomson Tina , Clarke Candice L. , Pickard Graham , Thomas David , McAdoo Stephen P. , Randell Paul , Kelleher Peter , Bedi Rachna , Lightstone Liz , Prendecki Maria , Willicombe Michelle 
Published: January 2022

AbstractBackgroundEmerging data suggest a reduction in SARS-CoV-2 vaccine effectiveness against Omicron SARS-CoV-2 infection. There is also evidence to show that Omicron is less pathogenic than previous variants. For clinically vulnerable populations, a less pathogenic variant may still have significant impact on morbidity and mortality. Herein we assess the clinical impact of Omicron infection, and vaccine effectiveness, in an in-centre haemodialysis (IC-HD) population.MethodsOne thousand, one hundred and twenty-one IC-HD patients were included in the analysis, all patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between 1st December 2021 and 16th January 2022. Screening for infection via weekly RT-PCR testing and 3-monthly serological assessment started prior to the vaccine roll out in 2020.ResultsOmicron infection was diagnosed in 145/1121 (12.9%) patients over the study period, equating to an infection rate of 3.1 per 1000 patient days. Vaccine effectiveness (VE) against Omicron infection in patients who had received a booster vaccine was 58 (23-75)%, p=0.002; VE was seen in patients who received either ChAdOx1, VE of 47(2-70)%, p=0.034, or BNT162b2, VE of 66 (36-81)%, p=0.0005, as their first two doses. No protection against infection was seen in patients who were partially vaccinated (2-doses), p=0.83. Prior infection was associated with reduced likelihood of Omicron infection, HR 0.69 (0.50-0.96), p=0.0289. Four (2.8%) patients died within 28 days of infection diagnosis, with no excess mortality was seen in patients with infection.Conclusion3-doses of SARS-CoV-2 vaccines are required in ICHD to provide protection against Omicron infection.
Live biotherapeutic throat spray for respiratory virus inhibition and interferon pathway induction
Authors: Spacova Irina , De Boeck Ilke , Cauwenberghs Eline , Delanghe Lize , Bron Peter A. , Henkens Tim , Simons Alix , Gamgami Imane , Persoons Leentje , Claes Ingmar , van den Broek Marianne F. L. , Schols Dominique , Delputte Peter , Coenen Samuel , Verhoeven Veronique , Lebeer Sarah 
Published: January 2022

AbstractRespiratory viruses such as influenza viruses, respiratory syncytial virus (RSV), and coronaviruses initiate infection at the mucosal surfaces of the upper respiratory tract (URT), where the resident respiratory microbiome has an important gatekeeper function. In contrast to gut-targeting administration of beneficial bacteria against respiratory viral disease, topical URT administration of probiotics is currently underexplored, especially for the prevention and/or treatment of viral infections. Here, we report the selection and formulation of a broad-acting throat spray with live lactobacilli which induce interferon regulatory pathways and are able to inhibit respiratory viruses. Rational selection of Lactobacillaceae strains was based on safety, applicability, and potential antiviral and immunostimulatory efficacy in the URT. Three strains, Lacticaseibacillus casei AMBR2, Lacticaseibacillus rhamnosus GG and Lactiplantibacillus plantarum WCFS1 significantly reduced the cytopathogenic effects of RSV, influenza A/H1N1 and B viruses, and HCoV-229E coronavirus in co-culture models with bacteria, virus and host cells. Subsequently, these strains were formulated in a throat spray and human monocytes were employed to confirm the formulation process did not reduce the interferon regulatory pathway-inducing capacity. Administration of the throat spray in healthy volunteers revealed that the lactobacilli were capable of temporary colonization of the throat in a metabolically active form.
Impacts of development and adult sex on brain cell numbers in the Black Soldier Fly, Hermetia illucens L. (Diptera: Stratiomyidae)
Authors: Barrett Meghan , Godfrey R. Keating , Sterner Emily J. , Waddell Edward A. 
Published: January 2022

AbstractThe Black Soldier Fly (Hermetia illucens, Diptera: Stratiomyidae) has been introduced across the globe, with numerous industry applications predicated on its tremendous growth during the larval stage. However, basic research onH. illucensbiology (for example, studies of their central nervous system) are lacking. Despite their small brain volumes, insects are capable of complex behaviors; understanding how these behaviors are completed with such a small amount of neural tissue requires understanding processing power (e.g. number of cells) within the brain. Brain cell counts have been completed in only a few insect species (mostly Hymenoptera), and almost exclusively in adults. This limits the taxonomic breadth of comparative analyses, as well as any conclusions about how development and body size growth may impact brain cell populations. Here, we present the first images and cell counts of theH. illucensbrain at four time points across development (early, mid, and late larval stages, and both male and female adults) using immunohistochemistry and isotropic fractionation. To assess sexual dimorphism in adults, we quantified the number of cells in the central brain vs. optic lobes of males and females separately. To assess if increases in body size during development might independently affect different regions of the CNS, we quantified the larval ventral nerve cord and central brain separately at all three stages. Together, these data provide the first description of the nervous system of a popular, farmed invertebrate and the first study of brain cell numbers using IF across developmental stages in any insect.
Verification of extracellular vesicle-mediated functional mRNA delivery via RNA editing
Authors: Somiya Masaharu , Kuroda Shun’ichi 
Published: January 2022

ABSTRACTThe secretion and delivery of mRNA by extracellular vesicles (EVs) may contribute to intercellular communications. Several reporter assays have been developed to quantify EV-mediated functional delivery of mRNA into recipient cells. However, mRNA delivery efficiency can often be overestimated by experimental artifacts, resulting in “pseudo-delivery” of reporter proteins rather than mRNA. In this study, we revealed that substantial amounts of reporter proteins expressed in donor cells are secreted into the medium and interfere with the reporter assay. To eliminate this pseudo-delivery, we established a functional RNA delivery assay that employs an RNA editing tool, enabling the verification of bona fide delivery of mRNA into recipient cells. The donor cells expressed a reporter gene containing a stop codon in a non-functional open reading frame. After EV-mediated delivery of reporter mRNAs to the recipient cells, guide RNAs and RNA editing enzymes (dCas13b-hADAR2 fusion proteins) correct the RNA sequence and induce the expression of functional reporter proteins in the recipient cells. Using this system, we showed that EVs containing alphavirus-derived replicon successfully delivered functional RNA and expressed the reporter proteins. The RNA delivery assay using RNA editing enables the precise analysis of EV-mediated mRNA delivery.
Structural insight into antibody evasion of SARS-CoV-2 omicron variant
Authors: Verma Jyoti , Subbarao Naidu 
Published: January 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to mutate and evolve with the emergence of omicron (B.1.1.529) as the new variant of concern. The rapid spread of this variant regionally and globally could be an allusion to increased infectivity, transmissibility, and antibody resistance. The omicron variant has a large set of mutations in its spike protein, specifically in the receptor binding domain (RBD), reflecting their significance in ACE2 interaction and antibody recognition. We have carried out the present study to understand how these mutations structurally impact the binding of the antibodies to their target epitope. We have computationally evaluated the binding of different classes of RBD targeted antibodies, namely, CB6 (etesevimab), REGN10933 (casirivimab), S309 (sotrovimab), and S2X259 to the omicron mutation-induced RBD. Molecular dynamics simulations and binding free energy calculations unveil the binding affinity and stability of the antibody-RBD complexes. All the four antibodies show reduced binding affinity towards the omicron RBD. The therapeutic antibody CB6 aka etesevimab was substantially affected due to numerous omicron mutations occurring in its target epitope. This study provides a structural insight into the reduced efficacy of RBD targeting antibodies against the SARS-CoV-2 omicron variant.
Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer’s disease
Authors: Martinsson I , Quintino L , Garcia MG , Konings SC , Torres-Garcia L , Svanbergson A , Stange O , England R , Deierborg T , Li JY , Lundberg C , Gouras GK 
Published: January 2022

AbstractThe proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimer’s disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (Aβ) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and Aβ-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and Aβ. To examine the individual roles of APP and Aβ in promoting hyperexcitability we used an APP construct that does not generate Aβ, or elevated Aβ levels independently of APP. Increasing either APP or Aβ in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we present evidence that both APP and Aβ influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.
Reduced inflammatory response and promoted multiciliated cell differentiation in mice protected by defective interfering influenza virus
Authors: Wang Chang , Honce Rebekah , Salvatore Mirella , Yang Jianjun , Twells Nicholas M. , Mahal Lara K. , Schultz-Cherry Stacey , Ghedin Elodie 
Published: January 2022

ABSTRACTInfluenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent viruses and to induce antiviral immunity. However, the mechanisms underlying DI-mediated antiviral immunity have not been extensively explored. Here, we demonstrated interferon (IFN) independent protection conferred by influenza DI virus against homologous virus infection in mice deficient in type I and III IFN signaling. By integrating transcriptional and post-transcriptional regulatory data we identified unique host signatures in response to DI co-infection. DI-treated mice exhibited reduced viral transcription, less intense inflammatory and innate immune responses, and primed multiciliated cell differentiation in their lungs at an early stage of infection, even in the absence of type I or III IFNs. Overall, our study provides mechanistic insight into the protection mediated by DIs, implying a unifying theme involving inflammation and multiciliogenesis in maintaining respiratory homeostasis, and reveals their IFN-independent antiviral activity.
The endoplasmic reticulum membrane protein complex (EMC) negatively regulates intestinal homeostasis through the Hippo signaling pathway
Authors: Shi Lin , Ma Hubing , Zhao Hang , Ma Meifang , Wang Jinjun , Kong Ruiyan , Li Zhengran , Ma Rui , Wang Jian-Hua , Wu Shian , Dong Meng-qiu , Li Zhouhua 
Published: January 2022

AbstractDisruption of tissue homeostasis often results in many diseases. Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological conditions remains not fully understood. Here, we find that the endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation in adultDrosophilamidgut. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC complex associates with and stabilizes Hippo (Hpo), the key component of the Hpo signaling pathway. In the absence of the EMC complex, Yki (Yorkie) is activated to promote ISC proliferation. Furthermore, the role of the EMC complex in stem cell proliferation control is evolutionarily conserved. Thus, our study uncovers the molecular mechanism of the EMC complex in controlling stem cell proliferation. Our results provide new insight into the underlying mechanisms of how stem cell proliferation is properly controlled under physiological conditions.
Whole-brain in vivo base editing reverses autistic-like behaviors in mice
Authors: Li Weike , Chen Jinlong , Peng Wanling , Yuan Bo , Han Wenjian , Yuan Yiting , Xue Zhenyu , Wang Jincheng , Chen Zhifang , Shan Shifang , Zhu Shujia , Xu Min , Cheng Tianlin , Qiu Zilong 
Published: January 2022

AbstractAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder associated with deficits in social communication and stereotypical behaviors. Numerous ASD-related genetic mutations have been identified and genome editing methods have been developed but successful genome editing in the whole-brain scale to alleviate autistic-like behaviors in animal models has not been achieved. Here we report the development of a new CRISPR-mediated cytidine base editor (CBE) system, which converts C·G base pairs to T·A. We demonstrate the effectiveness of this system by targeting an ASD-associated de novo mutation in the MEF2C gene (c.104T>C, p.L35P). We constructed a Mef2c L35P knock-in mouse and observed that Mef2c L35P heterozygous mice displayed autistic-like behaviors, including deficits in social behaviors and repetitive behaviors. We programmed the CBE to edit the C·G base pairs of the mutated Mef2c gene (c.104T>C, p.L35P) to T·A base pairs and delivered it via a single dose intravenous injection of blood brain barrier (BBB)-crossing AAV-PHP.eB vector into the mouse brain. This treatment restored MEF2C protein levels and reversed impairments in social interactions and repetitive behaviors in Mef2c L35P heterozygous mice. Together, this work presents an in vivo gene editing strategy in which correcting a single nucleotide mutation in the whole-brain scale could be successfully achieved, further providing a new therapeutic framework for neurodevelopmental disorders.
Replicative Aging Remodels Cell Wall and is Associated with Increased Intracellular Trafficking in Human Pathogenic Yeasts
Authors: Silva Vanessa K.A. , Bhattacharya Somanon , Oliveira Natalia Kronbauer , Savitt Anne G. , Zamith-Miranda Daniel , Nosanchuk Joshua D. , Fries Bettina C. 
Published: January 2022

ABSTRACTReplicative aging is an underexplored field of research in medical mycology.Cryptococcus neoformans(Cn) andCandida glabrata(Cg) are dreaded fungal pathogens that cause fatal invasive infections. The fungal cell wall is essential for yeast viability and pathogenesis. In this study, we provide data characterizing age-associated modifications to the cell wall ofCnandCg. Here, we report that old yeast cells upregulate genes of cell wall biosynthesis, leading to cell wall reorganization, and increased levels of all major components, including glucan, chitin and its derivatives, as well as mannan. This results in a significant thickening of the cell wall in aged cells. Old generation yeast cells exhibited drastic ultrastructural changes, including the presence of abundant vesicle-like particles in the cytoplasm, and enlarged vacuoles with altered pH homeostasis. Our findings suggest that the cell wall modifications could be enabled by augmented intracellular trafficking. This work furthers our understanding of the cell phenotype that emerges during aging. It highlights differences in these two fungal pathogens and elucidates mechanisms that explain the enhanced resistance of old cells to antifungals and phagocytic attacks.IMPORTANCECryptococcus neoformansandCandida glabrataare two opportunistic human fungal pathogens that cause life-threatening diseases. During infection, both microorganisms have the ability to persist for long periods, and treatment failure can occur even if standard testing identifies the yeasts to be sensitive to antifungals. Replicative lifespan is a trait that is measured by the number of divisions a cell undergoes before death. Aging in fungi is associated with enhanced tolerance to antifungals and resistance to phagocytosis, and characterization of old cells may help identify novel antifungal targets. The cell wall remains an attractive target for new therapies because it is essential for fungi and is not present in humans. This study shows that the organization of the fungal cell wall changes remarkably during aging and becomes thicker and is associated with increased intracellular trafficking as well as the alteration of vacuole morphology and pH homeostasis.
Biogenesis and Function of c-type Cytochromes in the Methanogenic Archaeon, Methanosarcina acetivorans
Authors: Gupta Dinesh , Shalvarjian Katie E. , Nayak Dipti D. 
Published: January 2022

AbstractC-type cytochromes (cyt c) are proteins that covalently bind heme and are integral to electron transport chains. A growing body of evidence suggests that cyt c play a vital role in both intra- and extra-cellular electron transfer processes in Archaea, especially in members that metabolize methane and other short chain alkanes. Elaborate mechanisms for the biogenesis of cyt c are known in Bacteria and Eukarya but this process remains largely uncharacterized in Archaea. Here, we have used the model methanogenic archaeon Methanosarcina acetivorans to characterize a distinct form of the system I cyt c maturation machinery (referred to as the Ccm machinery henceforth) that is broadly distributed in members of the Archaea. Phenotypic analyses of M. acetivorans mutants deficient in essential components of the Ccm machinery reveal that cyt c are broadly important for growth and methanogenesis, but the magnitude of their impact can vary substantially depending on the growth substrate. Heterologous expression of a synthetic operon with the Ccm machinery (CcmABCEF) from M. acetivorans is both necessary and sufficient for cyt c biogenesis in a non-native host (M. barkeri Fusaro) that is incapable of cyt c biogenesis. Even though components of the Ccm machinery are universally conserved across the Archaea, our evolutionary analyses indicate that different clades of Archaea acquired this pathway through multiple independent horizontal gene transfer events from different groups of Bacteria. Overall, we have demonstrated the convergent evolution of a novel Archaea-specific Ccm machinery for cyt c biogenesis and its role in methane metabolism.Significance StatementMicroorganisms belonging to the domain Archaea play an especially important role in regulating atmospheric methane levels. Specifically, methanogens are the primary source of biogenic methane and anaerobic methanotrophic archaea (ANME) consume a substantial proportion of methane released in marine sediments. Genomic studies have implicated a class of electron-transfer proteins called c-type cytochromes as being crucial in mediating archaeal methane metabolism in the environment. However, neither the biogenesis nor the role of c-type cytochromes in methane metabolism has ever been investigated. Here, we have used a model methanogen, Methanosarcina acetivorans, to characterize a distinct pathway for maturation of c-type cytochromes that seems to be uniformly conserved across the Archaea and have also identified substrate-specific functional roles for c-type cytochromes during methanogenesis.