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BioRxiv : the Preprint Server For... Apr 2024Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as...
Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in an system permissive to infection only in the presence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, both of which have known functions in regulated secretion. Using genetic knockout and -complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that are required for ADE of DENV infection. Our findings represent a first step towards advancing fundamental knowledge behind the biology of ADE that can ultimately be exploited to inform vaccination and therapeutic approaches.
PubMed: 38712102
DOI: 10.1101/2024.04.26.591029 -
Cureus Apr 2024Purpose Proximal humeral fractures (PHF) are common, particularly among the elderly due to low-energy trauma. Adequate rehabilitation is essential for functional...
Purpose Proximal humeral fractures (PHF) are common, particularly among the elderly due to low-energy trauma. Adequate rehabilitation is essential for functional recovery, whether through conservative or surgical treatment. Permissive weight bearing (PWB) is a relatively new rehabilitation concept, characterized by earlier mobilization of the affected limb/joint after trauma. Multiple studies demonstrated the value of PWB for the lower extremities, but this has not been translated to the upper extremity (i.e. PHF). Therefore, our aim was to investigate the current state and variability of rehabilitation of PHF and the role of implementing PWB principles in aftercare. Materials and methods An online survey, comprising 23 questions about the treatment of PHF, was distributed amongst an estimated 800 Dutch orthopaedic and trauma surgeons via the Dutch Orthopaedic and Dutch Trauma Society newsletter from May 2021 until July 2021. Results Among 88 respondents (n=69 orthopaedic, n=17 trauma surgeons, and n=2 other), most recommended early post-trauma mobilization (<6 weeks). Additionally, 53.4% (n=49) advised starting load bearing after six weeks for conservatively treated patients and 59.8% (n=52) for operative treatment. A wide variation of exercises used after immobilization was found in both groups. The usage of a sling after operative treatment was advised by 86% (n=74) of all 86 respondents. Conclusions The present study found limited consensus about PHF aftercare and the implementation of weight-bearing principles. The majority recommended early mobilization and advised the usage of a sling. A protocol capable of accommodating the diversity in aftercare (e.g. fracture type) is essential for maintaining structured rehabilitation, with PWB emerging as a promising example. More prospective studies are needed to form an evidence-based protocol focusing on the aftercare of PHF.
PubMed: 38707136
DOI: 10.7759/cureus.57670 -
PLoS Pathogens May 2024Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic...
Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.
Topics: Lysosomes; Mycobacterium tuberculosis; Animals; Monocytes; Mice; Macrophages, Alveolar; Lung; Mice, Inbred C57BL; Chronic Disease; Tuberculosis, Pulmonary; Humans; Tuberculosis; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
PubMed: 38701094
DOI: 10.1371/journal.ppat.1012205 -
PLoS Pathogens May 2024Noroviruses (NoVs) are a leading cause of viral gastroenteritis. Despite global clinical relevance, our understanding of how host factors, such as antiviral cytokines...
Noroviruses (NoVs) are a leading cause of viral gastroenteritis. Despite global clinical relevance, our understanding of how host factors, such as antiviral cytokines interferons (IFNs), modulate NoV population dynamics is limited. Murine NoV (MNoV) is a tractable in vivo model for the study of host regulation of NoV. A persistent strain of MNoV, CR6, establishes a reservoir in intestinal tuft cells for chronic viral shedding in stool. However, the influence of host innate immunity and permissive cell numbers on viral population dynamics is an open question. We generated a pool of 20 different barcoded viruses (CR6BC) by inserting 6-nucleotide barcodes at the 3' position of the NS4 gene and used this pool as our viral inoculum for in vivo infections of different mouse lines. We found that over the course of persistent CR6 infection, shed virus was predominantly colon-derived, and viral barcode richness decreased over time irrespective of host immune status, suggesting that persistent infection involves a series of reinfection events. In mice lacking the IFN-λ receptor, intestinal barcode richness was enhanced, correlating with increased viral intestinal replication. IL-4 treatment, which increases tuft cell numbers, also increased barcode richness, indicating the abundance of permissive tuft cells to be a bottleneck during CR6 infection. In mice lacking type I IFN signaling (Ifnar1-/-) or all IFN signaling (Stat1-/-), barcode diversity at extraintestinal sites was dramatically increased, implicating different IFNs as critical bottlenecks at specific tissue sites. Of interest, extraintestinal barcodes were overlapping but distinct from intestinal barcodes, indicating that disseminated virus represents a distinct viral population than that replicating in the intestine. Barcoded viruses are a valuable tool to explore the influence of host factors on viral diversity in the context of establishment and maintenance of infection as well as dissemination and have provided important insights into how NoV infection proceeds in immunocompetent and immunocompromised hosts.
Topics: Animals; Norovirus; Caliciviridae Infections; Mice; Interferons; Persistent Infection; Mice, Inbred C57BL; Intestinal Mucosa; Gastroenteritis; Virus Replication; Mice, Knockout; Immunity, Innate; Virus Shedding
PubMed: 38701091
DOI: 10.1371/journal.ppat.1011961 -
Systematic Parasitology May 2024A synopsis of Ortholinea Shulman, 1962 (Cnidaria: Myxosporea: Ortholineidae) is presented and identifies 26 nominal species presently allocated within this genus....
A synopsis of Ortholinea Shulman, 1962 (Cnidaria: Myxosporea: Ortholineidae) is presented and identifies 26 nominal species presently allocated within this genus. Species morphological and morphometric features, tissue tropism, type-host, and type-locality are provided from original descriptions. Data from subsequent redescriptions and reports is also given. Accession numbers to sequences deposited in GenBank are indicated when available, and the myxospores were redrawn based on original descriptions. The information gathered shows that Ortholinea infect a wide taxonomic variety of freshwater and marine fish. Nonetheless, the broad host specificity reported for several species is not fully supported by morphological descriptions and requires molecular corroboration. The members of this genus are coelozoic and mainly parasitize the urinary system, with few species occurring in the gallbladder. Ortholinea visakhapatnamensis is the only exception, being histozoic in the visceral peritoneum. Molecular data of the small subunit ribosomal RNA gene (SSU rDNA) is available for about one third of Ortholinea species, with genetic interspecific variation ranging between 1.65% and 29.1%. Phylogenetic analyses reveal Ortholinea to be polyphyletic, with available SSU rDNA sequences clustering within the subclades of the highly heterogenous freshwater urinary clade of the oligochaete-infecting lineage. The life cycles of two Ortholinea species have been clarified based on molecular inferences and identify triactinomyxon actinospores as counterparts, and marine oligochaetes of the family Naididae as permissive hosts to this genus.
Topics: Animals; Myxozoa; Species Specificity; Phylogeny; Host Specificity; Fishes; DNA, Ribosomal
PubMed: 38700664
DOI: 10.1007/s11230-024-10155-2 -
Research Square Apr 2024Adolescents increasingly view cannabis as a substance with limited harm. Their propensity to engage in risky driving, combined with their relative driving inexperience,...
BACKGROUND
Adolescents increasingly view cannabis as a substance with limited harm. Their propensity to engage in risky driving, combined with their relative driving inexperience, places adolescents at heightened risk for harm resulting from impaired driving. Driver education provides an opportunity to help prevent and reduce these risks, yet few interventions address cannabis-impaired driving, especially impairment from simultaneous use of both cannabis and alcohol.
METHODS
We adapted a single-session primary care brief intervention (CHAT) for driver education programs. First, we conducted two focus groups with adolescents aged 15-17 years (n = 6; n = 5) enrolled in driver education programs. Their feedback was integrated into a prototype of an online intervention called webCHAT that focuses on preventing alcohol and cannabis-impaired driving. Next, we recruited a new sample of adolescents who user tested webCHAT (n = 8) and provided qualitative and survey feedback. We analyzed qualitative data using classic content analysis and grouped themes according to the feasibility and acceptability of webCHAT.
RESULTS
Participants suggested that webCHAT should have adolescent narrators in short, informal, and interactive videos. In satisfaction surveys (n = 8), 88% of participants would recommend webCHAT to a friend and 88% reported that they learned helpful skills regarding impaired driving. General acceptability was also reflected in interviews (n = 6; 100% would recommend the intervention to a friend, 100% indicated overall positive impressions, and 67% stated it was easy to use). Participants reported that it was helpful to learn about the negative effects of both cannabis and alcohol on driving behavior, voicing that webCHAT would help adolescents make more informed decisions.
CONCLUSIONS
Soliciting adolescent perspectives is critical when developing interventions targeting cannabis use because of increasingly permissive attitudes and perceptions of minimal risk associated with use. The current study highlights how feedback can help increase both the feasibility and acceptability of interventions.
PubMed: 38699323
DOI: 10.21203/rs.3.rs-4249553/v1 -
Iranian Journal of Public Health Jan 2024Various factors are involved in the initiation of drug abuse, such as genetic and social factors. Among the factors that can be mentioned in associated with the tendency... (Review)
Review
BACKGROUND
Various factors are involved in the initiation of drug abuse, such as genetic and social factors. Among the factors that can be mentioned in associated with the tendency to addiction in children is the role of family prediction. This study aimed to explore the relationship between parenting styles and addiction tendency in Iran.
METHODS
We searched Persian database included Magiran, SID, IranDoc and Noormagz for articles from 2007- 2022 in Iran. Seven articles with 1734 subjects were ultimately included in the qualitative and quantitative syntheses. Five subscales (parenting method) were brought up for investigation of the relationship between parenting styles and addiction tendency. The pooled odds ratio (OR) and its 95% confidence interval (CI) were calculated for each associated factors using random-effects/fixed-effects models. Publication bias was assessed using funnel plot and the Eggers test and each effect size was calculated manually.
RESULTS
Based on Cohen's interpretation criterion are as follow: the mean effect size of the relationship with the permissive style is 0.33 (average), the mean effect size of the relationship with authoritative style is 0.31 (average), the mean effect size of the relationship with the dependent style is 0.28 (average), the mean effect size of the relationship with the freedom-control is - 0.02 (small), the mean effect size of the relationship with the method based on affection-rejection is 0.33 (moderate).
CONCLUSION
Parenting styles have a significant relationship with addiction tendencies in Iran. Therefore, appropriate programs can be provided to strengthen and educate the correct and suitable parenting methods with their children as safe as possible in order to avoid risky behaviors and injuries such as addiction.
PubMed: 38694850
DOI: 10.18502/ijph.v53i1.14684 -
Regenerative Therapy Dec 2024Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches...
Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.
PubMed: 38694448
DOI: 10.1016/j.reth.2024.04.002 -
Nature May 2024Sleep is a nearly universal behaviour with unclear functions. The synaptic homeostasis hypothesis proposes that sleep is required to renormalize the increases in...
Sleep is a nearly universal behaviour with unclear functions. The synaptic homeostasis hypothesis proposes that sleep is required to renormalize the increases in synaptic number and strength that occur during wakefulness. Some studies examining either large neuronal populations or small patches of dendrites have found evidence consistent with the synaptic homeostasis hypothesis, but whether sleep merely functions as a permissive state or actively promotes synaptic downregulation at the scale of whole neurons is unclear. Here, by repeatedly imaging all excitatory synapses on single neurons across sleep-wake states of zebrafish larvae, we show that synapses are gained during periods of wake (either spontaneous or forced) and lost during sleep in a neuron-subtype-dependent manner. However, synapse loss is greatest during sleep associated with high sleep pressure after prolonged wakefulness, and lowest in the latter half of an undisrupted night. Conversely, sleep induced pharmacologically during periods of low sleep pressure is insufficient to trigger synapse loss unless adenosine levels are boosted while noradrenergic tone is inhibited. We conclude that sleep-dependent synapse loss is regulated by sleep pressure at the level of the single neuron and that not all sleep periods are equally capable of fulfilling the functions of synaptic homeostasis.
Topics: Animals; Adenosine; Homeostasis; Larva; Models, Neurological; Neurons; Single-Cell Analysis; Sleep; Synapses; Wakefulness; Zebrafish; Norepinephrine
PubMed: 38693264
DOI: 10.1038/s41586-024-07367-3 -
Cell Death & Disease Apr 2024Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's...
Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.
Topics: alpha-Synuclein; Animals; Humans; Caenorhabditis elegans; Wiskott-Aldrich Syndrome Protein, Neuronal; Actins; Parkinson Disease; Synapsins; Caenorhabditis elegans Proteins
PubMed: 38693139
DOI: 10.1038/s41419-024-06686-7