Project description:In recent years, the study of mammalian acrosomal exocytosis has produced some major advances that challenge the long-held, general paradigms in the field. Principally, the idea that sperm must be acrosome-intact to bind to the zona pellucida of unfertilized eggs, based largely on in vitro fertilization studies of mouse oocytes denuded of the cumulus oophorus, has been overturned by experiments using state-of-the-art imaging of cumulus-intact oocytes and fertilization experiments where eggs were reinseminated by acrosome-reacted sperm recovered from the perivitelline space of zygotes. In light of these results, this minireview highlights a number of unresolved questions and emphasizes the fact that there is still much work to be done in this exciting field. Future experiments using recently advanced technologies should lead to a more complete and accurate understanding of the molecular mechanisms governing the fertilization process in mammals.
Project description:The dominant hypothesis of Alzheimer's disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.
Project description:Impact statementEarly availability of the sequence, the genetic material of SARS-CoV-2 (the virus that causes COVID-19), has prompted efforts towards identifying a safe and effective vaccine in the current public health emergency. To that end, understanding the pathophysiology of disease is crucial for scientists around the world. Since conventional vaccine development and manufacturing may take several years, it is important to think about alternative strategies that we could use to mitigate imminent catastrophe. We hope that this article will open up new avenues and provide insights that could potentially save hundreds of lives affected by COVID-19.
Project description:The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide. Recent evidence raised the question about the possibility that cats may be a domestic host for SARS-CoV-2 with unknown implications in disease dissemination. Based on the fact that the domestic cat flea, Ctenocephalides felis, are abundant ectoparasites infesting humans, companion animals and wildlife and that coronavirus-like agents have been identified in the ectoparasite tick vector, Ixodes uriae of seabirds, herein we considered the presence of coronaviruses in general and SARS-CoV-2 in particular in C. felis. We identified coronavirus-derived and cell receptor angiotensin-converting enzyme RNA/proteins in C. felis. Although current evidence suggests that pets are probably dead-end-hosts with small risk of transmission to humans, our results suggested that cat flea may act as biological and/or mechanical vectors of SARS-CoV. Although preliminary, these results indicate a possibility of ectoparasites acting as reservoirs and vectors of SARS-CoV and related beta-coronavirus although with little disease risk due to systemic transmission route, low viremia, virus attenuation or other unknown factors. These results support the need to further study the role of animal SARS-CoV-2 hosts and their ectoparasite vectors in COVID-19 disease spread.
Project description:The RBR (RING-BetweenRING-RING) or TRIAD [two RING fingers and a DRIL (double RING finger linked)] E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. This unique family of E3 ligases includes parkin, whose dysfunction is linked to the pathogenesis of early-onset Parkinson's disease, and HOIP (HOIL-1-interacting protein) and HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), members of the LUBAC (linear ubiquitin chain assembly complex). The RBR E3 ligases share common features with both the larger RING and HECT (homologous with E6-associated protein C-terminus) E3 ligase families, directly catalysing ubiquitin transfer from an intrinsic catalytic cysteine housed in the C-terminal domain, as well as recruiting thioester-bound E2 enzymes via a RING domain. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-for-catalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity. The present review discusses how three-dimensional structures of RBR (RING1-BRcat-Rcat) E3 ligases have provided new insights into our understanding of the biochemical mechanisms of these important enzymes in ubiquitin biology.
Project description:Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.
Project description:BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) represents a current threat to the Arabian Peninsula, and potential pandemic disease. As of June 3, 2014, MERS CoV has reportedly infected 688 people and killed 282. We briefly summarize the state of the outbreak, and highlight unanswered questions and various explanations for the observed epidemiology. FINDINGS: The continuing but infrequent cases of MERS-CoV reported over the past two years have been puzzling and difficult to explain. The epidemiology of MERS-CoV, with many sporadic cases and a few hospital outbreaks, yet no sustained epidemic, suggests a low reproductive number. Furthermore, a clear source of infection to humans remains unknown. Also puzzling is the fact that MERS-CoV has been present in Saudi Arabia over several mass gatherings, including the 2012 and 2013 Hajj and Umrah pilgrimages, which predispose to epidemics, without an epidemic arising. CONCLUSIONS: The observed epidemiology of MERS-CoV is quite distinct and does not clearly fit either a sporadic or epidemic pattern. Possible explanations of the unusual features of the epidemiology of MERS-CoV include sporadic ongoing infections from a non-human source; human to human transmission with a large proportion of undetected cases; or a combination of both. The virus has been identified in camels; however the mode of transmission of the virus to humans remains unknown, and many cases have no history of animal contact. In order to gain a better understanding of the epidemiology of MERS CoV, further investigation is warranted.
Project description:Haematopoietic stem cell (HSC) niches provide an environment essential for life-long HSC function. Intense investigation of HSC niches both feed off and drive technology development to increase our capability to assay functionally defined cells with high resolution. A major driving force behind the desire to understand the basic biology of HSC niches is the clear implications for clinical therapies. Here, with particular emphasis on cell type-specific deletion of SCL and CXCL12, we focus on unresolved issues on HSC niches, framed around some very recent advances and novel discoveries on the extrinsic regulation of HSC maintenance. We also provide ideas for possible paths forward, some of which are clearly within reach while others will require both novel tools and vision.
Project description:Background We describe the rationale and study design for " TRU sted r Esidents and H ousing A ssistance to decrease V iolence E xposure in N ew Haven (TRUE HAVEN)," a prospective type 1 hybrid effectiveness/implementation study of a multi-level intervention using a stepped wedge design. TRUE HAVEN aims to lower rates of community gun violence by fostering the stability, wealth, and well-being of individuals and families directly impacted by incarceration through the provision of stable housing and by breaking the cycle of trauma. Design: TRUE HAVEN is a multi-level intervention with three primary components: financial education paired with housing support (individual level), trauma-informed counseling (neighborhood level), and policy changes to address structural racism (city/state level). Six neighborhoods with among the highest rates of gun violence in New Haven, Connecticut, will receive the individual and neighborhood level intervention components sequentially beginning at staggered 6-month steps. Residents of these neighborhoods will be eligible to participate in the housing stability and financial education component if they were recently incarcerated or are family members of currently incarcerated people; participants will receive intense financial education and follow-up for six months and be eligible for special down payment and rental assistance programs. In addition, trusted community members and organization leaders within each target neighborhood will participate in trauma-informed care training sessions to then be able to recognize when their peers are suffering from trauma symptoms, to support these affected peers, and to destigmatize accessing professional mental health services and connect them to these services when needed. Finally, a multi-stakeholder coalition will be convened to address policies that act as barriers to housing stability or accessing mental healthcare. Interventions will be delivered through existing partnerships with community-based organizations and networks. The primary outcome is neighborhood rate of incident gun violence. To inform future implementation and optimize the intervention package as the study progresses, we will use the Learn As You Go approach to optimize and assess the effectiveness of the intervention package on the primary study outcome. Discussion Results from this protocol will yield novel evidence for whether and how addressing structural racism citywide leads to a reduction in gun violence. Trial registration ClinicalTrials.gov Identifier: NCT05723614. Registration date: February 01, 2023.
Project description:BackgroundWe describe the rationale and study design for "TRUsted rEsidents and Housing Assistance to decrease Violence Exposure in New Haven (TRUE HAVEN)," a prospective type 1 hybrid effectiveness/implementation study of a multi-level intervention using a stepped wedge design. TRUE HAVEN aims to lower rates of community gun violence by fostering the stability, wealth, and well-being of individuals and families directly impacted by incarceration through the provision of stable housing and by breaking the cycle of trauma.DesignTRUE HAVEN is an ongoing, multi-level intervention with three primary components: financial education paired with housing support (individual level), trauma-informed counseling (neighborhood level), and policy changes to address structural racism (city/state level). Six neighborhoods with among the highest rates of gun violence in New Haven, Connecticut, will receive the individual and neighborhood level intervention components sequentially beginning at staggered 6-month steps. Residents of these neighborhoods will be eligible to participate in the housing stability and financial education component if they were recently incarcerated or are family members of currently incarcerated people; participants will receive intense financial education and follow-up for six months and be eligible for special down payment and rental assistance programs. In addition, trusted community members and organization leaders within each target neighborhood will participate in trauma-informed care training sessions to then be able to recognize when their peers are suffering from trauma symptoms, to support these affected peers, and to destigmatize accessing professional mental health services and connect them to these services when needed. Finally, a multi-stakeholder coalition will be convened to address policies that act as barriers to housing stability or accessing mental healthcare. Interventions will be delivered through existing partnerships with community-based organizations and networks. The primary outcome is neighborhood rate of incident gun violence. To inform future implementation and optimize the intervention package as the study progresses, we will use the Learn As You Go approach to optimize and assess the effectiveness of the intervention package on the primary study outcome.DiscussionResults from this protocol will yield novel evidence for whether and how addressing structural racism citywide leads to a reduction in gun violence.Trial registrationClinicalTrials.gov Identifier: NCT05723614. Registration date: February 01, 2023. Please refer to https://clinicaltrials.gov/ct2/show/NCT05723614 for public and scientific inquiries.