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Medium term health and quality of life outcomes in a cohort of children with MIS-C in Cape Town, South Africa
No full textBackground: Multisystem inflammatory syndrome in children (MIS-C) is a disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its short-term effects have been documented but little data exist on the longer term effects of MIS-C on the health and quality of life (QOL) of patients. The objective of this study was to assess the long-term effects of MIS-C on the QOL of children.
Methods: This study was a descriptive prospective study. We included 24 participants with previous MIS-C and 20 children with juvenile idiopathic arthritis (JIA) as a positive comparator group. All children were examined and completed a paediatric quality of life (PedsQL) generic inventory score. This score was used to evaluate the School Functioning, Social, Emotional, and Physical QOL domains.
Results: All participants with previous MIS-C made a full recovery, with no medical complaints, and normal physical examinations after a median of 705 days post acute diagnosis. The PedsQL inventory revealed that 16.7% of the children with previous MIS-C showed a deficit in the physical domain compared to 60% of the children with JIA (p< 0.001). 12.5% of the children with previous MIS-C had a deficit in their psychosocial domain which included emotional, social, and educational scores, compared to 40% of the children with JIA (p = 0.035).
Conclusions: In a cohort of 24 South African children with previous MIS-C, no medical complications were reported. A small proportion felt a prolonged effect on their QOL even after making a full recovery, although this was not as severe as children with JIA, a known chronic disease that affects QOL. This highlights the need to continue to follow up these patients and offer more comprehensive long-term care
SubtiToolKit: a bioengineering kit for Bacillus subtilis and Gram-positive bacteria.
No full textBuilding DNA constructs of increasing complexity is key to synthetic biology. Golden Gate (GG) methods led to the creation of cloning toolkits - collections of modular standardized DNA parts hosted on hierarchic plasmids, developed for yeast, plants, Gram-negative bacteria, and human cells. However, Gram-positive bacteria have been neglected. Bacillus subtilis is a Gram-positive model organism and a workhorse in the bioindustry. Here, we present the SubtiToolKit (STK), a high-efficiency cloning toolkit for B. subtilis and Gram-positive bacteria. Its design permits DNA constructs for transcriptional units (TUs), operons, and knockin and knockout applications. The STK contains libraries of promoters, ribosome-binding site (RBSs), fluorescent proteins, protein tags, terminators, genome integration parts, a no-leakage genetic device to control the expression of toxic products during Escherichia coli assembly, and a toolbox for industrially relevant strains of Geobacillus and Parageobacillus as an example of the STK versatility for other Gram-positive bacteria and its future perspective as a reference toolkit
An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.
No full textSplicing factor proline- and glutamine-rich (SFPQ) is an RNA binding protein that broadly regulates RNA metabolism. Although its nuclear roles are well studied, evidence of SFPQ's cytoplasmic functionality is emerging. Altered expression and nuclear-to-cytoplasmic redistribution of SFPQ have been recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined. We identified altered SFPQ splicing in ALS, increasing the expression of an alternative mRNA isoform lacking a nuclear localization sequence, which we termed "altSFPQ." We find that altSFPQ mRNA contributes to SFPQ autoregulation and is highly unstable yet exhibits context-specific translation with cytoplasm-predominant localization. Notably, reduced canonical SFPQ coincides with increased altSFPQ transcript expression in familial and sporadic ALS models, providing a mechanistic basis for SFPQ nuclear-to-cytoplasmic redistribution in patients with ALS. Last, we observe that the altSFPQ protein has reduced phase separation potential and differential protein binding compared to its canonical counterpart, providing insight into its mechanistic relevance to physiology and ALS pathogenesis
Crick Research Data Integrity Report – First Year Review: July 2024- July 2025
No full textThe Crick’s Research Integrity Data Archive was launched in July 2024, and applies to primary research published at the Crick. It ensures the integrity of data in the long term, to comply with funders’ data management requirements, and to safeguard our researchers against any potential research integrity allegations. One year on, this report details some of the successes, obstacles, and future plans relating to the process.</p
Cryogenic electron tomography reveals helical organization of lipoprotein lipase in storage vesicles.
No full textLipoprotein lipase (LPL) is a triglyceride lipase that is contained in intracellular vesicles in an inactive storage form before secretion, but the precise structural details have not yet been resolved. Using cryo-electron tomography (cryo-ET), we observe that LPL exists inside of storage vesicles as a filament with an 11-nanometer diameter and is packed in these vesicles in two distinct patterns. Next, we solved a 4.2-Å resolution cryo-electron microscopy (cryo-EM) structure of this 11-nanometer LPL filament using purified protein. The filament is made of repeating pairs of LPL molecules with occluded active sites, rendering the LPL inactive. The comparison of the in situ subtomogram average and the in vitro cryo-EM structure indicates that the previously uncharacterized physiological storage form of LPL is an inactive filament
Mesenchymal stromal cells from JAK2 V617F myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.
No full textMyeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as JAK2 V617F . Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear. Furthermore, in vivo studies of ET/PV HSPCs remain a challenge due to low engraftment levels in xenograft models. We employed a 3D scaffold model to create an MPN humanized xenograft mouse model, enabling in vivo functional studies of primary MPN progenitor cells and the supportive role of human MSCs. Using this model, we first demonstrated robust hematopoietic support of healthy (HD) HSPCs by PV and ET MSCs. We then investigated the role of MSCs in sustaining JAK2 V617F mutant cells by using a CRISPR-Cas9 editing model, along with primary PV and ET HSPCs. Our results showed consistent engraftment of CRISPR-edited JAK2 V617F mutant HSPCs and PV and ET patient-derived HSPCs in scaffolds seeded with HD, PV, and ET stroma, providing the first in vivo evidence that PV and ET MSCs can sustain both healthy and MPN-associated hematopoiesis. Furthermore, HD MSCs were also capable of sustaining PV and ET HSPCs in vivo. Overall, we present the first humanized MPN xenograft model that offers valuable insights into how human BM MSCs interact with JAK2 V617F mutant clones
Plasticity of the parental brain.
No full textParental behavior, like other instinctive behaviors, must strike a delicate balance between robustness and flexibility to ensure offspring survival in dynamic environments. While core features of parenting are genetically programmed, they can be modulated by the hormonal changes accompanying pregnancy and parturition, as well as by social experience. How such behavioral flexibility arises from plasticity within the underlying neural circuits is a topic of intense investigation. In this review, we summarize recent advances in understanding the multi-level plasticity of the parental brain in both males and females. We highlight emerging principles of hormone- and experience-driven circuit remodeling and discuss key challenges and opportunities for future research in this rapidly evolving field
Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia.
No full textNucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the redistribution of mitochondria-related transcripts across AD and FTD neurons. The significantly increased mitochondrial RNA (mtRNA) in the cytosol of AD and FTD mutant neurons raised the possibility of leakage, which motivated us to investigate mtDNA leakage. We reveal abnormal cytoplasmic accumulation of mtDNA in AD and FTD cortical neurons together with evidence of mitochondrial aberrance. Importantly, mislocalisation of nucleic acids, mitochondrial dysfunction and cGAS-STING activation can be ameliorated through VCP D2 ATPase inhibition
Mechanisms of COPII coat assembly and cargo recognition in the secretory pathway.
No full textOne third of all proteins in eukaryotes transit between the endoplasmic reticulum (ER) and the Golgi to reach their functional destination inside or outside of the cell. During export, secretory proteins concentrate at transitional zones of the ER known as ER exit sites, where they are packaged into transport carriers formed by the highly conserved coat protein complex II (COPII). Despite long-standing knowledge of many of the fundamental pathways that govern traffic in the early secretory pathway, we still lack a complete mechanistic model to explain how the various steps of COPII-mediated ER exit are regulated to efficiently transport diverse cargoes. In this Review, we discuss the current understanding of the mechanisms underlying COPII-mediated vesicular transport, highlighting outstanding knowledge gaps. We focus on how coat assembly and disassembly dictate carrier morphogenesis, how COPII selectively recruits a vast number of cargo and cargo adaptors, and finally discuss how COPII mechanisms in mammals might have adapted to enable transport of large proteins
Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field.
No full textIn this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections