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Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage
Get PDFGenomic instability drives the initiation, metastasis, and progression of T cell acute lymphoblastic leukemia (T-ALL) [1, 2]. During tumorigenesis, genomic instability resulting from p16INK4A deletion[3], mutations in mini-chromosome maintenance proteins MCM4/2[4-6] and impaired nonhomologous end joining (NHEJ)[7] acts cooperatively with MYC to increase cell proliferation, drive tumor initiation and expand early transformed cells. Although promotion of myeloid differentiation has been reported to inhibit leukemic self-renewal and malignant hematopoiesis in myeloid stem cells [8], efficient clearance of lymphocytes with genomic defects is a common way to prevent lymphoblastic leukemia [9-11]. This principle is also supported by the observation that inhibition of apoptosis in p53 mutant cells or overexpression of antiapoptotic signaling mediators drives leukemia [12-16], including T-ALL [13]. Therefore, during T lymphocyte development, immature lymphocytes appear to sensitively undergo cell death after undergoing DNA damage caused by gene mutations (chronic DNA replication stress) [6, 17, 18], while the surviving lymphocytes may progress to thymomas at later developmental stages [6, 19,59 20]. On the other hand, DNA damage arises from both endogenous gene mutations and transient exposure to environmental stress [21, 22]. When DNA damage is caused by transient replication stress, anti-apoptotic signaling is activated to prevent rapid cell death to help preserve life and evolution [20, 23]. Thus, organisms must evolve mechanisms to differentiate chronic DNA damage induced by gene mutations from transient DNA replication stress. Using such mechanisms, organisms can eliminate lymphocytes with severe and unrepaired DNA damage to maintain a stable genome and prevent leukemia, preserve life and enhance evolution under 4 / 45 transient environmental replication stress. However, these 66 mechanisms are far from beingelucidated. Early studies have shown that the Mcm4(D573H) allele destabilizes the MCM2–7 complex, resulting in chromosome instability and the formation of spontaneous T cell lymphoblastic leukemia/lymphoma (T-ALL) [6]. Mice with reduced expression of MCM2 due to an MCM2 mutant allele die with lymphoma within the first few months after birth [5]. MCM5 is also a crucial component of the DNA replication licensing system (MCM2-7 complex), and in Steere’s early screening work, a MCM5 variant allele was identified with pathogenic potential [24]. MCM5 is highly expressed in T cells from patients with T-ALL as well as in T-ALL cell lines(Fig. S1A-C Fig. S1B Gel Supplementary). These findings imply that MCM5 may play a pivotalrole in T lymphocytic leukemia and early T cell development. Here, we focused on studying therole of Mcm5 in T cell development and found that in mice and zebrafish, Mcm5 loss disruptedDNA replication in immature T lymphocytes and sequentially led to upregulation of Tp53signaling, which resulted in apoptosis of immature T lymphocytes. Moreover, in mcm5 mutants, the absence of mcm5 inhibited the phosphorylation of Stat1 and sequentially inhibited the enhancement of bcl2 signaling, which accelerated the apoptosis of immature T lymphocytes. Our results provide a mechanism by which immature T cells with DNA damage resulting from gene mutations are rapidly cleared during T-cell development
Last-millennium volcanic forcing and climate response using SO2 emissions
Get PDFClimate variability in the last millennium (past 1000 years) is dominated by the effects of large-magnitude volcanic eruptions; however, a long-standing mismatch exists between model-simulated and tree-ring-derived surface cooling. Accounting for the self-limiting effects of large sulfur dioxide (SO2) injections and the limitations in tree-ring records, such as lagged responses due to biological memory, reconciles some of the discrepancy, but uncertainties remain, particularly for the largest tropical eruptions. The representation of volcanic forcing in the latest generation of climate models has improved significantly, but most models prescribe the aerosol optical properties rather than using SO2 emissions directly and including interactions between the aerosol, chemistry, and dynamics. Here, we use the UK Earth System Model (UKESM) to simulate the climate of the last millennium (1250–1850 CE) using volcanic SO2 emissions. Averaged across all large-magnitude eruptions, we find similar Northern Hemisphere (NH) summer cooling compared with other last-millennium climate simulations from the Paleoclimate Modelling Intercomparison Project Phase 4 (PMIP4), run with both SO2 emissions and prescribed forcing, and a continued overestimation of surface cooling compared with tree-ring reconstructions. However, for the largest-magnitude tropical eruptions in 1257 (Mt. Samalas) and 1815 (Mt. Tambora), some models, including UKESM1, suggest a smaller NH summer cooling that is in better agreement with tree-ring records. In UKESM1, we find that the simulated volcanic forcing differs considerably from the PMIP4 dataset used in models without interactive aerosol schemes, with marked differences in the hemispheric spread of the aerosol, resulting in lower forcing in the NH when SO2 emissions are used. Our results suggest that, for the largest tropical eruptions, the spatial distribution of aerosol can account for some of the discrepancies between model-simulated and tree-ring-derived cooling. Further work should therefore focus on better resolving the spatial distribution of aerosol forcing for past eruptions
An encodable amino acid for targeted photocatalysis
Get PDFPhotocatalysts are excellent scaffolds for the light-mediated control of bioactive molecules. Current photocatalytic structures are not compatible with genetic encoding and therefore cannot be directly incorporated into the sequences of native proteins. Herein, we developed new amino acids incorporating Si-rosamine photocatalytic units, and introduced them via aminoacylation of tRNAs into specific positions of different proteins to enable targeted photocatalytic reactions in defined populations of immune cells. </p
Emulation of the subjective experience of visual dorsal stream dysfunction:A description of three in depth case studies
Get PDFThese case studies explore the subjective visual experiences of individuals with cerebral visual impairment (CVI), specifically dorsal stream dysfunction (DSD) characterized by simultanagnosia. Through three in-depth case studies, this work documents the challenges these individuals face when navigating cluttered environments. The individuals were asked to describe their visual experiences while watching videos of varying complexity, with the future aim of creating a simulation of simultanagnosia. This process revealed a dynamic constriction of their attentional visual fields as scene complexity increased, and vice versa. Notably, the volunteers experienced a phenomenon where their vision could “get stuck” on specific items, with an apparent concurrent reduction in their ability to perceive and describe visual information as visual clutter increased. These consistent observations indicate that the symptoms of simultanagnosia are not simply limited to perceiving one or two objects at a time but can vary dynamically in response to environmental complexity. They enhance our understanding of how DSD impacts visual search and perceptual experiences, prompting us to propose the term “simultanagnostic vision” to describe this more nuanced and dynamic manifestation of CVI. The results are critical for developing effective interventions and optimizing support strategies for individuals affected by DSD, particularly children at sensitive developmental stages. Furthermore, we recommend deeper investigation into how different visual processing streams in the brain interconnect and influence each other, which may open new avenues for targeted therapeutic interventions.</p
Veterinary killing: history and ethics
Get PDFKilling/euthanasia is a common procedure in veterinary medicine. While generally seen as unproblematic in terminal disease, and when carried out for welfare reasons, the process is complicated by advances in veterinary care which can prolong animals’ lives to an extent that may be considered overtreatment. Veterinarians may experience moral distress if they feel they are keeping animals alive when they should be euthanased. At the same time, healthy animals are sometimes killed to prevent diseases from spreading or for spurious reasons. Such decisions do not operate solely across animal category lines (e.g. companion vs. farmed) but reflect differing conceptions of animal value within species as well. This chapter takes a historical approach to the ethics of killing animals. It concludes that veterinarians may be helped in decision-making by trying to triangulate thinking across species lines, and focusing on sentience not species when considering the profession’s broader ethical responsibilities towards all animals
Human papillomavirus vaccination uptake among men who have sex with men living with HIV: A systematic review and narrative synthesis
Get PDFBackground: Human papillomavirus (HPV) is a very common sexually transmitted infection. Persistent infection with high-risk subtypes can lead to a variety of cancers. Men who have sex with men (MSM), particularly those who are living with HIV (MSMLWH), have a high prevalence of HPV infection and are at greatest risk of HPV-related diseases such as anal cancer. HPV vaccines are effective in preventing new infections, and many countries have implemented HPV vaccination for MSM. Methods: This systematic review aimed to examine HPV vaccine uptake among MSM and MSMLWH. Quantitative studies published between 2010 and 2022 were screened and included if they detailed HPV vaccination uptake data for MSM and MSMLWH. Identified studies were screened using Covidence, data were extracted from the final included studies and narratively synthesised, and risk of bias of studies was assessed using the Joanna Briggs Institute Checklist tool for prevalence studies. Results: There were 19 studies all from high-income countries, included in the final review. This review showed a wide variety of HPV vaccine uptake, ranging from 2.7% to 91.5% for HIV-negative MSM and among MSMLWH ranging from 5.6% to 90%. Although limited by the heterogeneity of studies and settings, there was evidence of a consistent, steady increase in HPV vaccination particularly among younger men. MSMLWH generally had higher rates of HPV vaccination, but overall HPV vaccine uptake remained suboptimal. Conclusion: MSMLWH are at high risk of HPV-related disease. Despite an available and efficacious vaccine in many countries, this review showed overall rates of HPV vaccination uptake remain inadequate. Further research and policy should aim to address and overcome barriers to HPV vaccination. PROSPERO registration number CRD42023382251.</p
N-doped Fe<sub>3</sub>O<sub>4</sub> nanoparticles loaded-carbon foam for a highly efficient and recyclable desalination-photocatalysis solar evaporator
Get PDFSolar-powered evaporation technology is a green and sustainable solution to freshwater scarcity. However, massive evaporation of seawater may lead to localized accumulation of pollutants in the waterbody, causing secondary pollution. Herein, we developed a recyclable solar evaporator with a synergistic effect of solar thermal evaporation and photocatalysis by introducing Fe3O4 nanoparticles (NPs) into carbon foam scaffold. The incorporation of Fe3O4 NPs can not only enhance the light absorption capability of carbon foam composite from visible to infrared regions, but also, the photocatalytic activity of the loaded Fe3O4 has been facilitated due to the dopant of N on Fe3O4 during the carbonization process. Additionally, the combined magnetic carbon foam (N-Fe3O4@CF) exhibits sustained stability, salt resistance and good recyclability, which can avoid secondary pollution. As a result, the integrated desalination-photocatalysis system achieved an evaporation efficiency up to 93.27 % under 1.0 solar irradiation, evaporation rate reached 1.5303 kg m−2 h−1 and simultaneously the degradation rate of organic pollutant reached more than 96 % within 1 h, which provides a feasible solution to alleviate global water/energy scarcity.</p
The cultural legacy of historical ethnic violence:The impact on access to finance and innovation
Get PDFUsing the case of the pogroms that took place in the historical region of the 'Pale of Settlement' in Eastern Europe, this paper analyzes the cultural legacy of ethnic violence and its long-term economic impact on access to finance and on corporate innovation. We find that firms in regions with a higher historical intensity of ethnic persecution face greater financial constraints, relying more on internal finance and experiencing reduced access to external finance. These financial limitations are linked to sluggish innovation activities among present-day firms. We propose that a mechanism of financial antipathy, rooted in a persistent anti-market culture fostered by historical ethnic animosity, explains these effects and reflects a long-term degradation of local social capital. Our results are supported by causal evidence using instrumental variables based on the precursors of historical inter-ethnic violence. The animosity and discrimination against the minority group appear to transfer to the broader economic activities in which that group was involved, creating lasting economic consequences for the majority population – consequences that continue to affect financial development and innovation to the present day.</p
Development and predictors of bipolar disorder in children and adolescents with depressive disorders:a systematic review, meta-analysis, and meta-regression
Get PDFBACKGROUND: Estimating the risk of developing bipolar disorder (BD) in children and adolescents (C&A) with depressive disorders is important to optimize prevention and early intervention efforts. We aimed to quantitatively examine the risk of developing BD from depressive disorders and identify factors which moderate this development.METHODS: In this systematic review and meta-analysis (PROSPERO:CRD42023431301), PubMed and Web-of-Science databases were searched for longitudinal studies reporting the percentage of C&A with ICD/DSM-defined depressive disorders who developed BD during follow-up. Data extraction, random-effects meta-analysis, between-study heterogeneity analysis, quality assessment, sub-group analyses, and meta-regressions were conducted.RESULTS: Thirty-nine studies were included, including 72,371 individuals (mean age=13.9 years, 57.1% females); 14.7% of C&A with a depressive disorder developed BD after 20.4-288 months: 9.5% developed BD-I (95% CI=4.7 to 18.1); 7.7% developed BD-II (95% CI=3.2% to 17.3%); 19.8% (95% CI=9.9% to 35.6%) of C&A admitted into the hospital with a depressive disorder developed BD. Studies using the DSM (21.6%, 95% CI=20.2% to 23.1%) and studies evaluating C&A with a major depressive disorder only (19.8%, 95% CI=16.8% to 23.1%) found higher rates of development of BD. Younger age at baseline, a history of hospitalization and recruitment from specialized clinics were associated with an increased risk of developing BD at follow-up. Quality of included studies was good in 76.9% of studies.CONCLUSIONS: There is a substantial risk of developing BD in C&A with depressive disorders. This is particularly the case for C&A with MDD, DSM-diagnosed depressive disorders, and C&A admitted into the hospital. Research exploring additional predictors and preventive interventions is crucial.</p
Cardiac troponin I and T ratio and risk of cardiovascular or non-cardiovascular events in a general population
Get PDFBACKGROUND: Emerging evidence suggests that the ratio between cardiac troponin (cTn) I and T may provide information on the risk of adverse outcomes in individuals with cardiovascular disease. Whether the cTn I/T ratio provides prognostic insights in the general population is unknown. METHODS: The cTn I/T ratio was calculated in 8855 participants (43% female, median age 56 years) from the Generation Scotland Study where both cTnI and cTnT concentrations were above the limit of blank. Multivariable cause-specific Cox proportional hazard models were used to estimate the associations between cTn I/T ratio and the primary outcome of cardiovascular or non-cardiovascular death. RESULTS: The median cTn I/T ratio was 0.5 (25th–75th percentile, 0.3–0.8) and median follow-up was 11.4 (10.8–12.7) years. Individuals in the highest ratio tertile (≥0.64) were more likely to be male, have a higher body mass index and systolic blood pressure, and a history of cardiovascular disease. Those in the lowest ratio tertile (<0.38) were more likely to be smokers or have diabetes. After adjustment for cardiovascular risk factors, the cTn I/T ratio was positively associated with cardiovascular death (per doubling increase, adjusted hazard ratio [HR] 1.16 [95% CI, 1.05–1.28]), while an inverse association was observed for non-cardiovascular death (HR 0.89 [95% CI, 0.81–0.99]). CONCLUSIONS: The cTn I/T ratio is positively associated with cardiovascular death in the general population, while inversely associated with non-cardiovascular death. Future research is needed to unravel underlying mechanisms and determine whether the cTn I/T ratio provides valuable information regarding risk of cardiovascular and non-cardiovascular mortality to guide further management.</p
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