The Permo-Triassic mass extinction has been resolved into two closely spaced crises that both saw enormous extinction losses. However, food web modelling suggests they were not ecologically ...equivalent, only the second destabilised communities.
The Permo-Triassic mass extinction has been resolved into two closely spaced crises that both saw enormous extinction losses. However, food web modelling suggests they were not ecologically equivalent, only the second destabilised communities.
Chromosome segregation depends on the attachment of spindle microtubules to sites on chromosomal DNA known as centromeres, through kinetochore protein complexes. Although RNA was found in ...kinetochores in the 1970s, only with recent investigations has evidence emerged that loading of the centromere-specific nucleosomes that form the foundation of the kinetochore may be coupled to centromeric transcription. Centromeric transcripts are bound by several kinetochore proteins that require them for stabilization or localization. At least some centromeres have promoter activity, and many have non-B form DNA that may facilitate their transcription. Whereas other noncoding RNAs regulate gene expression or silence transposons, cotranscriptional assembly of kinetochores is a novel function for noncoding RNAs.
Centromeres are transcribed at a low level and transcripts are incorporated into centromeric chromatin, where they serve essential functions.
Several kinetochore proteins bind centromeric transcripts, which may be necessary to stabilize or localize the proteins.
Loading of centromere-specific nucleosomes may be coupled to centromeric transcription.
Some centromeres have known promoter activity and most centromeres are enriched in non-B form DNA that may facilitate transcription or loading of centromere-specific nucleosomes.
COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed ...very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.
Display omitted
•Mice are sensitized for SARS-CoV-2 infection by Ad5-hACE2 transduction•Genetically deficient strains can be directly assessed without additional breeding•Mice useful for determining host factors necessary for optimal virus clearance•Useful for assessing efficacy of vaccines and therapies such as convalescent plasma
An adenoviral transduction-based mouse model that can be infected with SARS-CoV-2 provides a tool to understand host factors involved in viral infection and clearance as well as potential therapeutic modalities.
Antimicrobial proteins constitute a phylogenetically ancient form of innate immunity that provides host defence at skin and mucosal surfaces. Although some components of this system are ...constitutively expressed, new evidence reviewed in this Progress article shows that the production of certain antimicrobial proteins by epithelial cells can also be regulated by cytokines of the innate and adaptive immune systems. In particular, the effector cytokines interleukin-17 and interleukin-22, which are produced by the T-helper-17-cell subset, are emerging as crucial regulators of antimicrobial-peptide production in the gut and the lungs. This suggests that this T-cell lineage and its cytokines have important roles in skin and mucosal immunity.
Idiosyncratic adverse drug reactions (IADRs) encompass a diverse group of toxicities that can vary by drug and patient. The complex and unpredictable nature of IADRs combined with the fact that they ...are rare makes them particularly difficult to predict, diagnose, and treat. Common clinical characteristics, the identification of human leukocyte antigen risk alleles, and drug-induced proliferation of lymphocytes isolated from patients support a role for the adaptive immune system in the pathogenesis of IADRs. Significant evidence also suggests a requirement for direct, drug-induced stress, neoantigen formation, and stimulation of an innate response, which can be influenced by properties intrinsic to both the drug and the patient. This Perspective will provide an overview of the clinical profile, mechanisms, and risk factors underlying IADRs as well as new approaches to study these reactions, focusing on idiosyncratic drug-induced liver injury.
There is currently insufficient data to know if people are adequately accessing health services, including continuity of care for infectious and non-communicable diseases and essential maternal and ...child health services,5 such as vaccines and pregnancy-related care.6 Although access to health services for Ukrainian refugees is the same as for EU nationals, the rules vary by country, including those for co-payments, dental coverage, and mental health treatment. Furthermore, in many host countries there are an insufficient number of general practitioners, who are the gatekeepers to the health-care system.7 Unique workarounds, such as Ukrainian Medical Points, have been instituted in some countries to allow Ukrainian refugees to see nationally licensed Ukrainian health-care providers, but an examination of how health systems and financing need to adapt due to the refugee influx is needed. Mental health and psychosocial support, gender-based violence, and risk communication and community engagement are three essential and multisectoral issues whose importance was repeated throughout my missions in the region.6,9,10 The provision of adequate mental health and psychosocial support to the refugees will remain constrained due to insufficient numbers of existing national psychiatrists and psychologists, language issues, and implementation of policies that eventually allow Ukrainian refugee health-care workers to practise in EU countries.
The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene and protein expression, biochemical pathways, as well as cell morphology and size. Such RCDs have a ...significant impact on development, tissue homeostasis, and the occurrence and progression of disease. Among different forms of RCD, ferroptosis appears to be the main cause of tissue damage driven by iron overload and lipid peroxidation. In fact, the dysfunctional ferroptotic response is implicated in a variety of pathological conditions and diseases, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, tumorigenesis, infections, and immune diseases. Ferroptotic response can be fine-tuned through various oxidative stress and antioxidant defense pathways, coupling with metabolism, gene transcription, and protein degradation machinery. Accordingly, a series of ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins or signal transduction have been developed. Although this kind of RCD has recently attracted great interest in basic and clinical research, detecting and monitoring a ferroptotic response still faces challenges. In this mini-review, we not only summarize the latest knowledge about the characteristics of ferroptosis
and
, but also discuss the specificity and limitations of current biomarkers of ferroptosis.
Noninvasive brain stimulation has been demonstrated to modulate cortical activity in humans. In particular, theta burst stimulation (TBS) has gained notable attention due to its ability to induce ...lasting physiological changes after short stimulation durations. The present study aimed to provide a comprehensive meta-analytic review of the efficacy of two TBS paradigms; intermittent (iTBS) and continuous (cTBS), on corticospinal excitability in healthy individuals. Literature searches yielded a total of 87 studies adhering to the inclusion criteria. iTBS yielded moderately large MEP increases lasting up to 30 min with a pooled SMD of 0.71 (p<0.00001). cTBS produced a reduction in MEP amplitudes lasting up to 60 min, with the largest effect size seen at 5 min post stimulation (SMD=-0.9, P<0.00001). The collected studies were of heterogeneous nature, and a series of tests conducted indicated a degree of publication bias. No significant change in SICI and ICF was observed, with exception to decrease in SICI with cTBS at the early time point (SMD=0.42, P=0.00036). The results also highlight several factors contributing to TBS efficacy, including the number of pulses, frequency of stimulation and BDNF polymorphisms. Further research investigating optimal TBS stimulation parameters, particularly for iTBS, is needed in order for these paradigms to be successfully translated into clinical settings.
Superconducting qubits are electronic circuits comprising lithographically defined Josephson tunnel junctions, inductors, capacitors, and interconnects. When cooled to dilution refrigerator ...temperatures, these circuits behave as quantum mechanical “artificial atoms,” exhibiting quantized states of electronic charge, magnetic flux, or junction phase depending on the design parameters of the constituent circuit elements. Their potential for lithographic scalability, compatibility with microwave control, and operability at nanosecond time scales place superconducting qubits among the leading modalities being considered for quantum information science and technology applications. Over the past decade, the quantum coherence of superconducting qubits has increased more than five orders of magnitude, due primarily to improvements in their design, fabrication, and, importantly, their constituent materials and interfaces. In this article, we review superconducting qubits, articulate the important role of materials research in their development, and provide a prospectus for the future as these devices transition from scientific curiosity to the threshold of technical reality.
PDF
