DNA double-strand breaks (DSBs) are harmful lesions leading to genomic instability or diversity. Non-homologous end-joining (NHEJ) is a prominent DSB repair pathway, which has long been considered to ...be error-prone. However, recent data have pointed to the intrinsic precision of NHEJ. Three reasons can account for the apparent fallibility of NHEJ: 1) the existence of a highly error-prone alternative end-joining process; 2) the adaptability of canonical C-NHEJ (Ku- and Xrcc4/ligase IV-dependent) to imperfect complementary ends; and 3) the requirement to first process chemically incompatible DNA ends that cannot be ligated directly. Thus, C-NHEJ is conservative but adaptable, and the accuracy of the repair is dictated by the structure of the DNA ends rather than by the C-NHEJ machinery. We present data from different organisms that describe the conservative/versatile properties of C-NHEJ. The advantages of the adaptability/versatility of C-NHEJ are discussed for the development of the immune repertoire and the resistance to ionizing radiation, especially at low doses, and for targeted genome manipulation.
Following the initial surges of the Alpha (B.1.1.7) and the Beta (B.1.351) variants, a more infectious Delta variant (B.1.617.2) is now surging, further deepening the health crises caused by the ...pandemic. The sharp rise in cases attributed to the Delta variant has made it especially disturbing and is a variant of concern. Fortunately, current vaccines offer protection against known variants of concern, including the Delta variant. However, the Delta variant has exhibited some ability to dodge the immune system as it is found that neutralizing antibodies from prior infections or vaccines are less receptive to binding with the Delta spike protein. Here, we investigated the structural changes caused by the mutations in the Delta variant's receptor-binding interface and explored the effects on binding with the ACE2 receptor as well as with neutralizing antibodies. We find that the receptor-binding β-loop-β motif adopts an altered but stable conformation causing separation in some of the antibody binding epitopes. Our study shows reduced binding of neutralizing antibodies and provides a possible mechanism for the immune evasion exhibited by the Delta variant.
•Compared the spike protein receptor-binding interface of SARS-CoV2 variants.•Delta variant RBD features different dynamical properties compared to other variants.•Receptor-binding beta-loop-beta motif can adopt an altered conformation in the Delta variant.•The changes in the interface include the separation of the antibody-binding epitope regions.•Due to the structural changes, antibodies have reduced binding to the RBD interface.
Out-of-hospital cardiac arrest (OHCA) during COVID-19 has been reported by countries with high case numbers and overwhelmed healthcare services. Imposed restrictions and treatment precautions may ...have also influenced OHCA processes-of-care. We investigated the impact of the COVID-19 pandemic period on incidence, characteristics, and survival from OHCA in Victoria, Australia.
Using data from the Victorian Ambulance Cardiac Arrest Registry, we compared 380 adult OHCA patients who received resuscitation between 16th March 2020 and 12th May 2020, with 1218 cases occurring during the same dates in 2017−2019. No OHCA patients were COVID-19 positive. Arrest incidence, characteristics and survival rates were compared. Regression analysis was performed to understand the independent effect of the pandemic period on survival.
Incidence of OHCA did not differ during the pandemic period. However, initiation of resuscitation by Emergency Medical Services (EMS) significantly decreased (46.9% versus 40.6%, p = 0.001). Arrests in public locations decreased in the pandemic period (20.8% versus 10.0%; p < 0.001), as did initial shocks by public access defibrillation/first-responders (p = 0.037). EMS caseload decreased during the pandemic period, however, delays to key interventions (time-to-first defibrillation, time-to-first epinephrine) significantly increased. Survival-to-discharge decreased by 50% during the pandemic period (11.7% versus 6.1%; p = 0.002). Survivors per million person-years dropped in 2020, resulting in 35 excess deaths per million person-years. On adjusted analysis, the pandemic period remained associated with a 50% reduction in survival-to-discharge.
The COVID-19 pandemic period did not influence OHCA incidence but appears to have disrupted the system-of-care in Australia. However, this could not completely explain reductions in survival.
Productive upwelling zones such as the southern Benguela can exhibit phytoplankton biomass variability over several orders of magnitude, from near oligotrophic offshore waters to hypertrophic inshore ...blooms of >100 mg m −3. This introduces complexity for ocean colour applications such as Harmful Algal Bloom (HAB) monitoring. As low and high biomass algorithmic approaches for ocean colour differ, no single algorithm can optimally retrieve accurate Chl a over such a wide range of biomass. We propose a novel technique to apply and blend two different Chl a algorithms — an empirical blue-green algorithm for low to moderate biomass and a red-NIR band-ratio algorithm for moderate to high biomass. The blending method is based on the 708 and 665 nm reflectance wavelength ratio, where the blue-green algorithm is applied when the ρw(708)/ρw(665) ratio is <0.75, the red-NIR algorithm is applied >1.15, whilst the two are blended using a weighted approach in between these values. When applied to in situ and satellite match-up data this method provides a median absolute relative difference (MARD) of 37.9 and 45.7%, respectively, and a RMSD of 0.27 and 0.35 respectively, over Chl a concentrations spanning three orders of magnitude. Application is demonstrated for both MERIS and OLCI sensors, providing a smooth transition between different biomass levels and algorithm Chl a returns.
•A novel approach for weighted blending of Chl-a algorithms is proposed.•The blending approach uses the reflectance ratio between 709 and 665 nm.•Chl-a is accurately retrieved over concentrations spanning three orders of magnitude.
Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying ...neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
•Spinal B5-I interneurons function to inhibit itch•B5-I neurons release the kappa opioid dynorphin•Kappa opioid signaling bidirectionally modulates itch within the spinal cord•Spinal B5-I interneurons mediate the inhibition of itch by menthol
Kardon et al. identify a population of spinal interneurons that function to inhibit itch. Release of the kappa opioid dynorphin from these neurons mediates the inhibition of itch by chemical counterstimuli such as menthol, suggesting that kappa opioids may be a broadly effective therapy for pathological itch.
We determine how pediatric emergency department (ED) visits changed during the COVID-19 pandemic in a large sample of U.S. EDs.
Using retrospective data from January–June 2020, compared to a similar ...2019 period, we calculated weekly 2020–2019 ratios of Non-COVID-19 ED visits for adults and children (age 18 years or less) by age range. Outcomes were pediatric ED visit rates before and after the onset of pandemic, by age, disposition, and diagnosis.
We included data from 2,213,828 visits to 144 EDs and 4 urgent care centers in 18 U.S. states, including 7 EDs in children's hospitals. During the pandemic period, adult non-COVID-19 visits declined to 60% of 2019 volumes and then partially recovered but remained below 2019 levels through June 2020. Pediatric visits declined even more sharply, with peak declines through the week of April 15 of 74% for children age < 10 years and 67% for 14–17 year. Visits recovered by June to 72% for children age 14–17, but to only 50% of 2019 levels for children < age 10 years. Declines were seen across all ED types and locations, and across all diagnoses, with an especially sharp decline in non-COVID-19 communicable diseases. During the pandemic period, there was 22% decline in common serious pediatric conditions, including appendicitis.
Pediatric ED visits fell more sharply than adult ED visits during the COVID-19 pandemic, and remained depressed through June 2020, especially for younger children. Declines were also seen for serious conditions, suggesting that parents may have avoided necessary care for their children.
The controlled synthesis of boron nitride at the nanoscale with predefined and uniform nanostructures and architectures is in general a big challenge, and making full use of these materials in ...applications still requires great effort. In this article, recent progress on the synthesis of nanostructured and architectured boron nitride involving molecular and polymeric precursors which contain only boron, nitrogen and hydrogen are reviewed. The potential applications of these materials with controlled porosity and/or dimensions controlled at the nanoscale as zero, one, two and three dimensional materials are discussed. Finally, future prospects for boron nitride in terms of synthesis and applications are considered.
This review illustrates common lesions of peripheral nerve myelinated fibers that occur in toxic neuropathy. These distinctive structural changes help to define the site of toxicant activity and thus ...predict the course of neurotoxic disease and recovery. Neuronopathy is the condition where the primary injury is directed to the neuronal cell body giving rise to a peripheral nerve axon. Axonopathy occurs when the axon is the primary target, and myelinopathy develops where the Schwann cell and/or myelin sheath is the primary target; these conditions can be discriminated early during the course of nerve fiber degeneration, but reciprocal influences between axon and myelin result in degeneration of both structures late in the disease.
We provide a suitable theoretical foundation for the notion of the quantum coherent state which describes the electrostatic field due to a static external macroscopic charge distribution introduced ...by the author in 1998 and use it to rederive the formulae obtained in 1998 for the inner product of a pair of such states. (We also correct an incorrect factor of
4
π
in some of those formulae.) Contrary to what one might expect, this inner product is usually non-zero whenever the total charges of the two charge distributions are equal, even if the charge distributions themselves are different. We actually display two different frameworks that lead to the same inner-product formulae, in the second of which Gauss’s law only holds in expectation value. We propose an experiment capable of ruling out the latter framework. We then address the problem of finding a
product picture
for QED—i.e. a reformulation in which it has a total Hamiltonian, arising as a sum of a free electromagnetic Hamiltonian, a free charged-matter Hamiltonian and an interaction term, acting on a Hilbert space which is a subspace (the
physical subspace
) of the full tensor product of a charged-matter Hilbert space and an electromagnetic-field Hilbert space. (The traditional Coulomb gauge formulation of QED isn’t a product picture in this sense because, in it, the longitudinal part of the electric field is a function of the charged matter operators.) Motivated by the first framework for our coherent-state construction, we find such a product picture and exhibit its equivalence with Coulomb gauge QED both for a charged Dirac field and also for a system of non-relativistic charged balls. For each of these systems, in all states in the physical subspace (including the vacuum in the case of the Dirac field) the charged matter is entangled with longitudinal photons and Gauss’s law holds as an operator equation; albeit the electric field operator (and therefore also the full Hamiltonian) while self-adjoint on the physical subspace, fails to be self-adjoint on the full tensor-product Hilbert space. The inner products of our electrostatic coherent states and the product picture for QED are relevant as analogues to quantities that play a rôle in the author’s matter-gravity entanglement hypothesis. Also, the product picture provides a temporal gauge quantization of QED which appears to be free from the difficulties which plagued previous approaches to temporal-gauge quantization.
Summary Background BCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to ...enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants. Methods In our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927 Findings Between July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 89% of 1399 MVA85A recipients and 628 45% of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 80% and 1059 76%) or serious adverse events (257 18% and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years 95% CI 0·79 to 1·62; with conversion in 178 13% of 1398 infants 95% CI 11·0 to 14·6) as did 39 (3%) of 1395 controls (1·39 per 100 person-years 1·00 to 1·91; with conversion in 171 12% of 1394 infants 10·6 to 14·1). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9). Interpretation MVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration. Funding Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).
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