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Integrating genomic, transcriptomic, and phenotypic information to explore drug resistance in Mycobacterium tuberculosis sub-lineage 4.2.2.2.
No full textAIMS: Mycobacterium tuberculosis (Mtb) remains a major global health challenge, particularly due to increasing drug resistance. Beyond the well-characterized mutations, the mechanisms involved in driving resistance appear to be more complex. This study investigated the differential gene expression of Ethiopian drug-resistant Mtb sub-lineage 4.2.2.2 clinical isolates through an integrated approach combining phenotypic, transcriptomic, and genomic analyses. METHOD AND RESULTS: RNA sequencing was performed by isolating RNA from six Mtb strains (three drug-sensitive and three drug-resistant) during mid-logarithmic phase growth. Drug resistance was assessed through whole-genome analysis and phenotypic testing using the BACTEC Mycobacteria growth indicator tube (MGIT)™ 960 system. RNA profiling revealed significantly reduced expression of six genes: Rv0096, Rv2780, Rv3136, Rv3136A, Rv3137, and Rv3230c in drug-resistant isolates. These genes are not associated with known drug targets nor resistance mechanisms. Additionally, a discrepancy was noted between phenotypic resistance profiles and whole genome-based predictions, with the latter suggesting broader resistance. For instance, the missense mutation in rpoB p.Ser450Leu and katG p.Ser315Thr were identified with no change in phenotypic drug sensitivity to rifampicin and isoniazid, respectively. CONCLUSION: Identification of these differentially expressed genes and their networks could be useful in unraveling the complexities of Mtb drug resistance and in understanding the impact that drug resistance conferring mutations have on the physiology of drug-resistant Mtb.</p
David Marquand and progressive politics
No full textThroughout his career, David Marquand grappled with the shape of modern British history, arranging it into different traditions, lineages, timelines. The Progressive Dilemma was the culmination of one such strand of work, centred around his interest in the relationship between social democracy and social liberalism. This informed both Marquand’s historical work and his practical politics – most obviously in the SDP-Liberal Alliance. But though this resurrection of the ‘progressive tradition’ now feels intuitive, I want to suggest that this was by no means inevitable. Indeed, to many Liberals, the idea of resurrecting an historic partnership with social democrats seemed more of a threat than an opportunity.</p
How should we study heterogeneity in entrepreneurship? Moving the field to an inclusive approach
No full textEntrepreneurship scholarship faces challenges related to diverse populations, striving to balance inclusivity with the recognition of unique entrepreneurial identities. Applying optimal distinctiveness theory, we explore the relationship between belongingness and uniqueness in entrepreneurship research. Catalyzed by Bakker and McMullen’s 2023 article on inclusivity in entrepreneurship, we utilized natural language processing to examine responses about inclusive entrepreneurship from 29 scholars dedicated to marginalized populations. Findings suggest that employing varied research methods and integrating structural and epistemological considerations can enhance our understanding of entrepreneurial heterogeneity. We advocate for entrepreneurship research that values individual experiences while promoting inclusive practices, highlighting the need for evolving scholarly paradigms to reflect entrepreneurial differences.</p
Advances in understanding the mechanisms of the human papillomavirus oncoproteins
No full textHigh-risk human papillomaviruses (HPVs) are responsible for almost all cervical cancer cases and a growing number of oropharyngeal and anogenital cancers. The primary HPV oncoproteins, E6 and E7, act together to manipulate multiple cellular pathways that can ultimately result in malignant transformation. This includes the deregulation of several signalling pathways that regulate cell proliferation, cell cycle progression and cell survival. Although multiple functions of HPV E6 and E7 in driving oncogenesis are well known, recent studies have uncovered novel oncogenic functions of the HPV oncoproteins, including the manipulation of emerging mechanisms of cancer development, such as epigenetic modifications, cellular plasticity and genomic instability. This review explores current advances in understanding how the HPV oncoproteins interact with these cellular processes, highlighting potential therapeutic targets in HPV-associated cancers.</p
A standardized nomenclature for the rods and cones of the vertebrate retina
No full textVertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably—and often confusingly—named according to morphology, presence/absence of ‘rhodopsin’, spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor type’s putative evolutionary history. This classification is informed by the functional, anatomical, developmental, and molecular identities of the neuron as a whole, including the expression of deeply conserved transcription factors required for development. The proposed names will be applicable across all vertebrates and indicative of the widest possible range of properties, including their postsynaptic wiring, and hence will allude to their common and species-specific roles in vision. Furthermore, the naming system is open-ended to accommodate the future discovery of as-yet unknown photoreceptor types.</p
Validation of routine lymphatic filariasis morbidity surveillance in the Upper West Region, Ghana
No full textIn Ghana and other countries pursuing elimination of lymphatic filariasis (LF), suspect cases of lymphoedema and hydrocele are routinely enumerated by community health workers (CHWs) during mass drug administration (MDA). These data, in addition to cases captured through the routine out-patient department are used for burden estimation and health service planning. To date there has been no systematic evaluation of the reliability of these data in Ghana. In December 2022, we conducted a cross-sectional survey of LF morbidity in two evaluation units in the Upper West Region of Ghana, including 19,180 participants. Participants with swelling affecting the scrotum or limbs were examined by clinicians to confirm whether symptoms were due to LF. Participants were asked whether their household had been visited by a CHW during the previous MDA. Suspect cases were asked whether they had reported their condition to a CHW or sought care elsewhere. We estimated the prevalence of each condition according to survey data and pre-existing routine data collected by CHWs and compared estimates. Lymphoedema prevalence rates were 87.3 and 61.2 per 10,000 in the two evaluation units, and hydrocele prevalence rates were 111.3 and 65.3 per 10,000 males. Routine enumeration underestimated lymphoedema prevalence by 81% in both cases, and underestimated hydrocele prevalence by 41%–52%. Nearly all households were visited during the previous MDA, but only 60.7% of lymphoedema and 28.3% of hydrocele cases had reported symptoms. 61.8% of lymphoedema and 42.9% of hydrocele cases had sought care from health facilities. Routine surveillance underestimates the prevalence of LF morbidity in the study area. Process modifications, including re-training of CHWs and health workers should be considered to improve data for service planning and validation of LF elimination. Anticipating cessation of MDA, continuous health service delivery, with periodic coverage evaluation, should be prioritised to strengthen passive surveillance.</p
Search for the jet-induced diffusion wake in the quark-gluon plasma via measurements of jet-track correlations in photon-jet events in (Formula presented) collisions at (Formula presented) with the ATLAS detector
No full textThis paper presents a measurement of jet-track correlations in photon-jet events, using 1.72 (Formula presented) of (Formula presented) data at (Formula presented) recorded with the ATLAS detector at the LHC. Events with energetic photon-jet pairs are selected, where the photon and jet are approximately back-to-back in azimuth. The angular correlation between jets and charged-particle tracks with transverse momentum ((Formula presented)) in the range 0.5-2.0 GeV in the hemisphere opposite to the jet, (Formula presented), is measured as a function of their relative pseudorapidity difference, (Formula presented). In central (Formula presented) collisions, these correlations are predicted to be sensitive to the diffusion wake in the quark-gluon plasma resulting from the lost energy of high-(Formula presented) partons traversing the plasma, with a characteristic modification as a function of (Formula presented). The correlations are examined with different selections on the jet-to-photon (Formula presented) ratio to select events with different degrees of energy loss. No diffusion wake signal is observed within the current sensitivity and upper limits at 95% confidence level on the diffusion wake amplitude are reported.</p
Postnatal development of dendritic morphology and action potential shape in rat substantia nigra dopaminergic neurons
No full textSubstantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by specific morphological and electrophysiological properties. First, in ∼90% of the cases, their axon arises from an axon-bearing dendrite (ABD) at highly variable distances from the soma. Second, they display a highly regular pattern of spontaneous activity (aka pacemaking) and a broad action potential (AP) that faithfully back-propagates through the entire dendritic arbor. In previous studies (Moubarak et al., 2019; Moubarak et al., 2022), we demonstrated that the presence of a high density of sodium current in the ABD and the complexity of this dendrite played a critical role in the robustness of pacemaking and setting the half-width of the AP. In the current study, we investigated the postnatal development of both morphology and AP shape in SNc DA neurons in order to determine when and how the mature electrophysiological phenotype of these neurons was achieved. To do so, we performed electrophysiological recordings of SNc DA neurons at four postnatal ages (P3, P7, P14, P21) and fully reconstructed their dendritic and proximal axon morphology. Our results show that several morphological parameters, including the length of the ABD, display abrupt changes between P7 and P14, such that a mature morphology is reached by P14. We then showed that AP shape followed a similar timecourse. Using realistic multicompartment Hodgkin–Huxley modeling, we then demonstrated that the rapid morpho-electrical maturation of SNc DA neurons likely arises from synergistic increases in dendritic length and in somatodendritic sodium channel density.</p
Measurement of ????2????/????|→????|????????avail in charged current ????????-nucleus interactions at ⟨????????⟩=1.86 GeV using the NOvA Near Detector
No full textDouble- and single-differential cross sections for inclusive charged-current νμ-nucleus scattering are reported for the kinematic domain 0 to 2 GeV/c in three-momentum transfer and 0 to 2 GeV in available energy, at a mean νμ energy of 1.86 GeV. The measurements are based on an estimated 995,760 νμ charged-current (CC) interactions in the scintillator medium of the NOvA Near Detector. The subdomain populated by 2-particle-2-hole (2p2h) reactions is identified by the cross section excess relative to predictions for νμ-nucleus scattering that are constrained by a data control sample. Models for 2-particle-2-hole processes are rated by χ2 comparisons of the predicted-versus-measured νμ CC inclusive cross section over the full phase space and in the restricted subdomain. Shortfalls are observed in neutrino generator predictions obtained using the theory-based València and SuSAv2 2p2h models.</p
Fast-response low-power atomic oven for integration into an ion microchip
No full textWe present a microfabricated neutral atom source for quantum technologies that can be easily integrated onto microchip devices using well-established micro-electromechanical systems fabrication techniques, and contrast this to conventional off-chip ion loading mechanisms. The heating filament of the device is shown to be as small as 90×90 µm2. Testing of the 171Yb fluorescence response is found to be in the low tens of milliseconds, two orders of magnitude faster compared to previous literature at a power of milliwatts, making it desirable for low-power device packages. We demonstrate how the evaporation material can be capped in vacuum to work with materials such as Ba that oxidizes easily in air, which can avoid the need for ablation lasers in the loading process. We calculate oven lifetimes to be over 10 years of continuous use for commonly used ion species in quantum technology.</p