Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two ...unknown proteases: β-secretase and γ-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of β-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of β-secretase cleavage products, and these were cleaved exactly and only at known β-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of β-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as β-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for β-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.
Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing ...to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years.
We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis.
Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100,000 population per year in Oxfordshire, compared with 3·5 cases per 100,000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 95% CI 1·2-2·9; p=0·009), social risk factors (4·4 2·0-9·4; p<0·0001), and be part of a local transmission cluster (4·8 1·6-14·8; p=0·006).
Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised.
UK Clinical Research Collaboration (Wellcome Trust, Medical Research Council, National Institute for Health Research NIHR), and NIHR Oxford Biomedical Research Centre.
People who use drugs (PWUD) often have elevated sexually transmitted infection (STI) risk and unmet healthcare needs. Self-directed STI specimen collection (i.e., individuals collect the specimen and ...mail to the laboratory) may be valuable in addressing STI testing barriers among PWUD.
Within a cohort study among PWUD in New York City, we conducted a cross-sectional substudy from November 2021-August 2022 assessing sexual health with a one-time online survey (
= 120); participants could opt-in to receive a self-collection kit. Participants who opted-in were mailed a kit containing collection materials (males: urine cup, females: vaginal swab), pre-paid return label, instructions, and educational information. Specimens were sent to the laboratory and tested for
(CT) and
(GC). We measured the number of kits requested, delivered, mailed to the lab, and CT/GC positive; and examined differences in requesting a kit by sociodemographic and behavioral characteristics.
Sixty-three total kits were requested by 44 unique participants. Of the 63 requested, 41 were delivered; one kit was undeliverable at the provided address and the rest were not sent due to no address provided or being duplicate requests. Of the 41 kits delivered, three participants returned the kit to the lab; of those, one was positive for CT and GC. The greatest differences in those who did and did not request a kit were observed by age, sexual orientation, past-year sex trade and casual partnerships, and experiences of relationship violence.
Self-directed specimen collection may be desirable for PWUD, but research is needed to understand barriers to this testing approach for this population.
Psychological stress exacerbates many pathological conditions including inflammatory skin conditions. The effect of psychological stress on acute radiation‐induced skin reactions has not been ...documented before. Here, we aimed to explore if psychological stress could aggravate skin reaction severity in breast cancer patients. We conducted a secondary analysis of patient data obtained during a randomised, controlled clinical trial for acute radiation‐induced skin reaction severity in 78 breast cancer patients. Patients were assessed three times a week during treatment. Skin reaction severity was measured using the modified Radiation‐Induced Skin Reaction Assessment Scale (RISRAS) and Radiation Therapy Oncology Group grades. Stress levels were determined using a 5‐point LIKERT scale to rate physical well‐being, managing stress levels, house, family, work and other commitments. A total of 20 patients (26%) of the 78‐patient cohort were considered stressed. Skin reaction severity in stressed patients was twice that of non‐stressed patients (p < 0.001) and stressed patients were five times more likely to develop moist desquamation. Our results show that psychological stress aggravates skin reaction severity during radiation therapy. This research needs to be validated in a more rigorous manner by incorporating a validated scale such as the Distress Thermometer and Impact Thermometer in future skin trials.
Dendritic cells (DC) play a pivotal role in the control of T cell immunity due to their ability to stimulate naive T cells and direct effector function. Murine and human DC are composed of a number ...of phenotypically, and probably developmentally, distinct subsets, which may play unique roles in the initiation and regulation of T cell responses. The skin is populated by at least two subsets of DC: Langerhans cells (LC), which form a contiguous network throughout the epidermis, and dermal DC. LC have classically been thought vital to initiate T cell responses to cutaneous Ags. However, recent data have highlighted the importance of dermal DC in cutaneous immunity, and the requirement for LC has become unclear. To define the relative roles of LC and dermal DC, we and others generated mouse models in which LC were specifically depleted in vivo. Unexpectedly, these studies yielded conflicting data as to the role of LC in cutaneous contact hypersensitivity (CHS). Extending our initial finding, we demonstrate that topical Ag is inefficiently transported to draining lymph nodes in the absence of LC, resulting in suboptimal priming of T cells and reduced CHS. However, dermal DC may also prime cutaneous T cell responses, suggesting redundancy between the two different skin DC subsets in this model.
•We investigated cortical axon en passant boutons (EPB) in the APP/PS1 and wildtype (WT) mouse brain.•Synapse density and inter-EPB distance are maintained across the lifespan in APP/PS1 and WT ...cortex.•Midlife environmental enrichment does not alter EPB density or inter-EPB distance in APP/PS1 or WT.•EPB turnover (gains and losses) in cortical axons is lower in APP/PS1 axons compared to WT.
Synaptic dysfunction is one of the key mechanisms associated with cognitive deficits observed in Alzheimer's disease (AD), yet little is known about the presynaptic axonal boutons in AD. Focusing on cortical en passant boutons (EPBs) along axons located in the motor, sensory and prefrontal regions of the cerebral cortex in the APP/PS1 mouse model of AD, we investigated structural properties of EPBs over the lifespan and in response to a midlife environmental enrichment (EE) intervention. At 3, 12, and 18-22 months and following 6 months of midlife EE, we found that EPBs showed remarkable resilience in preserving overall synaptic output, as evidenced by the maintained density of EPBs along the axon shaft across all experimental conditions. Using cranial window imaging to monitor synaptic changes in real time, we report that despite maintaining a stable synaptic density, the dynamic fraction (gains and losses) of EPBs was significantlyreduced at 10-13 months of age in APP/PS1 axons compared to age matched controls.
Many mammalian species are adapted to living in burrows for most of their lives. Inhabiting such thermally stable environments may influence the variation on the species thermogenic capacity, ...particularly non‐shivering thermogenesis (NST). African mole‐rats (Bathyergidae) are subterranean rodents occurring in fynbos, grassland and wooded savannas across sub‐Saharan Africa that vary in the complexity of their social systems, ranging from strictly solitary to highly social species. The presence and magnitude of NST are well known in social bathyergids, but no such data exist for their solitary counterparts. In this study, we quantified NST in three solitary mole‐rat species represented by three distinct genera together with one social species. Our results showed that NST in all species is functional. Maximum metabolic rate after norepinephrine injection was equivalent to 269% of resting values in the social giant mole‐rat Fukomys mechowii and 166%, 282% and 157% in the three solitary species: the silvery mole‐rat Heliophobius argenteocinereus, the Cape mole‐rat Georychus capensis and the Cape dune mole‐rat Bathyergus suillus, respectively. To test our prediction that NST capacity is higher in solitary bathyergids, we combined our data with those available for other members of this family. In contrast to our prediction, NST did not differ between social and solitary bathyergids. Body mass, as the main factor, and minimum air temperature (Tmin), accounts for more than 80% of NST variation in bathyergid mole‐rats.
African mole‐rats (Bathyergidae) are subterranean rodents occurring in fynbos, grassland and wooded savannas across sub‐Saharan Africa that vary in the complexity of their social systems, ranging from strictly solitary to highly social species. In this study, we quantified non‐shivering thermogenesis (NST) in three solitary mole‐rat bathyergid species represented by three distinct genera together with one social species. Our results showed that NST is functional in all studied species, the social giant mole‐rat Fukomys mechowii, the solitary silvery mole‐rat Heliophobius argenteocinereus, the solitary Cape mole‐rat Georychus capensis and the solitary Cape dune mole‐rat Bathyergus suillus. By combining our data with those available for other members of this family, NST showed no differences between social and solitary bathyergids. Body mass, as the main factor, and minimum air temperature, accounts for more than 80% of NST variation in bathyergid mole‐rats.
For the first time, the International Symposium on Fungal Stress was joined by the XIII International Fungal Biology Conference. The International Symposium on Fungal Stress (ISFUS), always held in ...Brazil, is now in its fourth edition, as an event of recognized quality in the international community of mycological research. The event held in São José dos Campos, SP, Brazil, in September 2022, featured 33 renowned speakers from 12 countries, including: Austria, Brazil, France, Germany, Ghana, Hungary, México, Pakistan, Spain, Slovenia, USA, and UK. In addition to the scientific contribution of the event in bringing together national and international researchers and their work in a strategic area, it helps maintain and strengthen international cooperation for scientific development in Brazil.
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We present the complete mitochondrial genomes of the Critically Endangered whitespotted wedgefish, Rhynchobatus djiddensis (Forsskål, 1775), and bottlenose wedgefish, Rhynchobatus australiae ...(Whitley, 1939), with the R. djiddensis mitogenome documented for the first time. The genomes for R. djiddensis and R. australiae are 16,799 and 16,805 bp in length, respectively. Both comprise 13 protein-coding regions, 22 tRNA genes, two rRNA genes, and a non-coding control region. All protein-coding regions consistently start with the ATG start codon; however, the alternative start codon GTG is observed at the start of the COX1 gene. NADH2, COX2, and NADH4 have incomplete stop codons: T or TA, and tRNA
Leu
and tRNA
Ser
, have atypical codons: UAA, UGA, GCU, and UAG. The phylogenetic analysis places R. djiddensis and R. australiae within the Rhynchobatus genus, separate from other families in the order Rhinopristiformes. We also highlight the most variable gene regions to expedite future primer design, of which NADH2 was the most variable (4.5%) when taking gene length into account. These molecular resources could promote the taxonomic resolution of the whitespotted wedgefish species complex and aid in the genetic characterization of populations of these and related species.
Here, the presence of 240Pu in nuclear fuels for reactors has resulted in high uncertainties in the results of reactor and nuclear transmutation calculations because of deficiencies in 240Pu-related ...nuclear data. Specifically for the prompt fission neutron spectrum (PFNS) of 240Pu, there is only one neutron-induced, (n,f), measurement at 0.85 MeV incident neutron energy and only one complete spontaneous fission, (sf), measurement. This limited availability of data does not sufficiently guide nuclear data evaluations of these quantities. Here we report on a measurement of both the 240Pu(sf) and the 240Pu(n,f) PFNS, both over the emitted neutron energy range of 0.79–10.0 MeV, and from incident neutron energies of 1.0–20.0 MeV for the (n,f) reaction. Measurements were made with a hemispherical array of liquid scintillators at the high-energy Los Alamos Neutron Science Center white neutron source at the Weapons Neutron Research facility as part of the joint LANL-LLNL Chi-Nu experimental campaign to measure actinide fission neutron spectra. These measurements are the first of their kind, and provide clear experimental evidence for second-chance fission, third chance fission, and pre-equilibrium neutron emission processes in neutron-induced fission of 240Pu, and are the first ever measurements above 1 MeV incident neutron energy.
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