Significance
This work shows that, under strong immune pressure, SARS-CoV-2 can use mutations in both the N-terminal domain and the receptor-binding domain to escape potent polyclonal neutralizing ...responses. Indeed, after a long period under immune selective pressure, SARS-CoV-2 evolved to evade the immunity of a potent polyclonal serum from a COVID-19 convalescent donor. Only three mutations were sufficient to generate this escape variant. The new virus was resistant to 70% of the neutralizing antibodies tested and had a decreased susceptibility to all convalescent sera. Our data predict that, as the immunity in the population increases, following infection and vaccination, new variants will emerge, and therefore vaccines and monoclonal antibodies need to be developed to address them.
To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.
Atopic dermatitis is associated with work productivity loss. Little is known about how patients perceive their work ability and quality of working life, and how this is affected by treatment. Our ...primary objective was to investigate work ability and quality of working life at baseline and during treatment in the long term. A registry‐embedded prospective observational cohort study was conducted consisting of patients with atopic dermatitis starting dupilumab in routine clinical care. The instruments used were the Work Ability Index (WAI; questions 1, 2, and 3) and the Quality of Working Life Questionnaire (QWLQ). Ninety‐three patients were included of whom 72 were (self‐)employed (77%). From baseline to 48 weeks, the mean WAI‐1 score (general work ability, range 0–10) improved from 6.8 (±2.0) to 7.9 (±1.3), WAI‐2 (physical work ability, range 1–5) from 3.7 (±0.9) to 4.3 (±0.7), and WAI‐3 (mental/emotional work ability, range 1–5) from 3.4 (±0.9) to 3.9 (±0.8) (p = 0.001, p = 0.005, p < 0.001, respectively). The mean QWLQ total score improved from 74.0 (±9.1) to 77.5 (±9.6) and subscale “Problems due to health situation” improved from 37.4 (±22.3) to 61.5 (±23.1) (range 0–100; p = 0.032, p < 0.001, respectively). In conclusion, patients with moderate‐to‐severe atopic dermatitis starting dupilumab report decreased work ability and quality of working life, mainly due to health‐related problems. Significant improvement of work ability and quality of working life is observed with dupilumab treatment.
Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve ...glucose control while alleviating the risk of hypoglycaemia in adults with HbA1c below 7·5% (58 mmol/mol).
In this open-label, randomised, crossover study, we recruited adults (aged ≥18 years) with type 1 diabetes and HbA1c below 7·5% from Addenbrooke's Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria). After a 2–4 week run-in period, participants were randomly assigned (1:1), using web-based randomly permuted blocks of four, to receive insulin via the day-and-night hybrid closed-loop system or usual pump therapy for 4 weeks, followed by a 2–4 week washout period and then the other intervention for 4 weeks. Treatment interventions were unsupervised and done under free-living conditions. During the closed-loop period, a model-predictive control algorithm directed insulin delivery, and prandial insulin delivery was calculated with a standard bolus wizard. The primary outcome was the proportion of time when sensor glucose concentration was in target range (3·9–10·0 mmol/L) over the 4 week study period. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02727231, and is completed.
Between March 21 and June 24, 2016, we recruited 31 participants, of whom 29 were randomised. One participant withdrew during the first closed-loop period because of dissatisfaction with study devices and glucose control. The proportion of time when sensor glucose concentration was in target range was 10·5 percentage points higher (95% CI 7·6–13·4; p<0·0001) during closed-loop delivery compared with usual pump therapy (65·6% SD 8·1 when participants used usual pump therapy vs 76·2% 6·4 when they used closed-loop). Compared with usual pump therapy, closed-loop delivery also reduced the proportion of time spent in hypoglycaemia: the proportion of time with glucose concentration below 3·5 mmol/L was reduced by 65% (53–74, p<0·0001) and below 2·8 mmol/L by 76% (59–86, p<0·0001). No episodes of serious hypoglycaemia or other serious adverse events occurred.
Use of day-and-night hybrid closed-loop insulin delivery under unsupervised, free-living conditions for 4 weeks in adults with type 1 diabetes and HbA1c below 7·5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted.
Swiss National Science Foundation (P1BEP3_165297), JDRF, UK National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).
Display omitted
•PDLA-PEG-PDLA-b-PLLA copolymers with different ratios of PEG% were synthesized.•Microspheres of copolymers with higher PEG% showed faster degradation and erosion.•Sunitinib loaded ...microspheres showed sustained release over more than 5months.•Either zero-order or sigmoidal release profiles were observed.•Sunitinib microspheres inhibited neovascularization in CAM assay.
Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(d,l-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(l-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼30μm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.
is an obligate intracellular pathogen that causes sexually transmitted disease. In women, chlamydial infections may cause pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The ...role of antibodies in protection against a primary
infection is unclear and was a focus of this work. Using the
mouse infection model, we show that intestinal mucosa is infected via intranasal (i.n.) or per-oral (p.o.)
inoculation and that unlike the female reproductive tract (FRT) mucosa, it halts systemic
dissemination. Moreover, p.o. immunization or infection with
confers protection against per-vaginal (p.v.) challenge, resulting in significantly decreased bacterial burden in the FRT, accelerated
clearance, and reduced hydrosalpinx pathology. In contrast, subcutaneous (s.c.) immunization conferred no protection against the p.v. challenge. Both p.o. and s.c. immunizations induced
-specific serum IgA. However, IgA was found only in the vaginal washes and fecal extracts of p.o.-immunized animals. Following a p.v. challenge, unimmunized control and s.c.-s.c.-immunized animals developed
-specific intestinal IgA yet failed to develop IgA in the FRT, indicating that IgA response in the FRT relies on the FRT to gastrointestinal tract (GIT) antigen transport. Vaginal secretions of p.o.-immunized animals neutralize
, resulting in significantly lower
burden in the FRT and
transport to the GIT. We also show that infection of the GIT is not necessary for induction of protective immunity in the FRT, a finding that is important for the development of p.o. subunit vaccines to target
and possibly other sexually transmitted pathogens.
Extending phylogeography to account for lineage fusion Garrick, Ryan C.; Banusiewicz, John D.; Burgess, Stephanie ...
Journal of biogeography,
February 2019, 2019-02-00, 20190201, Letnik:
46, Številka:
2
Journal Article
Recenzirano
Secondary contact between long isolated populations has several possible outcomes. These include the strengthening of preexisting reproductive isolating mechanisms via reinforcement, the emergence of ...a hybrid lineage that is distinct from its extant parental lineages and which occupies a spatially restricted zone between them, or complete merging of two populations such that parental lineages are no longer extant (“lineage fusion” herein). The latter scenario has rarely been explicitly considered in single‐species and comparative phylogeographic studies, yet it has the potential to impact inferences about population history and levels of congruence. In this paper, we explore the idea that insights into past lineage fusion may now be possible, owing to the advent of next‐generation sequencing. Using simulated DNA sequence haplotype datasets (i.e., loci with alleles comprised of a set of linked nucleotide polymorphisms), we examined basic requirements (number of loci and individuals sampled) for identifying cases when a present‐day panmictic population is the product of lineage fusion, using an exemplar statistical framework—approximate Bayesian computation. We found that with approximately 100 phased haplotype loci (each 400 bp long) and modest sample sizes of individuals (10 per population), lineage fusion can be detected under rather challenging scenarios. This included some scenarios where reticulation was fully contained within a Last Glacial Maximum timeframe, provided that mixing was symmetrical, ancestral gene pools were moderately to deeply diverged, and the lag time between the fusion event and gene pool sampling was relatively short. However, the more realistic case of asymmetrical mixing is not prohibitive if additional genetic data (e.g., 400 loci) are available. Notwithstanding some simplifying assumptions of our simulations and the knowledge gaps that remain about the circumstances under which lineage fusion is potentially detectable, we suggest that the recent release from data limitation allows phylogeographers to expand the scope of inferences about long‐term population history.
PDF
