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Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes.Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours.Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred.Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

Little is known about how proteostasis is maintained during viral infection. Here, the authors identify unexpected crosstalk between the calnexin cycle, ERAD, and reticulophagy, resulting in suppression of ebolavirus glycoprotein expression.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

ABSTRACT Purpose to investigate prosodic boundary effects on the comprehension of attachment ambiguities in Brazilian Portuguese and to test two hypotheses relying on the notion of boundary strength: the absolute boundary hypothesis (ABH) and the relative boundary hypothesis (RBH). Manipulations of prosodic structure influence how listeners interpret syntactically ambiguous sentences. However, the role of prosody in spoken language comprehension of sentences has received limited attention in languages other than English, particularly from a developmental perspective. Methods Twenty-three adults and 15 children participated in a computerized sentence comprehension task involving syntactically ambiguous sentences. Each sentence was recorded in eight different prosodic forms with acoustic manipulations of F0, duration and pause varying the boundary size to reflect predictions of the ABH and RBH. Results Children and adults differed in how prosody influenced their syntactic processing and children were significantly slower than adults. Results indicated that interpretation of sentences varied according to their prosodic forms. Conclusion Neither the ABH or the RBH explained how children and adults who speak Brazilian Portuguese use prosodic boundaries to disambiguate sentences. There is evidence that the way prosodic boundaries influence disambiguation varies cross-linguistically.

The effectiveness of small-bubble gas injection to mitigate cavitation-induced erosion damage and decrease strain in Spallation Neutron Source (SNS) target vessels was characterized using photography, laser-line scanning, and in-situ vessel strain measurements. Observations from early targets showed that erosion damage caused appreciable mass loss along the target vessel inner wall. Later target designs incorporated a cavitation mitigation technique called small-bubble gas injection, in which small helium gas bubbles were introduced into the flowing mercury during operation. Samples removed from target vessels after operation revealed that gas injection greatly reduced or eliminated erosion damage. Photographs of the target interiors showed areas where significant erosion damage occurred in targets that were operated without gas injection. The same areas had no observable erosion damage in targets that were operated with gas injection. Laser-line scan measurements were performed on samples from several target vessels operated with and without gas injection to measure the extent of erosion damage and quantify the effect of gas injection on erosion. In-situ strain measurements during operation showed that gas injection reduced the target vessel strain by 25%–75%. These results provide conclusive confirmation that gas injection effectively mitigated erosion damage and reduced strain in SNS target vessels during operation.

We provide evidence that children with Developmental Language Disorder (DLD) are impaired in predictive syntactic processing. In the current study, children listened passively to auditorily-presented sentences, where the critical condition included an unexpected “filled gap” in the direct object position of the relative clause verb. A filled gap is illustrated by the underlined phrase in “The zebra that the hippo kissed the camel on the nose…”, rather than the expected “the zebra that the hippo kissed [e] on the nose”, where [e] denotes the gap. Brain responses to the filled gap were compared to a control condition using adverb-relative clauses with identical substrings: “The weekend that the hippo kissed the camel on the nose [e]…”. Here, the same noun phrase is not unexpected because the adverb gap occurs later in the structure. We hypothesized that a filled gap would elicit a prediction error brain signal in the form of an early anterior negativity, as we have previously observed in adults. We found an early (bilateral) anterior negativity to the filled gap in a control group of children with Typical Development (TD), but the children with DLD exhibited no brain response to the filled gap during the same early time window. This suggests that children with DLD fail to predict that a relativized object should correspond to an empty position after the relative clause verb, suggesting an impairment in predictive processing. We discuss how this lack of a prediction error signal can interact with language acquisition and result in DLD.

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.

Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat.

Avian influenza: A vaccine for a deadly emergent strain A vaccine candidate to treat a deadly subtype of avian influenza was shown to induce protective antibodies in initial clinical trials. As of March 2017, avian influenza strain A/H7N9 has killed 497 people since 2013, with 1349 confirmed cases. Julie Ledgerwood and her team from the United States’ National Institutes of Health in collaboration with colleagues at the Centers for Disease Control and Prevention tested their two-stage vaccine protocol in humans, showing it to be effective and safe. The vaccine consists of an initial injection of viral DNA, which ‘primes’ the immune system to the pathogen, followed by a follow-up injection of an inactivated purified viral protein, which further boosts the host’s production of protective antibodies. The study shows the viability of this vaccine regimen and suggests further investigation into its appropriateness for treating avian influenza in humans.