Apples are a highly pollinator-dependent crop that require a minimum number of accumulated chill hours to break dormancy in preparation for bud development and blooming. In the Indian Western Himalayas, apple production is shifting to higher elevations to counteract climate change-associated temperature increases. But it is unclear if and to what extent pollinators are able to match these shifts, or how these altitudinal shifts impact pollinator contribution to apple production. To address these knowledge gaps, we manipulated pollination conditions for apple blossom clusters in 13 orchards distributed along an elevational gradient (1680–2360 m) and measured early fruit set. Fruit set was significantly impacted by pollination treatment and elevation, and in some cases by their interaction. Averaged across elevations, fruit set in the pollinator exclusion treatment was only 6% of that observed under open pollination conditions, but fruit set in the open pollination treatment decreased markedly with elevation. Predicted pollinator contribution to fruit set also decreased with elevation, from 0.96 at the lowest modeled elevation to 0.76 at the highest modeled elevation. Fruit set was enhanced by supplementary hand pollination, demonstrating pollination limitation. We found that pollination deficit increased with elevation, ranging from 0.05 at the lowest modeled elevation (1650 m) to 0.24 at the highest modeled elevation (2400 m). Our findings demonstrate that at least some of the productivity gains realized with increased availability of chilling units at higher elevations might be compromised by pollination limitation. Future studies to determine more clearly the extent and underlying causes of elevation effects on pollination deficits are needed.

Alzheimer's disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aβ, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aβ proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aβ substrate. Our examination of BACE1 APP/Aβ proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog is found in cnidarians, while ctenophores, placozoa, and choanoflagellates have genes equally orthologous to BACE1 and BACE2. BACE1 from a cnidarian (Hydra) can cleave APP to release Aβ, pushing back the date of the origin of its function to near the origin of animals. We tested more divergent BACE1/2 genes from a ctenophore (Mnemiopsis) and a choanoflagellate (Monosiga), and neither has this activity. These findings indicate that the specific proteolytic function of BACE1 evolved during the very earliest diversification of animals, most likely after a gene-duplication event.

Multi-year and multi-site demographic data for rare plants allow researchers to observe threats and project population growth rates and thus long-term persistence of the species, generating knowledge, which allows for effective conservation planning. Demographic studies across more than a decade are extremely rare but allow for the effects of threats to be observed and assessed within the context of interannual environmental variation. We collected demographic data on the Threatened plant Cirsium pitcheri in two sites from 2011-2022. These sites were chosen because one exhibited the presence of non-native seed predators while the other did not, and we hypothesized that we would see declines and potentially extinction of the population threatened by predation. Over the course of our study, we observed additional threats, such as human trampling and high lake levels, which led to significant erosion, sand burial, and storm damage to plants. We find high interannual variation in vital rates and population growth rates for both populations, which mask the overall effects of predation. We observed dramatic declines in plant survivorship and population growth rates in both sites in the years with high lake levels. We conclude that high lake levels, which are expected to become more frequent with climate change, pose a significant threat to all near-shore populations of C. pitcheri.

In this contribution, we examine a virtual, cross-campus collaboration during the fall of 2020. Our goal was for students to develop deeper knowledge of the materiality of borders through course content as well as getting to know each other and their different contexts in iterative ways. We approached this goal by intentionally seeking to engage our students, who were facing virtual classes for the second or third time given the Covid-19 pandemic. We knew students struggled with online platforms in previous terms and aimed to provide a classroom experience that recognized the limits of screen-based interaction and the multitude of precarities accentuated by the pandemic. While attending our classes, students were also facing the interlocking effects of Covid-19 including illness and death in their families, effects on their employment and mobility, and associated mental health struggles. Thus, community building within and across these classes was key as we navigated teaching online. Finally, we address our social location regarding course content given our complicated histories of migration and identities as undocuscholars: growing up and attending higher education undocumented in the U.S. (though no longer undocumented).

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m2. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use’s (ICH) renovation of Good Clinical Practice (GCP) represents a philosophical shift in the conduct of clinical research away from a one-size-fits-all application to promoting a proactive, risk-based approach. The aim of this paper is to enhance the understanding of specific topics detailed in ICH E8 based on direct feedback from TransCelerate member companies who identified Quality by Design (QbD), Critical to Quality (CtQ), Fit for Purpose, and Stakeholder Engagement, as most changed and open to interpretation. The TransCelerate framework seeks to highlight and expand each of these central topics to support utilization and implementation of a strong foundation for quality in clinical development.

Media outlets tend to cover rare events like school shootings. However, some school shootings receive more media coverage than others, and little is empirically known why, or what school shooting characteristics might attract greater media attention. This study addresses this gap and conducts a distortion analysis using data from The American School Shooting Study (TASSS), a national, open-source database. TASSS includes all publicly known shootings that resulted in at least one injury on K-12 school grounds in the United States between January 1, 1990, and December 31, 2016. The findings reveal that school shooters with a criminal record, who have psychological issues, committed a shooting post-Columbine, and who injured or killed more victims received more coverage.