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Abstract Physical exercise induces acute psychophysiological responses leading to chronic adaptations when the exercise stimulus is applied repeatedly, at sufficient time periods, and with appropriate magnitude. To maximize long-term training adaptations, it is crucial to control and manipulate the external load and the resulting psychophysiological strain. Therefore, scientists have developed a theoretical framework that distinguishes between the physical work performed during exercise (i.e., external load/intensity) and indicators of the body's psychophysiological response (i.e., internal load/intensity). However, the application of blood flow restriction (BFR) during exercise with low external loads/intensities (e.g., ≤ 30% of the one-repetition-maximum, ≤ 50% of maximum oxygen uptake) can induce physiological and perceptual responses, which are commonly associated with high external loads/intensities. This current opinion aimed to emphasize the mismatch between external and internal load/intensity when BFR is applied during exercise. In this regard, there is evidence that BFR can be used to manipulate both external load/intensity (by reducing total work when exercise is performed to exhaustion) and internal load/intensity (by leading to higher physiological and perceptual responses compared to exercise performed with the same external load/intensity without BFR). Furthermore, it is proposed to consider BFR as an additional exercise determinant, given that the amount of BFR pressure can determine not only the internal but also external load/intensity. Finally, terminological recommendations for the use of the proposed terms in the scientific context and for practitioners are given, which should be considered when designing, reporting, discussing, and presenting BFR studies, exercise, and/or training programs.

Making sure all key stakeholders are included in community-engaged partnership projects is a difficult but important task. A systematic methodology for identifying partners would help avoid this problem. The double rainbow model is a systematic approach designed to identify all potential partners that can contribute to or might be affected by the project. This model was introduced almost 30 years ago and has been tested, implemented, and found to be effective numerous times. Its development, theoretical bases, and several examples are provided here.

ABSTRACT Malaria rapid diagnostic tests (RDTs), which detect Plasmodium falciparum (Pf)-specific histidine-rich protein-2 (HRP2), have increasing importance for the diagnosis and control of malaria, especially also in regions where routine diagnosis by microscopy is not available. HRP2-based RDTs have a similar sensitivity to expert microscopy, but their reported low specificity can lead to high false positivity rates, particularly in high-endemic areas. Despite the widespread use of RDTs, models investigating the dynamics of HRP2 clearance following Pf treatment focus rather on short-term clearance of the protein. The goal of this observational cohort study was to determine the long-term kinetic of HRP2-levels in peripheral blood after treatment of uncomplicated malaria cases with Pf mono-infection using a 3-day course of artesunate/amodiaquine. HRP2 levels were quantified at enrollment and on days 1, 2, 3, 5, 7, 12, 17, 22, and 28 post-treatment initiation. The findings reveal an unexpectedly prolonged clearance of HRP2 after parasite clearance from capillary blood. Terminal HRP2 half-life was estimated to be 9 days after parasite clearance using a pharmacokinetic two-compartmental elimination model. These results provide evidence that HRP2 clearance has generally been underestimated, as the antigen remains detectable in capillary blood for up to 28 days following successful treatment, influencing RDT-based assessment following a malaria treatment for weeks. A better understanding of the HRP2 clearance dynamics is critical for guiding the diagnosis of malaria when relying on RDTs.IMPORTANCEDetecting Plasmodium falciparum, the parasite responsible for the severest form of malaria, typically involves microscopy, polymerase chain reaction (PCR), or rapid diagnostic tests (RDTs) targeting the histidine-rich protein 2 or 3 (HRP2/3). While microscopy and PCR quickly turn negative after the infection is cleared, HRP2 remains detectable for a prolonged period. The exact duration of HRP2 persistence had not been well defined. Our study in Gabon tracked HRP2 levels over 4 weeks, resulting in a new model for antigen clearance. We discovered that a two-compartment model accurately predicts HRP2 levels, revealing an initial rapid reduction followed by a much slower elimination phase that can take several weeks. These findings are crucial for interpreting RDT results, as lingering HRP2 can lead to false positives, impacting malaria diagnosis and treatment decisions.

Abstract Assessing bone growth trajectories in mammals is crucial for understanding life history dynamics, but the quantification of bone growth in natural settings can be challenging. Bone resorption markers that can be measured in urine, such as C‐telopeptide of type I collagen (CTX‐I), offer a non‐invasive solution to assess bone growth. Although measurement of urinary CTX‐I levels has been applied extensively in human studies, its use in other species is so far limited to a few clinical studies. To validate urinary CTX‐I as a bone resorption marker under less controlled conditions, we investigated within‐individual day‐to‐day variation, diurnal patterns, and sex and age‐specific variation in zoo‐housed bonobos (Pan paniscus). We then also correlated urinary CTX‐I levels with forearm growth velocity measures. We found a day‐to‐day variability in urinary CTX‐I levels of around 25%, comparable to human variation. Diurnally, CTX‐I levels decreased, aligning with observations in humans and other species. Both sexes showed an age‐related decline in urinary CTX‐I levels, with a steady decrease after the age of 10 years. Additionally, we found a positive correlation between forearm growth velocity and urinary CTX‐I levels across age in female, but not in male, bonobos. Our results demonstrate that urinary CTX‐I levels are a meaningful measure of bone growth and highlight its potential to examine bone growth trajectories also in wild populations to investigate life history dynamics.

BackgroundThrough the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species.ResultsOur results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further suggest that this merging process, which is highly conserved across bats, occurs through modulation of the programs controlling the development of the periderm of the epidermal epithelium. Finally, our results suggest that the shape of the plagiopatagium begins to diversify in bats only after this merging has occurred.ConclusionsThis study demonstrates how focusing on the evolution of cellular processes can inform an understanding of the developmental factors shaping the evolution of novel, highly adaptive structures.

The All of Us Research Program seeks to engage at least one million diverse participants to advance precision medicine and improve human health. We describe here the cloud-based Researcher Workbench that uses a data passport model to democratize access to analytical tools and participant information including survey, physical measurement, and electronic health record (EHR) data. We also present validation study findings for several common complex diseases to demonstrate use of this novel platform in 315,000 participants, 78% of whom are from groups historically underrepresented in biomedical research, including 49% self-reporting non-White races. Replication findings include medication usage pattern differences by race in depression and type 2 diabetes, validation of known cancer associations with smoking, and calculation of cardiovascular risk scores by reported race effects. The cloud-based Researcher Workbench represents an important advance in enabling secure access for a broad range of researchers to this large resource and analytical tools.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

Summary: We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term “forerunner” genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.