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Background and Objective The International Dermatology Outcome Measures (IDEOM) has defined a core set of domains to be measured in all psoriasis clinical trials. This set comprises the following domains: skin manifestations, psoriasis and psoriatic arthritis symptoms, health-related quality of life, investigator global, patient global, and treatment satisfaction. The next step is to define how to measure these domains. The objective of this article was to evaluate the quality of available instruments to assess ‘investigator global’ and ‘patient global’ domains to identify the most appropriate instruments. Methods Reviewers conducted a systematic literature review to retrieve studies on the measurement properties of instruments including either an investigator global assessment or a patient global assessment. Following the COnsensus based standards for the Selection of health Measurement INstruments (COSMIN) checklist, three independent reviewers rated the quality of each study. We then performed a qualitative synthesis of the evidence. Results We identified nine investigator global assessments and three patient global assessments, reflecting substantial variability in global assessment instruments. Overall, most measures lacked evidence for content validity and feasibility. The Lattice System-Physician Global Assessment, Product of the Investigator Global Assessment and Body Surface Area, and the professional-Simplified Psoriasis Index had higher levels of evidence for validity, reliability, and/or responsiveness than the 5- and 6-point investigator global assessments. The self-assessment-Simplified Psoriasis Index was the only patient global assessment with evidence for validity, reliability, and responsiveness. Conclusions The 5- and 6-point investigator global assessments, which are the most widely used investigator global assessments in registered clinical trials, have less evidence for measurement properties as compared with the Lattice System-Physician Global Assessment, professional-Simplified Psoriasis Index, and the Product of the Investigator Global Assessment and Body Surface Area. However, all instruments lack evidence for content validity and feasibility. Further validation studies of investigator global assessments and patient global assessments are required to recommend the best global measure for psoriasis clinical trials.

Innovative, online models of specialty-care delivery are critical to improving patient access and outcomes. To determine whether an online, collaborative connected-health model results in equivalent clinical improvements in psoriasis compared with in-person care. The Patient-Centered Outcomes Research Institute Psoriasis Teledermatology Trial is a 12-month, pragmatic, randomized clinical equivalency trial to evaluate the effect of an online model for psoriasis compared with in-person care. Participant recruitment and study visits took place at multicenter ambulatory clinics from February 2, 2015, to August 18, 2017. Participants were adults with psoriasis in Northern California, Southern California, and Colorado. The eligibility criteria were an age of 18 years or older, having physician-diagnosed psoriasis, access to the internet and a digital camera or mobile phone with a camera, and having a primary care physician. Analyses were on an intention-to-treat basis. Participants were randomized 1:1 to receive online or in-person care (148 randomized to online care and 148 randomized to in-person care). The online model enabled patients and primary care physicians to access dermatologists online asynchronously. The dermatologists provided assessments, recommendations, education, and prescriptions online. The in-person group sought care in person. The frequency of online or in-person visits was determined by medical necessity. All participants were exposed to their respective interventions for 12 months. The prespecified primary outcome was the difference in improvement in the self-administered Psoriasis Area and Severity Index (PASI) score between the online and in-person groups. Prespecified secondary outcomes included body surface area (BSA) affected by psoriasis and the patient global assessment score. Of the 296 randomized participants, 147 were women, 149 were men, 187 were white, and the mean (SD) age was 49 (14) years. The adjusted difference between the online and in-person groups in the mean change in the self-administered PASI score during the 12-month study period was -0.27 (95% CI, -0.85 to 0.31). The difference in the mean change in BSA affected by psoriasis between the 2 groups was -0.05% (95% CI, -1.58% to 1.48%). Between-group differences in the PASI score and BSA were within prespecified equivalence margins, which demonstrated equivalence between the 2 interventions. The difference in the mean change in the patient global assessment score between the 2 groups was -0.11 (95% CI, -0.32 to 0.10), which exceeded the equivalence margin, with the online group displaying greater improvement. The online, collaborative connected-health model was as effective as in-person management in improving clinical outcomes among patients with psoriasis. Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic diseases. ClinicalTrials.gov Identifier: NCT02358135.

We report a strategy for realizing tunable electrical conductivity in metal-organic frameworks (MOFs) in which the nanopores are infiltrated with redox-active, conjugated guest molecules. This approach is demonstrated using thin-film devices of the MOF Cu₃(BTC)₂ (also known as HKUST-1; BTC, benzene-1,3,5-tricarboxylic acid) infiltrated with the molecule 77,8,8-tetracyanoquinododimethane (TCNQ). Tunable, air-stable electrical conductivity over six orders of magnitude is achieved, with values as high as 7 Siemens per meter. Spectroscopic data and first-principles modeling suggest that the conductivity arises from TCNQ guest molecules bridging the binuclear copper paddlewheels in the framework, leading to strong electronic coupling between the dimeric Cu subunits. These ohmically conducting porous MOFs could have applications in conformai electronic devices, reconfigurable electronics, and sensors.

Maintaining and restoring ecological connectivity will be key in helping to prevent and reverse the loss of biodiversity. Fortunately, a growing body of research conducted over the last few decades has advanced our understanding of connectivity science, which will help inform evidence‐based connectivity conservation actions. Increases in data availability and computing capacity have helped to dramatically increase our ability to model functional connectivity using more sophisticated models. Keeping track of these advances can be difficult, even for connectivity scientists and practitioners. In this article, we highlight some key advances from the past decade and outline many of the remaining challenges. We describe the efforts to increase the biological realism of connectivity models by, for example, isolating movement behaviors, population parameters, directional movements, and the effects of climate change. We also discuss considerations of when to model connectivity for focal or multiple species. Finally, we reflect on how to account for uncertainty and increase the transparency and reproducibility of connectivity research and discuss situations where decisions may require forgoing sophistication for more simple approaches. A graphical representation of the important connectivity concepts discussed in our review and how they relate to each other. We discuss how connectivity models have increased in biological realism and why that is important, advances in directional and climate connectivity as well as multi‐ and single‐species connectivity models.

Elevated eripheral serotonin reduces brown adipose tissue thermogenesis and promotes obesity and metabolic dysfunction. Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue 1 , 2 , but its thermogenic potential is reduced with obesity and type 2 diabetes 3 , 4 , 5 for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively 6 , 7 , 8 . Recent findings suggest that increased peripheral serotonin 9 and polymorphisms in TPH1 are associated with obesity 10 ; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1 -deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro . As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.

Understanding how predation risk and plant defenses interactively shape plant distributions is a core challenge in ecology. By combining global positioning system telemetry of an abundant antelope (impala) and its main predators (leopards and wild dogs) with a series of manipulative field experiments, we showed that herbivores’ risk-avoidance behavior and plants’ antiherbivore defenses interact to determine tree distributions in an African savanna.Well-defended thorny Acacia trees (A. etbaica) were abundant in low-risk areas where impala aggregated but rare in high-risk areas that impala avoided. In contrast, poorly defended trees (A. brevispica) were more abundant in high- than in low-risk areas. Our results suggest that plants can persist in landscapes characterized by intense herbivory, either by defending themselves or by thriving in risky areas where carnivores hunt.

Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6 - RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process. The ETV6 - RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6 - RUNX1 –positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

Indigenous Peoples around the northern hemisphere have long relied on caribou for subsistence and for ceremonial and community purposes. Unfortunately, despite recovery efforts by federal and provincial agencies, caribou are currently in decline in many areas across Canada. In response to recent and dramatic declines of mountain caribou populations within their traditional territory, West Moberly First Nations and Saulteau First Nations (collectively, the \"Nations\") came together to create a new vision for caribou recovery on the lands they have long stewarded and shared. The Nations focused on the Klinse-Za subpopulation, which had once encompassed so many caribou that West Moberly Elders remarked that they were \"like bugs on the landscape.\" The Klinse-Za caribou declined from ~250 in the 1990s to only 38 in 2013, rendering Indigenous harvest of caribou nonviable and infringing on treaty rights to a subsistence livelihood. In collaboration with many groups and governments, this Indigenous-led conservation initiative paired short-term population recovery actions, predator reduction and maternal penning, with long-term habitat protection in an effort to create a self-sustaining caribou population. Here, we review these recovery actions and the promising evidence that the abundance of Klinse-Za caribou has more than doubled from 38 animals in 2013 to 101 in 2021, representing rapid population growth in response to recovery actions. With looming extirpation averted, the Nations focused efforts on securing a landmark conservation agreement in 2020 that protects caribou habitat over a 7986-km² area. The Agreement provides habitat protection for >85% of the Klinse-Za subpopulation (up from only 1.8% protected pre-conservation agreement) and affords moderate protection for neighboring caribou subpopulations (29%–47% of subpopulation areas, up from 0%–20%). This Indigenous-led conservation initiative has set both the Indigenous and Canadian governments on the path to recover the Klinse-Za subpopulation and reinstate a culturally meaningful caribou hunt. This effort highlights how Indigenous governance and leadership can be the catalyst needed to establish meaningful conservation actions, enhance endangered species recovery, and honor cultural connections to now imperiled wildlife.

Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational “anchor extension” methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC 50 values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain. Cyclic peptides are of particular interest due to their pharmacological properties, but their design for binding to a target protein is challenging. Here, the authors present a computational “anchor extension” methodology for de novo design of cyclic peptides that bind to the target protein with high affinity, and validate the approach by developing cyclic peptides that inhibit histone deacetylases 2 and 6.

Optimizing energy acquisition and expenditure is a fundamental trade-off for consumers, strikingly reflected in how mobile organisms use space. Several studies have established that home range size decreases as resource density increases, but the balance of costs and benefits associated with exploiting a given resource density is unclear. We evaluate how the ability of consumers to exploit their resources through movement (termed “resource exploitation”) interacts with resource density to influence home range size. We then contrast two hypotheses to evaluate how resource exploitation influences home range size across a vast gradient of productivity and density of human-created linear features (roads and seismic lines) that are known to facilitate animal movements. Under the Diffusion Facilitation Hypothesis, linear features are predicted to lead to more diffuse space use and larger home ranges. Under the Exploitation Efficiency Hypothesis, linear features are predicted to increase foraging efficiency, resulting in less space being required to meet energetic demands and therefore smaller home ranges. Using GPS telemetry data from 142 wolves (Canis lupus) distributed over more than 500,000 km², we found that wolf home range size was influenced by the interaction between resource density and exploitation efficiency. Home range size decreased as linear feature density increased, supporting the Exploitation Efficiency Hypothesis. However, the effect of linear features on home range size diminished in more productive areas, suggesting that exploitation efficiency is of greater importance when resource density is low. These results suggest that smaller home ranges will occur where both linear feature density and primary productivity are higher, thereby increasing regional wolf density.