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A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight <500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability. Replicating the functionality of bioactive proteins using rationally designed small molecule mimics is both economically valuable and synthetically challenging. Here the authors develop a mimic of the inflammatory protein C3a with equal biological potency but enhanced stability and bioavailability.

As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’ 1 , 2 . Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management 3 . Ecosystems vary in their biota 4 , service provision 5 and relative exposure to risks 6 , yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework. The International Union for Conservation of Nature’s Global Ecosystem Typology has been developed to provide a systematic framework for data on all of Earth’s ecosystems in a unified theoretical context to support biodiversity conservation and ecosystem services.

In this study, the authors show that PTEN alters synaptic function after PDZ-dependent recruitment into spines induced by amyloid-β. This mechanism is crucial for pathogenesis, as preventing PTEN-PDZ interactions renders neurons resistant to amyloid-β and rescues cognitive function in Alzheimer's disease models. This suggests that PTEN is a critical effector of the synaptic pathology associated with Alzheimer's disease. Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non-Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole-genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome-wide SV analyses were performed with AD-related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome-wide significance (p <5×10 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome-wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ) was linked to diffuse plaques. All three SVs associated with AD (p <5×10 ) in replication. Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

The L-type Ca(2+) channel (Ca(V)1.2) plays an important role in action potential (AP) generation, morphology, and duration (APD) and is the primary source of triggering Ca(2+) for the initiation of Ca(2+)-induced Ca(2+)-release in cardiac myocytes. In this article we present: 1), a detailed kinetic model of Ca(V)1.2, which is incorporated into a model of the ventricular mycoyte where it interacts with a kinetic model of the ryanodine receptor in a restricted subcellular space; 2), evaluation of the contribution of voltage-dependent inactivation (VDI) and Ca(2+)-dependent inactivation (CDI) to total inactivation of Ca(V)1.2; and 3), description of dynamic Ca(V)1.2 and ryanodine receptor channel-state occupancy during the AP. Results are: 1), the Ca(V)1.2 model reproduces experimental single-channel and macroscopic-current data; 2), the model reproduces rate dependence of APD, [Na(+)](i), and the Ca(2+)-transient (CaT), and restitution of APD and CaT during premature stimuli; 3), CDI of Ca(V)1.2 is sensitive to Ca(2+) that enters the subspace through the channel and from SR release. The relative contributions of these Ca(2+) sources to total CDI during the AP vary with time after depolarization, switching from early SR dominance to late Ca(V)1.2 dominance. 4), The relative contribution of CDI to total inactivation of Ca(V)1.2 is greater at negative potentials, when VDI is weak; and 5), loss of VDI due to the Ca(V)1.2 mutation G406R (linked to the Timothy syndrome) results in APD prolongation and increased CaT.

BACKGROUND Few rare variants have been identified in genetic loci from genome‐wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS Eighty‐six rare missense or loss‐of‐function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)‐𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE‐𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non‐Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non‐Hispanic families.

Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance (p <5×10‐8) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10‐5), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10‐6) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10‐6) was linked to diffuse plaques. All three SVs associated with AD (p <5×10‐6) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

DXA scans may offer a novel means of evaluating radiographic knee OA (rKOA) in large population studies and through opportunistic screening. We aimed to develop and apply a semi-automated method for assessing rKOA using ≈20 000 knee DXA images from UK Biobank (UKB) and assess its face validity by checking for expected relationships with clinical outcomes. Right knee DXA scans were manually annotated for osteophytes to derive corresponding grades. Joint space narrowing (JSN) grades in the medial joint compartment were determined from automatically measured minimum joint space width. Overall rKOA grade (0-4) was determined by combining osteophyte and JSN grades. Logistic regression was employed to investigate the associations of osteophyte, JSN and rKOA grades with knee pain and hospital-diagnosed KOA. Cox proportional hazards modelling was used to examine the associations of these variables with risk of subsequent total knee replacement (TKR). Of the 19 595 participants included (mean age 63.7 years), 19.5% had rKOA grade ≥1 (26.1% female, 12.5% male). Grade ≥1 osteophytes and grade ≥1 JSN were associated with knee pain, hospital-diagnosed KOA and TKR. Higher rKOA grades were linked to stronger associations with these clinical outcomes, with the most pronounced effects observed for TKR. Hazard ratios for the association of rKOA grades with TKR were 3.28, 8.75 and 28.63 for grades 1, 2 and 3-4, respectively. Our DXA-derived measure of rKOA demonstrated a progressive relationship with clinical outcomes. These findings support the use of DXA for classifying rKOA in large epidemiological studies and in future population-based screening.

Background. Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women. Methods. Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF. Results. In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, −0.91% [95% confidence interval {CI}, −1.44% to −.38%]; P = .001) and hip (−0.61% [95% CI, −.96% to −.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged −1.42% ± 29% and −0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD. Conclusions. In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter. Clinical Trials Registration. NCT00458393.

Background Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.