Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Altered development of face recognition among infants born amid the COVID-19 pandemic.

To effectively contain the spread of COVID-19, public health agencies mandated special regulations. Although they protected us from COVID-19, these restrictions have inevitably changed the environment around us. It remains unclear how these changes may have affected early cognitive development among infants born during the pandemic. Thus, this study examined how the COVID-19 restrictions have affected infants' face recognition ability, a hallmark of their cognitive capacities. Specifically, we used the familiarization and visual pair comparison paradigm to examine face recognition performance among infants aged 6 to 14 months amid the second wave of the pandemic (February to July 2021). Experiment 1 investigated the recognition of unmasked faces and found that only younger infants, but not older infants, recognized faces by showing a novelty preference. Experiment 2 examined the recognition of faces wearing masks and found that only older infants, but not younger ones, recognized faces by exhibiting a familiarity preference. These results suggest that with limited interactions during the pandemic, infants could have developed an overly specialized face processing ability that failed to recognize the faces of strangers. Moreover, infants could have obtained more information on masked faces during the pandemic and adapted to the current situation. In Expreiment 3, we further confirmed the restriction on infants' interpersonal experiences with a survey conducted both before and during the pandemic. Overall, these findings demonstrated how the pandemic altered early perceptual development and further confirmed that interpersonal experiences during infancy are critical in their cognitive development.

Multilevel Factors for Adiposity Change in a Population-Based Prospective Study of Black Breast Cancer Survivors.

PURPOSE: Unfavorable weight change after breast cancer diagnosis increases the risk of mortality, but individual and neighborhood risk factors affecting postdiagnosis weight and body fat changes are unclear among Black women, who have higher rates of obesity and mortality than any other racial/ethnic group. METHODS: Adiposity changes during the period approximately 10 months-24 months after diagnosis were evaluated among 785 women diagnosed between 2012 and 2018 and enrolled in the Women's Circle of Health Follow-Up Study, a population-based prospective cohort of Black breast cancer survivors in New Jersey. Multilevel factors for weight and fat mass change (with gain or loss defined as a relative difference of 3% or more, and considering whether changes were intentional or unintentional) were estimated using multivariable polytomous logistic regressions and multilevel models. RESULTS: Adiposity gain was prevalent: 28% and 47% gained weight and body fat, respectively, despite a high baseline prevalence of overweight or obesity (86%). Risk factors for fat mass gain included receiving chemotherapy (relative risk ratio: 1.59, 95% CI, 1.08 to 2.33) and residing in neighborhoods with a greater density of fast-food restaurants (relative risk ratio comparing highest with lowest tertile: 2.18, 95% CI, 1.38 to 3.46); findings were similar for weight gain. Only 9% of women had intentional weight loss, and multilevel risk factors differed vastly from unintentional loss. CONCLUSION: Both individual and neighborhood factors were associated with adiposity change among Black breast cancer survivors. Residential environment characteristics may offer clinically meaningful information to identify cancer survivors at higher risk for unfavorable weight change and to address barriers to postdiagnosis weight management.

Integrins alpha1beta1 and alpha2beta1 are receptors for the rotavirus enterotoxin.

Rotavirus NSP4 is a viral enterotoxin capable of causing diarrhea in neonatal mice. This process is initiated by the binding of extracellular NSP4 to target molecule(s) on the cell surface that triggers a signaling cascade leading to diarrhea. We now report that the integrins alpha1beta1 and alpha2beta1 are receptors for NSP4. NSP4 specifically binds to the alpha1 and alpha2 I domains with apparent K(d) = 1-2.7 muM. Binding is mediated by the I domain metal ion-dependent adhesion site motif, requires Mg(2+) or Mn(2+), is abolished with EDTA, and an NSP4 point mutant, E(120)A, fails to bind alpha2 integrin I domain. NSP4 has two distinct integrin interaction domains. NSP4 amino acids 114-130 are essential for binding to the I domain, and NSP4 peptide 114-135 blocks binding of the natural ligand, collagen I, to integrin alpha2. NSP4 amino acids 131-140 are not associated with the initial binding to the I domain, but elicit signaling that leads to the spreading of attached C2C12-alpha2 cells, mouse myoblast cells stably expressing the human alpha2 integrin. NSP4 colocalizes with integrin alpha2 on the basolateral surface of rotavirus-infected polarized intestinal epithelial (Caco-2) cells as well as surrounding noninfected cells. NSP4 mutants that fail to bind or signal through integrin alpha2 were attenuated in diarrhea induction in neonatal mice. These results indicate that NSP4 interaction with integrin alpha1 and alpha2 is an important component of enterotoxin function and rotavirus pathogenesis, further distinguishing this viral virulence factor from other microbial enterotoxins.

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

Time course of focused ultrasound effects on ß-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer's disease.

Previous studies have demonstrated that temporarily increasing the permeability of the blood-brain barrier using focused ultrasound can reduce ß-amyloid plaque load and improve cognitive function in animal models of Alzheimer's disease. However, the underlying mechanism and duration for which the effects of one treatment persists for are unknown. Here, we used in vivo two-photon fluorescence microscopy to track changes in ß-amyloid plaque sizes in the TgCRND8 mouse model of Alzheimer's disease after one focused ultrasound treatment. We found that one treatment reduced plaques to 62 ± 16% (p ≤ 0.001) of their original volume two days post-sonication; this decrease in size persisted for two weeks. We then sought to evaluate the effectiveness of biweekly focused ultrasound treatments using magnetic resonance imaging-guided focused ultrasound treatments. Three to five biweekly treatments resulted in a 27 ± 7% (p ≤ 0.01) decrease in plaque number and 40 ± 10% (p ≤ 0.01) decrease in plaque surface area compared to untreated littermates. This study demonstrates that one focused ultrasound treatment reduces the size of existing ß-amyloid plaques for two weeks, and that repeated biweekly focused ultrasound treatments is an effective method of reducing ß-amyloid pathology in moderate-to-late stages of Alzheimer's disease.