Neutralizing antibodies (nAbs) elicited against the receptor binding site (RBS) of the spike protein of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally less ...effective against recent variants of concern. RBS residues Glu
, Lys
, and Asn
are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on angiotensin-converting enzyme 2 binding, as well as the effects of two of these mutations (K417N and E484K) on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternative binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.
The glass transition temperature (T
) is a key property that dictates the applicability of conjugated polymers. The T
demarks the transition into a brittle glassy state, making its accurate ...prediction for conjugated polymers crucial for the design of soft, stretchable, or flexible electronics. Here we show that a single adjustable parameter can be used to build a relationship between the T
and the molecular structure of 32 semiflexible (mostly conjugated) polymers that differ drastically in aromatic backbone and alkyl side chain chemistry. An effective mobility value, ζ, is calculated using an assigned atomic mobility value within each repeat unit. The only adjustable parameter in the calculation of ζ is the ratio of mobility between conjugated and non-conjugated atoms. We show that ζ correlates strongly to the T
, and that this simple method predicts the T
with a root-mean-square error of 13 °C for conjugated polymers with alkyl side chains.
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 ...mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
Key Points
Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating ...adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.Sex steroid receptor activity controls the distribution and growth of adipose tissues. Here, the authors reveal that Cxcr4 regulates the Pparg-marked adipose lineage to restrict female fat mass by modifying estrogen receptor expression and activity.
Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass ...and metabolic pathologies. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta (Pdgfrβ) to prevent beige adipogenesis. We show that genetically deleting Pdgfrβ, in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation. Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5. Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals.
The Multi-angle Imaging SpectroRadiometer (MISR)
instrument has been operational on the National Aeronautics and Space
Administration (NASA) Earth Observing System (EOS) Terra satellite since
early ...2000, creating an extensive data set of global Earth observations.
Here we introduce the latest version of the MISR aerosol products. The level
2 (swath) product, which is reported on a 4.4 km spatial grid, is designated as version 23 (V23) and contains retrieved aerosol optical depth (AOD) and
aerosol particle property information derived from MISR's multi-angle
observations over both land and water. The changes from the previous version
of the algorithm (V22) have significant impacts on the data product and its
interpretation. The V23 data set is created from two separate retrieval
algorithms that are applied over dark water and land surfaces, respectively.
Besides increasing the horizontal resolution to 4.4 km compared with the
coarser 17.6 m resolution in V22 and streamlining the format and content,
the V23 product has added geolocation information, pixel-level uncertainty
estimates, and improved cloud screening. MISR data can be obtained from the
NASA Langley Research Center Atmospheric Science Data Center at https://eosweb.larc.nasa.gov/project/misr/misr_table (last access: 11 October 2019). The
version number for the V23 level 2 aerosol product is F13_0023. The level 3 (gridded) aerosol product is still reported at
0.5∘×0.5∘ spatial resolution with results aggregated
from the higher-resolution level 2 data. The format and content at level 3
have also been updated to reflect the changes made at level 2. The level 3
product associated with the V23 level 2 product version is designated as
F15_0032. Both the level 2 and level 3 products are now
provided in NetCDF format.
Photoactivatable molecules enable ablation of malignant cells under the control of light, yet current agents can be ineffective at early stages of disease when target cells are similar to healthy ...surrounding tissues. In this work, we describe a chemical platform based on amino-substituted benzoselenadiazoles to build photoactivatable probes that mimic native metabolites as indicators of disease onset and progression. Through a series of synthetic derivatives, we have identified the key chemical groups in the benzoselenadiazole scaffold responsible for its photodynamic activity, and subsequently designed photosensitive metabolic warheads to target cells associated with various diseases, including bacterial infections and cancer. We demonstrate that versatile benzoselenadiazole metabolites can selectively kill pathogenic cells - but not healthy cells - with high precision after exposure to non-toxic visible light, reducing any potential side effects in vivo. This chemical platform provides powerful tools to exploit cellular metabolic signatures for safer therapeutic and surgical approaches.
Controlling the reduction midpoint potential of heme B is a key factor in many bioelectrochemical reactions, including long-range electron transport. Currently, there are a number of globular model ...protein systems to study this biophysical parameter; however, there are none for large polymeric protein model systems (e.g., the OmcS protein from G. sulfurreducens). Peptide amphiphiles, short peptides with a lipid tail that polymerize into fibrous structures, fill this gap. Here, we show a peptide amphiphile model system where one can tune the electrochemical potential of heme B by changing the loading ratio and peptide sequence. Changing the loading ratio resulted in the most significant increase, with values as high as −22 mV down to −224 mV. Circular dichroism spectra of certain sequences show Cotton effects at lower loading ratios that disappear as more heme B is added, indicating an ordered environment that becomes disrupted if heme B is overpacked. These findings can contribute to the design of functional self-assembling biomaterials.
Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly ...defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.
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•Vascular smooth muscle cells support BAT homeostasis and thermogenesis•BAT SMCs express Cxcl12 to maintain sympathetic innervation and macrophage accrual•Loss of Cxcl12 impairs cold-induced BAT thermogenesis and energy expenditure•Cxcl12 administration to obese mice restores the BAT thermogenic niche and function
Lee et al. expose the role of Cxcl12+ smooth muscle cells in coordinating brown adipose tissue (BAT) homeostasis. They find that Cxcl12 is necessary for BAT sympathetic innervation and macrophage accrual to stimulate thermogenesis, enhancing energy expenditure. Moreover, Cxcl12 administration alleviates obesogenic BAT dysfunction to restore thermogenesis.
The research that links excessive screen time to adverse health outcomes is based on self-reported screen use. Few studies have documented how passively-sensed smartphone and app use relate to health ...behaviors like activity and sitting. Furthermore, they have not considered that daily fluctuations in smartphone/app use may have different relationships to these behaviors than a person’s usual smartphone/app use. This study evaluated whether physical activity or sedentary (sitting) behavior are associated with either smartphone screen time or specific smartphone app use by adolescents and young adults during the COVID-19 pandemic. Adolescents and young adults aged 13–29 years wore activPAL4 micro activity monitors while their smartphones logged daily screen time and app use durations for nine days. Data were collected in 2020–2021 and analyzed in 2022–2023. Participants (
N
= 125) had a mean (SD) age of 19.7 (4.3) years. Participants’ usual smartphone screen time was negatively associated with daily step counts. Daily deviations in smartphone screen time were negatively associated with daily step counts and moderate-vigorous physical activity durations. Time spent on Instagram, YouTube and, to a lesser extent, TikTok were linked with reduced activity levels. Daily sedentary behavior was not associated with usual or daily screen time. Interventions to promote physical activity during the transition into adulthood may benefit from limiting excessive smartphone screen time. Specific intervention targets could include limiting use of apps with infinite scrolling feeds algorithmically tuned to maintain user engagement, such as Instagram, YouTube and TikTok.
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