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Epithelia are continuously self-renewed, but how epithelial integrity is maintained during the morphological changes that cells undergo in mitosis is not well understood. Here, we show that as epithelial cells round up when they enter mitosis, they exert tensile forces on neighboring cells. We find that mitotic cell-cell junctions withstand these tensile forces through the mechanosensitive recruitment of the actin-binding protein vinculin to cadherin-based adhesions. Surprisingly, vinculin that is recruited to mitotic junctions originates selectively from the neighbors of mitotic cells, resulting in an asymmetric composition of cadherin junctions. Inhibition of junctional vinculin recruitment in neighbors of mitotic cells results in junctional breakage and weakened epithelial barrier. Conversely, the absence of vinculin from the cadherin complex in mitotic cells is necessary to successfully undergo mitotic rounding. Our data thus identify an asymmetric mechanoresponse at cadherin adhesions during mitosis, which is essential to maintain epithelial integrity while at the same time enable the shape changes of mitotic cells.
Previous studies comparing emergency surgery outcomes with surgeon experience have been small or used administrative databases without controlling for patient physiology or operative complexity.

To evaluate the association of acute care surgeon experience with patient morbidity and mortality after emergency surgical procedures.

This cohort study evaluated the association of surgeon experience with emergency surgery outcomes at 5 US academic level 1 trauma centers where the same surgeons provided emergency general surgical care. A total of 772 patients who presented with a traumatic injury and required an emergency surgical procedure or who presented with or developed a condition requiring an emergency general surgical intervention were operated on by 1 of 56 acute care surgeons. Surgeon groups were divided by experience of less than 6 years (early career), 6 to 10 years (early midcareer), 11 to 30 years (late midcareer), and 30 years or more (late career) from the end of training. Surgeons with less thating room may improve with experience. Early-career surgeons' outcomes may be improved if they are supported while experience is garnered.Omecamtiv mecarbil (OM), a direct myosin motor activator, is currently being tested as a therapeutic replacement for conventional inotropes in heart failure (HF) patients. It is known that HF patients exhibit dysregulated β-adrenergic signaling and decreased cardiac myosin-binding protein C (cMyBPC) phosphorylation, a critical modulator of myocardial force generation. However, the functional effects of OM in conditions of altered cMyBPC phosphorylation have not been established. Here, we tested the effects of OM on force generation and cross-bridge (XB) kinetics using murine myocardial preparations isolated from wild-type (WT) hearts and from hearts expressing S273A, S282A, and S302A substitutions (SA) in the M domain, between the C1 and C2 domains of cMyBPC, which cannot be phosphorylated. At submaximal Ca2+ activations, OM-mediated force enhancements were less pronounced in SA than in WT myocardial preparations. click here Additionally, SA myocardial preparations lacked the dose-dependent increases in force that were observed in WT myocardial preparations. Following OM incubation, the basal differences in the rate of XB detachment (krel) between WT and SA myocardial preparations were abolished, suggesting that OM differentially affects the XB behavior when cMyBPC phosphorylation is reduced. Similarly, in myocardial preparations pretreated with protein kinase A to phosphorylate cMyBPC, incubation with OM significantly slowed krel in both the WT and SA myocardial preparations. Collectively, our data suggest there is a strong interplay between the effects of OM and XB behavior, such that it effectively uncouples the sarcomere from cMyBPC phosphorylation levels. Our findings imply that OM may significantly alter the in vivo cardiac response to β-adrenergic stimulation.
Observational studies have reported associations between antihypertensive medication and psychiatric disorders, although the reported direction of association appears to be dependent on drug class.

To estimate the potential effect of different antihypertensive drug classes on schizophrenia, bipolar disorder, and major depressive disorder.

This 2-sample mendelian randomization study assessed the association between a single-nucleotide variant (SNV) and drug target gene expression derived from existing expression quantitative trait loci (eQTL) data in blood (sample 1) and the SNV-disease association from published case-control genome-wide association studies (sample 2). Significant associations were corroborated using published brain eQTL and protein QTL data. Participants included 40 675 patients with schizophrenia and 64 643 controls, 20 352 patients with bipolar disorder and 31 358 controls, and 135 458 patients with major depressive disorder and 344 901 controls. Blood eQTL levels were measured in 31  in late-onset schizophrenia.
To characterize the peripheral defocus of isolated human crystalline lenses and its age dependence.

Data were acquired on 116 isolated lenses from 99 human eyes (age range, 0.03-61 years; postmortem time, 40.1 ± 21.4 hours). Lenses were placed in a custom-built combined laser ray tracing and optical coherence tomography system that measures the slopes of rays refracted through the lens for on-axis and off-axis incidence angles. Ray slopes were measured by recording spot patterns as a function of axial position with an imaging sensor mounted on a positioning stage below the tissue chamber. Delivery angles ranged from -30° to +30° in 5° increments using a 6 mm × 6 mm raster scan with 0.5-mm spacing. Lens power at each angle was calculated by finding the axial position that minimizes the root-mean-square size of the spot pattern formed by the 49 central rays, corresponding to a 3-mm zone on-axis. The age dependence of the on-axis and off-axis optical power and the relative peripheral defocus (difference between off-axis and on-axis power) of lenses were quantified.
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