Miracle-dz/UniFAR-FTUs huggingface dataset:
Omecamtiv mecarbil lowers the contractile deficit in a mouse model of nebulin-based nemaline myopathy

Nemaline myopathy (NEM) is a congenital neuromuscular disorder primarily caused by nebulin gene (NEB) mutations. NEM is characterized by muscle weakness for which currently no treatments exist. In NEM patients a predominance of type I fibers has been found. Thus, therapeutic options targeting type I fibers could be highly beneficial for NEM patients. Because type I muscle fibers express the same myosin isoform as cardiac muscle (Myh7), the effect of omecamtiv mecarbil (OM), a small molecule activator of Myh7, was studied in a nebulin-based NEM mouse model (Neb cKO). Skinned single fibers were activated by exogenous calcium and force was measured at a wide range of calcium concentrations. Maximal specific force of type I fibers was much less in fibers from Neb cKO animals and calcium sensitivity of permeabilized single fibers was reduced (pCa50 6.12 ±0.08 (cKO) vs 6.36 ±0.08 (CON)). OM increased the calcium sensitivity of type I single muscle fibers. The greatest effect occurred in type I fibers from Neb cKO muscle where OM restored the calcium sensitivity to that of the control type I fibers. Forces at submaximal activation levels (pCa 6.0–6.5) were significantly increased in Neb cKO fibers (~50%) but remained below that of control fibers. OM also increased isometric force and power during isotonic shortening of intact whole soleus muscle of Neb cKO mice, with the largest effects at physiological stimulation frequencies. We conclude that OM has the potential to improve the quality of life of NEM patients by increasing the force of type I fibers at submaximal activation levels.
Right ventricular function during and after thoracic surgery.

PURPOSE OF REVIEW Right ventricular (RV) dysfunction following thoracotomy and pulmonary resection is a known phenomenon but questions remain about its mechanism, risk factors, and clinical significance. Acute RV dysfunction can present intraoperatively and postoperatively, persisting for 2 months after surgery. RECENT FINDINGS Recently, the pulmonology literature has emphasized pulmonary arterial capacitance, rather than pulmonary vascular resistance, as a marker to predict disease progression and outcome in patients with pulmonary hypertension and heart failure. Diagnostic focus has emerged on the use of cardiac MRI and new echocardiographic parameters to better quantify the presence of RV dysfunction and the role of pulmonary capacitance in its development. SUMMARY In this review, we examine the most recent literature on RV dysfunction following lung resection, including possible mechanisms, time span of RV dysfunction, and available diagnostic modalities. The clinical relevance of these factors on preoperative assessment and risk stratification are presented.
Association of a P2Y12 Inhibitor Copayment Reduction Intervention With Persistence and Adherence With Other Secondary Prevention Medications: A Post Hoc Analysis of the ARTEMIS Cluster-Randomized Clinical Trial.

Importance The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) cluster-randomized trial found that copayment reduction for P2Y12 inhibitors improved 1-year patient persistence in taking that medication. Objective To assess whether providing copayment reduction for P2Y12 inhibitors increases patient persistence in taking other secondary prevention cardiovascular medications. Design, Setting, and Participants This post hoc analysis of the ARTEMIS trial includes data from 287 hospitals that enrolled patients between June 2015 and September 2016. Patients hospitalized with acute myocardial infarction were included. Data analysis occurred from May 2018 through August 2019. Interventions Hospitals randomized to the intervention provided patients vouchers that waived copayments for P2Y12 inhibitors fills for 1 year. Hospitals randomized to usual care did not provide study vouchers. Main Outcomes and Measures Persistence in taking β-blocker, statin, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker medications at 1 year, defined as the absence of a gap in medication supply of 30 or more days by pharmacy fill data in the intervention-arm (intent-to-treat) population. Results A total of 131 hospitals (with 5109 patients) were randomized to the intervention, and 156 hospitals (with 3264 patients) randomized to the control group. Patients discharged from intervention hospitals had higher persistence in taking statins (2247 [46.1%] vs 1300 [41.9%]; adjusted odds ratio, 1.11 [95% CI, 1.00-1.24]), and β-blockers (2235 [47.6%] vs 1277 [42.5%]; odds ratio, 1.23 [95% CI, 1.10-1.38]), although the association was smaller than that seen for P2Y12 inhibitors (odds ratio, 1.47 [95% CI, 1.29-1.66]). Persistence in taking angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers were also numerically higher among patients in the intervention arm than in the usual-care arm, but this was not significant after risk adjustment (1520 [43.9%] vs 847 [40.5%]; adjusted odds ratio, 1.10 [95% CI, 0.97-1.24]). Patients in the intervention arm reported greater financial burden associated with medication cost than the patients in the usual-care arm at baseline, but these differences were no longer significant at 1 year. Conclusions and Relevance Reducing patient copayments for 1 medication class increased persistence not only to that therapy class but may also have modestly increased persistence to other post-myocardial infarction secondary prevention medications. These findings have important implications for the clinical utility and cost-effectiveness of medication cost-assistance programs. Trial Registration ClinicalTrials.gov Identifier: NCT02406677.
Somatic mutations and genome stability maintenance in clonal coral colonies

One challenge for multicellular organisms is maintaining genome stability in the face of mutagens across long life spans. Imperfect genome maintenance leads to mutation accumulation in somatic cells, which is associated with tumors and senescence in vertebrates. Colonial reef-building corals are often large, can live for hundreds of years, rarely develop recognizable tumors, and are thought to convert somatic cells into gamete producers, so they are a pivotal group in which to understand long-term genome maintenance. To measure rates and patterns of somatic mutations, we analyzed transcriptomes from 17-22 branches from each of four Acropora hyacinthus colonies, determined putative single nucleotide variants, and verified them with Sanger resequencing. Unlike for human skin carcinomas, there is no signature of mutations caused by UV damage, indicating either higher efficiency of repair than in vertebrates, or strong sunscreen protection in these shallow water tropical animals. The somatic mutation frequency per nucleotide in A. hyacinthus is on the same order of magnitude (10−7) as noncancerous human somatic cells, and accumulation of mutations with age is similar. Unlike mammals, loss of heterozygosity variants outnumber gain of heterozygosity mutations about 2:1. Although the mutation frequency is similar in mammals and corals, the preponderance of loss of heterozygosity changes and potential selection may reduce the frequency of deleterious mutations in colonial animals like corals. This may limit the deleterious effects of somatic mutations on the coral organism as well as potential offspring.
Local unemployment changes the springboard effect of low pay: Evidence from England

There is considerable debate on whether the employment and earnings prospects are better for those on low pay or for the unemployed. Low-pay work tends to be undertaken more locally but no empirical analysis has focused on how local opportunities alter prospects. Using Understanding Society data for England matched with local unemployment rates, we estimate dynamic random effects panel models, which show robust evidence that the future unemployment risk is lower for those who are currently on low pay compared to those who are currently unemployed. The low-paid also have a higher chance than the unemployed of becoming higher-paid. These findings are most marked in neighbourhoods with high unemployment.
The impact of sodium chloride reduction on Grana-type cheese production and quality

Abstract With the aim to reduce the Na content, hard cheeses manufactured using the same technology as for Grana cheese (Grana-type) were salted using three brines containing different amounts of KCl (K-brines) and compared with control cheeses, salted with marine NaCl. A lower weight loss was observed in cheeses salted with K-brines (K-cheeses), whereas the yield and dry matter did not differ significantly between K-cheeses and controls. After 3 months of ripening (T3), the distribution of the Na cations (Na) was centripetal, with a higher Na concentration in the outer (0–3 cm of depth) layer, whereas the K cations (K) seemed to diffuse into the cheese more rapidly and homogeneously. Starting from the 6th month (T6), the distribution of both Na and K was stabilized through the different cheese layers. The use of the brine with the highest concentration of potassium (53.8% K) enabled us to successfully halve the Na content compared to the controls whereas, with the other brines, the reduction of Na was below 30%. At the end of ripening (T9), all the cheeses were without defects and the partial substitution of Na with K did not impact on the chemical composition, microbiological characteristics and ripening process. The sensory evaluation did not show any difference between K-salted and control cheeses in discriminant analysis.
Test-retest reliability and minimal detectable change of the computerized dynamic posturography PROPRIO for adults with chronic traumatic brain injury

Abstract Purpose Balance deficits after brain injury, including reactive recovery from unexpected perturbations, can persist well after rehabilitation is concluded. While traditional clinical assessments are practical, the anticipatory nature of the tasks may mask perceptible balance control. Computerized dynamic posturography can directly quantify capacity to respond to unexpected, external perturbations. This study examined the reliability of the computerized dynamic posturography assessment with the device PROPRIO® 4000 in adults with traumatic brain injury and created the minimal detectable change for its standardized test. Methods Ten adults (ages 21–55 years) with chronic (average 10 ± 6 years post-injury) severe (loss of consciousness 2–75 days) brain injury performed three trials of the Propriotest® on two separate days. The average of three trials and the best scores were used separately for analysis. Test-retest reliability was verified using Intraclass Correlation Coefficients with 95% confidence interval and standard error of measurement in relation to the Intraclass Correlation Coefficients at 95%. The minimal detectable change was calculated at 95% confidence level (minimal detectable change95) and Bland-Altman plots were created to express agreement between measurement days. Results The results exhibited excellent reliability for both average (Intraclass Correlation Coefficient of 0.969, standard error of measurement 50.9 points) and best (Intraclass Correlation Coefficient of 0.985, standard error of measurement 31.3 points) scores, with average and best minimal detectable change95 of 141.0 and 86.7 points, respectively. Conclusions Clinicians and rehabilitation researchers can use these findings to determine if a Propriotest® change score represents a true post-treatment effect with adults with chronic brain injury. IMPLICATIONS FOR REHABILITATION After brain injury, balance deficits are common and can persist well after completion of rehabilitation programs. Computerized dynamic posturography allows for objective quantification of one’s capacity to respond to external perturbations. The device PROPRIO® 4000 provides reliable quantification of balance deficits of community dwelling individuals who have experienced a severe traumatic brain injury. The minimal detectable change scores created can assist clinicians and rehabilitation researchers detect whether a change in balance score represents a true effect of an intervention at post-treatment.
Severe combined immunodeficiency pig as an emerging animal model for human diseases and regenerative medicines

Severe combined immunodeficiency (SCID) is a group of inherited disorders characterized by compromised T lymphocyte differentiation related to abnormal development of other lymphocytes [i.e., B and/or natural killer (NK) cells], leading to death early in life unless treated immediately with hematopoietic stem cell transplant. Functional NK cells may impact engraftment success of life-saving procedures such as bone marrow transplantation in human SCID patients. Therefore, in animal models, a T cell−/B cell−/NK cell+ environment provides a valuable tool for understanding the function of the innate immune system and for developing targeted NK therapies against human immune diseases. In this review, we focus on underlying mechanisms of human SCID, recent progress in the development of SCID animal models, and utilization of SCID pig model in biomedical sciences. Numerous physiologies in pig are comparable to those in human such as immune system, X-linked heritability, typical T−B+NK− cellular phenotype, and anatomy. Due to analogous features of pig to those of human, studies have found that immunodeficient pig is the most appropriate model for human SCID.
Kinase activity of ERBB3 contributes to intestinal organoids growth and intestinal tumorigenesis

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3‐K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase‐inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium‐induced colitis, the kinase‐inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin‐1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.
A network‐based predictive gene expression signature for recurrence risks in stage II colorectal cancer

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four‐gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease‐free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein‐protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients.
Dexamethasone fails to improve bleomycin‐induced acute lung injury in mice

Acute respiratory distress syndrome (ARDS) features an exudative phase characterized by alveolar damage, lung edema and exacerbated inflammatory response. Given their anti‐inflammatory properties, the potential therapeutic effect of corticosteroids has been evaluated in ARDS clinical trials and experimental models of ALI. These studies produced contradictory results. Therefore, our aim was to investigate the effects of dexamethasone in an animal model of bleomycin‐induced acute lung injury and then to determine if the lack of response could be related to an impairment in repair ability of alveolar epithelial cells after injury. NMRI mice were challenged with bleomycin and then treated daily with dexamethasone or saline. Bronchoalveolar lavages (BAL) and lungs were collected for assessment of the inflammatory response and wet/dry ratio (lung edema) and for histological analyses. The effect of bleomycin and dexamethasone on wound repair was also evaluated in vitro on primary alveolar epithelial cell (ATII) cultures. Our data first showed that dexamethasone treatment did not reduce the weight loss or mortality rates induced by bleomycin. Although the TNF‐α level in BAL of bleomycin‐treated mice was reduced by dexamethasone, the neutrophil infiltration remained unchanged. Dexamethasone also failed to reduce lung edema and damage scores. Finally, bleomycin elicited a time‐ and dose‐dependent reduction in repair rates of ATII cell cultures. This inhibitory effect was further enhanced by dexamethasone, which also affected the expression of β3‐ and β6‐integrins, key proteins of alveolar repair. Altogether, our data indicate that the inability of dexamethasone to improve the resolution of ALI might be due to his deleterious effect on the alveolar epithelium repair.
Transcriptome analysis during photostimulated recrudescence reveals distinct patterns of gene regulation in Siberian hamster ovaries†

Abstract In Siberian hamsters, exposure to short days (SDs, 8 h light:16 h dark) reduces reproductive function centrally by decreasing gonadotropin secretion, whereas subsequent transfer of photoinhibited hamsters to stimulatory long days (LDs, 16 L:8 D) promotes follicle stimulating hormone (FSH) release inducing ovarian recrudescence. Although differences between SD and LD ovaries have been investigated, a systematic investigation of the ovarian transcriptome across photoperiod groups to identify potentially novel factors that contribute to photostimulated restoration of ovarian function had not been conducted. Hamsters were assigned to one of four photoperiod groups: LD to maintain ovarian cyclicity, SD to induce ovarian regression, or post transfer (PT), where females housed in SD for 14-weeks were transferred to LD for 2-days or 1-week to reflect photostimulated ovaries prior to (PTd2) and following (PTw1) the return of systemic FSH. Ovarian RNA was extracted to create RNA-sequencing libraries and short-read sequencing Illumina assays that mapped and quantified the ovarian transcriptomes (n = 4/group). Ovarian and uterine masses, plasma FSH, and numbers of antral follicles and corpora lutea decreased in SD as compared to LD ovaries (P < 0.05). When reads were aligned to the mouse genome, 18 548 genes were sufficiently quantified. Most of the differentially expressed genes noted between functional LD ovaries and regressed SD ovaries; however, five main expression patterns were identified across photoperiod groups. These results, generally corroborated by select protein immunostaining, provide a map of photoregulated ovary function and identify novel genes that may contribute to the photostimulated resumption of ovarian activity. Summary sentence Changes in photoperiod that induce ovarian regression and recrudescence or maintain ovarian function alter ovarian transcriptomes in Siberian hamsters.
Personally familiar faces: Higher precision of memory for idiosyncratic than for categorical information.

Many studies have demonstrated that we can identify a familiar face on an image much better than an unfamiliar one, especially when various degradations or changes (e.g., image distortions or blurring, new illuminations) have been applied, but few have asked how different types of facial information from familiar faces are stored in memory. Here we investigated how well we remember personally familiar faces in terms of their identity, gender, and race. In 3 experiments, based on the faces personally familiar to our participants, we created sets of face morphs that parametrically varied the faces in terms of identity, sex, or race using a 3-dimensional morphable face model. For each familiar face, we presented those face morphs together with the original face and asked participants to pick the correct "real" face among morph distracters in each set. They were instructed to pick the face that most closely resembled their memory of that familiar person. We found that participants excelled in retrieving the correct familiar faces among the distracters when the faces were manipulated in terms of their idiosyncratic features (their identity information), but they were less sensitive to changes that occurred along the gender and race continuum. Image similarity analyses indicate that the observed difference cannot be attributed to different levels of image similarity between manipulations. These findings demonstrate that idiosyncratic and categorical face information is represented differently in memory, even for the faces of people we are very familiar with. Implications to current models of face recognition are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex

Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.