Miracle-dz/UniFAR-FTUs huggingface dataset:
A T-cell–engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer

Purpose: The B7 homolog 4 (B7-H4, VTCN1) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 mAb that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3-bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model. Experimental Design: cDNAs of the antibody-binding fragment (Fab)–single-chain variable fragment (scFv) and scFv-scFv of the anti-B7-H4/CD3 BsAb were synthesized, and the BsAb antibodies were produced in HEK293 cells. The antitumor activity against human breast cancer cells by human peripheral blood mononuclear cells (hPBMC) with BsAb was measured by lactate dehydrogenase release in vitro, and in vivo using hPBMC-transplanted MHC class I- and class II–deficient NOG mice. Results: hPBMCs with anti-B7-H4/CD3 BsAbs successfully lysed the human breast cancer cell line MDA-MB-468 (EC50: 0.2 ng/mL) and other B7-H4+ cell lines in vitro. When BsAb was injected in a humanized mouse model, there was an immediate and strong antitumor activity against MDA-MB-468, HCC-1954, and HCC-1569 tumors and CD8+ and granzyme B+ CTL infiltration into the tumor, and there were no adverse effects after long-term observation. CD8+ T-cell depletion by an anti-CD8 antibody mostly reduced the antitumor effect of BsAb in vivo. Conclusions: An anti-B7-H4/CD3 BsAb may be a good therapeutic tool for patients with B7-H4+ breast cancers.
Isolation and identification of two new compounds from the Penicillium sp. SYPF7381

Abstract Two new compounds, (7R, 2E, 5E)-3,5,7-trimethyl-2,5-octadienedioic-8-methyl ester (1) and neovasipyridone G (3), together with a new natural product compound (7R,2E,5E)-3,5,7-trimethyl-2,5-octadienedioic acid (2), and six known compounds (4–9) were isolated from Penicillium sp. SYPF7381. Their structures were elucidated on the basis of extensive spectroscopic analysis, and the absolute configurations of compounds 1 and 2 were determined by optical rotation. The absolute configuration of compound 3 was determined by means of electronic circular dichroism (ECD) calculation. In addition, the in vitro anti-inflammatory activities of all compounds were assayed in RAW 264.7 cells by assessing LPS-induced NO production. Furthermore, the structure-antiinflammation activity relationships for these isolated compounds were summarized based on the experimental as well as the docking results. Graphical abstract
Germ cell differentiation of bone marrow mesenchymal stem cells

Bone marrow mesenchymal stem cells (BM‐MSCs) were first cultured under induction of retinoic acid (RA), Sertoli cells conditioned medium and RA + con (conditioned medium) as treatment groups. The presence of Sertoli cells was confirmed by immunocytochemistry of follicle‐stimulating hormone receptor in Sertoli cells and flow cytometry by anti‐Gata4 antibody. Cell viability and morphology of nucleus and cytoplasm of BM‐MSCs were evaluated by MTT test and DAPI staining respectively. The expression of Oct4, Plzf, Scp3, Caspases 8, 9 and 3 genes was evaluated by RT‐PCR. For increasing the accuracy of experiment, the expression of Vasa and SCP3 genes was investigated quantitatively by real‐time PCR after 0, 5, 10, 15 days of culture. The results showed that the number of apoptotic cells increased in RA group. The expression of apoptosis genes (Caspases 3, 8 and 9) was also observed in this group all days of culture. Measurement of Vasa and Scp3 genes by RT‐PCR confirmed the positive effects of retinoic acid on increasing of genes expression. So, in this study, a group with maximum expression of differentiation genes and minimum expression of apoptotic genes was RA + conditioned medium group. DNA fragmentation was not observed in all groups.
Quality of life and functional capability of elderly Brazilian women.

BACKGROUND Quality of life is important at all ages, but maintaining a high quality of life is especially crucial to improve the functional capabilities of elder populations. AIM To investigate the relationship between quality of life and the functional capabilities of elderly Brazilian women participating in the Open University for senior citizens (UATI) in the state of Bahia, Brazil. METHODS A cross-sectional study involving 51 elderly women was performed along with the completion of sociodemographic, WHO Quality of life - BREF (WHOQOL-BREF) and WHO Quality of life - OLD (WHOQOL-OLD) questionnaires, and standardized functional capacity tests. RESULTS The one-way ANOVA with a post hoc Tukey test showed interactions between functional capacity tests and the intimacy, autonomy, and death or dying domains of the WHOQOL-OLD. CONCLUSION This study highlights the relationship between regular physical activity, improved functional capability, and quality of life, as demonstrated by better performances in the functional capacity tests resulting in a wider perception of quality of life for most of the senior women involved.
Accountable Care Organizations: Roles and Opportunities for Hospitals

Abstract Federal health reform has established Medicare Accountable Care Organizations (ACOs) as a new program, and some states and private payers have been independently developing ACO pilot projects. The objective is to hold provider groups accountable for the quality and cost of care to a population. The financial models for providers generally build off of shared savings between the payers and providers or some type of global payment that includes the possibility of partial or full capitation. For ACOs to achieve the same outcomes with lower costs or, better yet, improved outcomes with the same or lower costs, the delivery system will need to become more oriented toward primary care and care coordination than is currently the case. Providers of clinical services, in order to be more effective, efficient, and coordinated, will need to be supported by a variety of shared services, such as off-hours care, easy access to specialties, and information exchanges. These services can be organized by an ACO as a medical neighborhood or community. Hospitals, because they have a management structure, history of developing programs and services, and accessibility 24/7/365, are logical leaders of this enhancement of health care delivery for populations and other providers.
Risk factors for work-related musculoskeletal disorders among workers in the footwear industry: a cross-sectional study

The aim of the study was to investigate the influence of biomechanical, psychosocial, environmental and individual factors on local and multisite work-related musculoskeletal disorder (WMSD) symptoms among workers at a footwear manufacturing company. The sample comprised 267 workers. The results showed that: (a) age, sedentary lifestyle, inappropriate posture and perceived effort were associated with symptoms in the shoulders, and the combination of these factors increased the odds four-fold; (b) inappropriate posture, perceived effort and bullying were related to symptoms in the wrists, and the combination of these factors increased the odds seven-fold; (c) inappropriate posture, perceived effort, length of work at the company and low social support were associated with multisite symptoms, and their combination increased the odds up to 30-fold. Therefore, mainly biomechanical and psychosocial factors were associated with WMSD symptoms, and their combinations increased the odds of occurrence.
Hyperexcitability and plasticity induced by sustained hypoxia on rectus abdominis motoneurons

Acute hypoxia induces active expiration in rectus abdominis (RA) muscles in conscious freely moving rats, although its overall contribution is smaller than in internal oblique (IO) muscles. Tonically active and silent RA motoneurons were identified in in vitro preparations of rat spinal cords. Sustained hypoxia (SH) increased the synaptic strength and induced morphological changes in tonically active RA motoneurons. Expiratory RA motoneurons were recorded in the in situ preparation and SH enhanced both the excitability and the synaptic transmission in those firing during the stage 2 expiration. The present study contributes to a better understanding of the mechanisms involved in SH recruitment of RA motoneurons to induce active expiration in rats.
Structural basis of the target-binding mode of the G protein–coupled receptor kinase–interacting protein in the regulation of focal adhesion dynamics

Focal adhesions (FAs) are specialized sites where intracellular cytoskeleton elements connect to the extracellular matrix and thereby control cell motility. FA assembly depends on various scaffold proteins, including the G protein–coupled receptor kinase-interacting protein 1 (GIT1), paxillin, and liprin-α. Although liprin-α and paxillin are known to competitively interact with GIT1, the molecular basis governing these interactions remains elusive. To uncover the underlying mechanisms of how GIT1 is involved in FA assembly by alternatively binding to liprin-α and paxillin, here we solved the crystal structures of GIT1 in complex with liprin-α and paxillin at 1.8 and 2.6 Å resolutions, respectively. These structures revealed that the paxillin-binding domain (PBD) of GIT1 employs distinct binding modes to recognize a single α-helix of liprin-α and the LD4 motif of paxillin. Structure-based design of protein variants produced two binding-deficient GIT1 variants; specifically, these variants lost the ability to interact with liprin-α only or with both liprin-α and paxillin. Expressing the GIT1 variants in COS7 cells, we discovered that the two PBD-meditated interactions play different roles in either recruiting GIT1 to FA or facilitating FA assembly. Additionally, we demonstrate that, unlike for the known binding mode of the FAT domain to LD motifs, the PBD of GIT1 uses different surface patches to achieve high selectivity in LD motif recognition. In summary, our results have uncovered the mechanisms by which GIT1's PBD recognizes cognate paxillin and liprin-α structures, information we anticipate will be useful for future investigations of GIT1–protein interactions in cells.
Mechanistic dissection of alga recognition and uptake in coral-algal endosymbiosis

Many corals form a mutually beneficial relationship with the dinoflagellate algae called Symbiodiniaceae. Cells in the coral gastrodermis recognize, phagocytose, and house the algae in an organelle called symbiosome, which supports algae photosynthesis and nutrient exchange with corals1–3. Rising ocean temperature disrupts this endosymbiotic relationship, leading to alga loss, coral bleaching and death, and the degradation of marine ecosystems4–6. Mitigation of coral death requires a mechanistic understanding of coral-algal endosymbiosis. We have developed genomic resources to enable the use of a soft coral Xenia species as a model to study coral-algal endosymbiosis7. Here we report an effective RNA interference (RNAi) method and its application in the functional studies of genes involved in early steps of endosymbiosis. We show that an endosymbiotic cell marker called LePin (for its Lectin and kazal Protease inhibitor domains) is a secreted lectin that binds to algae to initiate the formation of alga-containing endosymbiotic cells. The evolutionary conservation of LePin among marine endosymbiotic anthozoans suggests a general role in coral-algal recognition. Coupling bioinformatics analyses with RNAi and single cell (sc)-RNA-seq, we uncover three gene expression programs (GEP) influenced by LePin during the early and middle stages of endosymbiotic lineage development. Further studies of genes in these GEPs lead to the identification of two scavenger receptors that support the formation of alga-containing endosymbiotic cells, most likely by initiating phagocytosis and modulating coral immune response. We also identify two actin regulators for endosymbiosis, which shed light on the phagocytic machinery and a possible mechanism for symbiosome formation. Our findings should usher in an era of mechanistic studies of coral-algal endosymbiosis.
The relationship between occupational stress, health status, and temporary and permanent work disability among security guards in Serbia

Purpose. This study aimed to examine the influence of occupational stress on health status and work disability among security guards in Serbia. Methods. Three hundred and ninty nine male security guards (aged 25–65 years) were examined during regular medical preventive check-ups at the Institute of Occupational Health. Data on their health status and permanent and temporary work disability were obtained, and correlations with the levels of occupational stress (measured by occupational stress index [OSI] questionnaire) were analysed. Results. A high prevalence of health impairments, including diabetes (38.8%), dyslipidaemia (82.7%), hypertension (69.9%) and metabolic syndrome (77.7%), was found. Highly significant correlations were shown between reported levels of total stress at work (total OSI score) and measured values of glucose, lipids, blood pressure, heart rate, Framingham cardiovascular risk scale, occurrence of diabetes and impaired fasting glucose, dyslipidaemia, hypertension, metabolic syndrome, coronary heart disease, cerebrovascular insults, degenerative eye-fundus changes, and temporary and permanent work disability. All of these correlations remained significant even after adjustments for age, body mass index and smoking status. Regression analysis confirmed the independent effect of occupational stress on the analysed parameters. Conclusions. There is a significant independent impact of occupational stress on development of health impairments and work disability among security guards.
Treatment by specialist surgical neurooncologists improves survival times for patients with malignant glioma.

OBJECT Surgeries for CNS tumors are frequently performed by general neurosurgeons and by those who specialize in surgical neurooncology. Subspecialization in neurosurgical practice has become common and may improve patient morbidity and mortality rates. However, the potential benefits for patients of having their surgeries performed by surgical neurooncologists remain unclear. Recently, a shift in patient care to those who practice predominantly surgical neurooncology has been promoted. Evidence for this practice is lacking and therefore requires fundamental investigation. METHODS The authors conducted a case-control study of neurooncology patients who underwent surgery for glioblastoma and anaplastic astrocytoma during 2006-2009. Outcomes were compared for patients whose surgery was performed by general neurosurgeons (generalists) or by specialist neurooncology neurosurgeons (specialists). An electronic record database and a picture archiving and communication system were used to collect data and assess the extent of tumor resection. Mortality rates and survival times were compared. Patient comorbidity and postoperative morbidity were assessed by using the Waterlow, patient handling, and falls risk assessment scores. Effects of case mix were adjusted for by using Cox regression and a hazards model. RESULTS Outcomes for 135 patients (65 treated by generalists and 70 by specialists) were analyzed. Survival times were longer for patients whose surgery was performed by specialists (p=0.026) and after correction for case mix (p=0.019). Extent of tumor resection was greater when performed by specialists (p=0.005) and correlated with increased survival times (p=0.004). There was a trend toward reduced surgical deaths when surgery was performed by specialists (2.8%) versus generalists (7%) (p=0.102), and inpatient stays were significantly shorter when surgery was performed by specialists (p=0.008). CONCLUSIONS The prognosis for glioblastoma multiforme remains dire, and improved treatments are urgently needed. This study provides evidence for a survival benefit when surgery is performed by specialist neurooncology neurosurgeons. The benefit might be attributable to increased tumor resection. Furthermore, specialist neurooncology surgical care may reduce the number of surgical patient deaths and length of inpatient stay. These findings support the recommendations for subspecialization within surgical neurooncology and advocate for care of these patients by specialists.
Relationship Between Nonsustained Ventricular Tachycardia After Non–ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death: Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN

Background— Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non–ST-elevation acute coronary syndrome receiving contemporary care have not been examined. Methods and Results— The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n=121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n=2764), there was no increased risk of SCD in patients with only ventricular triplets (n=1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n=1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P<0.001) and in patients with VT lasting at least 8 beats (n=431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P=0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD. Conclusion— Nonsustained VT is common after admission for non–ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. Clinical Trial Registration— URL: http://www.clinicaltrials. gov. Unique identifier: NCT00099788.
The effect of cerebellar transcranial direct current stimulation to improve standing balance performance early post-stroke, study protocol of a randomized controlled trial

Rationale Restoration of adequate standing balance after stroke is of major importance for functional recovery. POstural feedback ThErapy combined with Non-invasive TranscranIAL direct current stimulation (tDCS) in patients with stroke (POTENTIAL) aims to establish if cerebellar tDCS has added value in improving standing balance performance early post-stroke. Methods Forty-six patients with a first-ever ischemic stroke will be enrolled in this double-blind controlled trial within five weeks post-stroke. All patients will receive 15 sessions of virtual reality-based postural feedback training (VR-PFT) in addition to usual care. VR-PFT will be given five days per week for 1 h, starting within five weeks post-stroke. During VR-PFT, 23 patients will receive 25 min of cerebellar anodal tDCS (cb_tDCS), and 23 patients will receive sham stimulation. Study outcome Clinical, posturographic, and neurophysiological measurements will be performed at baseline, directly post-intervention, two weeks post-intervention and at 15 weeks post-stroke. The primary outcome measure will be the Berg Balance Scale (BBS) for which a clinical meaningful difference of six points needs to be established between the intervention and control group at 15 weeks post-stroke. Discussion POTENTIAL will be the first proof-of-concept randomized controlled trial to assess the effects of VR-PFT combined with cerebellar tDCS in terms of standing balance performance in patients early post-stroke. Due to the combined clinical, posturographical and neurophysiological measurements, this trial may give more insights in underlying post-stroke recovery processes and whether these can be influenced by tDCS.
Autonomic impairment in Alzheimer’s disease is revealed by complexity analysis of functional thermal imaging signals during cognitive tasks

Objective: Alzheimer’s disease (AD) is characterized by progressive memory failures and visuospatial impairment. Moreover, AD can be accompanied by autonomic system alterations, which, among other impacts, affect thermoregulatory activity. We here investigate differences in autonomic activity between AD patients and healthy controls (HC), employing a complexity analysis of functional infrared imaging (fIRI) data acquired at rest and during the execution of clinical cognitive and mnemonic tests. Approach: fIRI allows for contactless monitoring of autonomic activity and its thermoregulatory expression without interfering with the psychophysiological state of the subject, preserving free interaction with the doctor. The signal complexity analysis, based on the sample entropy, was compared to a standard frequency-based analysis of autonomic-related signals. Main results: AD patients exhibited lower complexity of fIRI signals during the tests, which could be indicative of a stronger sympathetic activity with respect to HC. No significant effects were found at rest. No differences were found on employing frequency-based analysis. Significance: This study confirms that AD patients may exhibit peculiar autonomic responses associated with the execution of cognitive tasks that can be measured through fIRI. Moreover, these responses could be highlighted by a nonlinear metric of signal predictability such as the sample entropy establishing autonomic impairment of AD patients.
Heart failure in the patient with diabetes: Epidemiology, aetiology, prognosis, therapy and the effect of glucose‐lowering medications

In people with type 2 diabetes the frequency of heart failure (HF) is increased and mortality from HF is higher than with non‐diabetic HF. The increased frequency of HF is attributable to the cardiotoxic tetrad of ischaemic heart disease, left ventricular hypertrophy, diabetic cardiomyopathy and an extracellular volume expansion resistant to atrial natriuretic peptides. Activation of the renin‐angiotensin‐aldosterone system and sympathetic nervous systems results in cardiac remodelling, which worsens cardiac function. Reversal of remodelling can be achieved, and cardiac function improved in people with HF with reduced ejection fraction (HFrEF) by treatment with angiotensin‐converting enzyme inhibitors and β‐blockers. However, with HF with preserved ejection fraction (HFpEF), only therapy for the underlying risk factors helps. Blockers of mineralocorticoid receptors may be beneficial in both HFrEF and HFpEF. Glucose‐lowering drugs can have a negative effect (insulin, sulphonylureas, dipeptidyl peptidase‐4 inhibitors and thiazolidinediones), a neutral effect (α‐glucosidase inhibitors and glucagon‐like peptide‐1 receptor agonists) or a positive effect (sodium‐glucose co‐transporter‐2 inhibitors and metformin).