Miracle-dz/UniFAR-FTUs huggingface dataset:
Assembly of the complexes of oxidative phosphorylation triggers the remodeling of cardiolipin

Significance Mitochondria contain cardiolipin, a special phospholipid that strongly interacts with proteins. Cardiolipin has a unique fatty acid composition, the disturbance of which causes the human disease Barth syndrome. However, neither the mechanism by which cardiolipin acquires specific fatty acids nor their actual function has been established. In this paper, we demonstrate that the expression of the complexes of oxidative phosphorylation is responsible for inducing the specific fatty acid composition in cardiolipin. We hypothesize that the purpose of this process is the stabilization of lipid–protein interactions in the extremely crowded environment of mitochondrial membranes. Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by tafazzin. However, in vitro tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I–V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid–protein complexes.
Comparison of the crystal structures of L2 and L8S8 Rubisco suggests a functional role for the small subunit.

Comparison of the crystal structures of the L2 and L8S8 forms of ribulose‐1,5‐bisphosphate carboxylase from Rhodospirillum rubrum and spinach respectively, reveals a remarkable similarity in the overall architecture of the L2 building blocks in the two enzymes. Within the L subunits, no large conformational differences such as domain‐domain rotations were found. In spite of a somewhat different packing of the L subunits in the L2 dimer, the active sites of the two enzymes are highly conserved. Significant local conformational differences are, however, observed for the C‐terminal part of the polypeptide chains as well as for loop 7, helix alpha 7, loop 8 and helix alpha 8 in the barrel domain. The small subunit forms extensive interactions with one of these alpha helices, alpha 8, in the spinach L8S8 enzyme. The loops are at the active site and one of them forms a phosphate binding site for the substrate. We suggest that the small subunit modulates substrate binding and, possibly, the carboxylation/oxygenation ratio by inducing conformational changes in the active site through interactions distant from this site.
“Regeneration of a Pediatric Alveolar Cleft Model using 3D Printed Bioceramic Scaffolds and Osteogenic Agents: Comparison of Dipyridamole and rhBMP-2.”

Purpose: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although rhBMP-2 is under investigation for alveolar cleft repair, safety concerns remain (e.g. growing suture pathology). Dipyridamole (DIPY) is an adenosine receptor indirect agonist with known osteogenic potential. This study compared DIPY to rhBMP-2 at alveolar cleft defects delivered via 3D-printed bioceramic (3DBC) scaffolds. Methods: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5mm x3.5mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with 3DBC scaffolds coated with 1000μm-DIPY (n=6), 10,000μm-DIPY (n=7), and 0.2 mg/mL-rhBMP-2 (n=5). At t=8 weeks, new bone was quantified using Amira 6.1 software. Non-decalcified histology was performed, and new bone was mechanically evaluated. Statistical analysis was performed using a generalized linear mixed model and Wilcoxon rank sum test. Results: Negative controls did not heal while new bone formation bridged all 3DBC treatment groups. 1,000μm-DIPY scaffolds regenerated 28.03±7.38%, 10,000μm-DIPY scaffolds regenerated 36.18±6.83% (p=0.104 1,000μm vs. 10,000μm DIPY), and rhBMP-2 coated scaffolds regenerated 37.17±16.69% bone (p=0.124 vs. 1,000μm-DIPY and p=0.938 vs. 10,000μm-DIPY). rhBMP-2 early of This study compares the effects of locally delivering Dipyridamole and rhBMP-2 on alveolar clefts in a skeletally immature translational rabbit model. The objective of this experiment was to assess the capacity of 3D-printed bioceramic (3DBC) scaffolds coated with these therapeutic agents to effectively and safely regenerate bone in an alveolar cleft defect. We hypothesized that 3DBC scaffolds coated with DIPY would achieve bone regeneration comparable to rhBMP-2 without concerning side effects.
Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non‐adrenergic inhibitory nerves in the gut

1 . Stimulation of the vagal non‐adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea‐pigs and toads. 2 . Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP). 3 . ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine. 4 . Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea‐pig isolated taenia coli, ATP and ADP were the most potent. 5 . ATP caused inhibition of twelve other gut preparations previously shown to contain non‐adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin. 6 . Quinidine antagonized relaxations of the guinea‐pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non‐adrenergic inhibitory nerve stimulation. 7 . When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non‐adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation. 8 . It is suggested that ATP or a related nucleotide is the transmitter substance released by the non‐adrenergic inhibitory innervation of the gut.
Increased Cognitive Load Reveals Unilateral Neglect and Altitudinal Extinction in Chronic Stroke

Abstract Objective: Neuropsychological studies suggest that the ability to compensate for the presence of spatial neglect highly depends on the attentional resources a patient can rely on. The present research aimed to study neglect in situations where attentional resources are limited due to multitasking. Method: We examined two patients more than 3 years after a right-hemispheric stroke. Both had received neuropsychological rehabilitation for left neglect and did not show any impairment in standard tests. We used a dual-task paradigm combining a peripheral target detection task with a central shape recognition task. Peripheral targets could appear in left/right positions but also in lower/upper positions. Results: In patient #1, dual-task condition exacerbated left neglect and extinction. Patient #2 did not show any sign of neglect along the horizontal axis, but omitted half of the lower targets when they were presented simultaneously with upper targets under dual-task condition. This behavior reflects altitudinal extinction as the detection of single targets appearing either in upper or lower position was preserved. Conclusion: The present findings show that dual-tasking is a sensitive tool for the quantitative and qualitative assessment of spatial attention deficits, which are often overlooked by standard methods, especially in chronic stage. (JINS, 2019, 25, 644–653)
Effect of Plyometric Training on Jumping, Sprinting and Change of Direction Speed in Child Female Athletes

Background: This study examined the effects of 8 weeks of plyometric training on jumping, sprinting, and change of direction (COD) performance. Methods: Fifty female 7–9-year-old gymnasts were randomly assigned to a plyometric training group (PG; n = 33), that performed supplementary plyometric training twice per week, and a control group (CG; n = 17) that continued regular training. The following tests were performed before and after the intervention: 10 and 20 m sprints, 5 + 5 m and 10 + 10 m COD tests, one-leg and two-leg countermovement jump (CMJ), drop jump (DJ), squat jump (SJ), and standing long jump (SLJ). Results: Only a main effect for time was found for all jumping performance parameters (p = 0.001). However, the improvement of one- and two-leg CMJ in PG had a greater effect size than CG (0.72 and 0.67 vs. 0.34 and 0.18, respectively). Group × time interactions were found for 10 and 20 m sprint tests (p = 0.018 and p = 0.011, respectively) and for 10 + 10 m COD (p = 0.008) with the post hoc test showing improvement only for the PG (p = 0.001, 0.001, and 0.003 and d = 1.1, 1.14, and 0.6, respectively). Conclusions: Supplementary plyometric training increased sprint and COD performance more than regular gymnastics training, while jumping performance was equally improved in both groups.
CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease.

AIMS Patients with chronic kidney disease (CKD) pose a worldwide growing burden to health care systems due to accelerated atherosclerosis and subsequent high cardiovascular (CV) morbidity. Atherogenesis is prominently driven by monocytes and monocyte-derived macrophages. The expression of CD14 and CD16 characterizes three monocyte subsets: CD14(++)CD16(-), CD14(++)CD16(+), and CD14((+))CD16(+) cells; the latter two are often denoted as 'proinflammatory' CD16(+) monocytes. Despite an association between CD16(+) monocyte counts and higher CV risk in cross-sectional cohorts, the prognostic impact of elevated CD16(+) monocyte counts is poorly understood. METHODS AND RESULTS We assessed monocyte heterogeneity using flow cytometry in 119 patients with non-dialysis CKD, who were prospectively followed for a median of 4.9 (inter-quartile range 4.8-5.0) years for the occurrence of CV events. In addition, we assessed expression of chemokine receptors on monocyte subsets. CD14(++)CD16(+) monocyte were independently associated with CV events [hazard ratio (for an increase of 10 cells/μL) 1.26 (confidence interval: 1.04-1.52; P = 0.018)] after adjustment for variables that significantly affected CD14(++)CD16(+) cell counts at baseline. Across the spectrum of CKD, CD14(++)CD16(+) monocytes selectively expressed CCR5. CONCLUSION We found that CD14(++)CD16(+) monocytes were independently associated with CV events in non-dialysis CKD patients. Our results support the notion that CD16(+) monocytes rather than CD16(-) monocytes are involved in human atherosclerosis.
SEL1L plays a major role in human malignant gliomas

Suppressor of Lin‐12‐like (C. elegans) (SEL1L) participates in the endoplasmic reticulum‐associated protein degradation pathway, malignant transformation and stem cell biology. We explored the role of SEL1L in 110 adult gliomas, of different molecular subtype and grade, in relation to cell proliferation, stemness, glioma‐associated microglia/macrophages (GAMs), prognostic markers and clinical outcome. SEL1L protein expression was assessed by immunohistochemistry and Western blotting. Genetic and epigenetic alterations were detected by molecular genetics techniques. SEL1L was overexpressed in anaplastic gliomas (World Health Organization [WHO] grade III) and in glioblastoma (GB, WHO grade IV) with the highest labelling index (LI) in the latter. Immunoreactivity was significantly associated with histological grade (p = 0.002) and cell proliferation index Ki‐67/MIB‐1 (p = 0.0001). In GB, SEL1L co‐localised with stemness markers Nestin and Sox2. Endothelial cells and vascular pericytes of proliferative tumour blood vessels expressed SEL1L suggesting a role in tumour neo‐vasculature. GAMs consistently expressed SEL1L. SEL1L overexpression was significantly associated with TERT promoter mutations (p = 0.0001), EGFR gene amplification (p = 0.0013), LOH on 10q (p = 0.0012) but was mutually exclusive with IDH1/2 mutations (p = 0.0001). SEL1L immunoreactivity correlated with tumour progression and cell proliferation, conditioning poor patient survival and response to therapy. This study emphasises SEL1L as a potential biomarker for the most common subgroup of TERT mutant/EGFR amplified/IDH‐WT GBs.
Evaluation of different criteria for the separation of pleural transudates from exudates.

OBJECTIVES To determine the relative usefulness of different criteria for the separation of pleural transudates from exudates. DESIGN Prospective evaluation of patients referred for thoracentesis. SETTING Community teaching hospital. PATIENTS Three hundred fifty-one consecutive patients with pleural effusions referred for thoracentesis. Fifty-four of these patients were excluded from the analysis. MEASUREMENTS We recorded clinical characteristics and final diagnosis and measured pleural fluid and serum levels of total protein, lactate dehydrogenase, and cholesterol. All patients included were followed up until final diagnosis. MEAN RESULTS: Forty-four (15 percent) pleural effusions were transudates and 253 (85 percent) were exudates. The criteria of Light et al, with a sensitivity of 98 percent and a specificity of 77 percent for exudates, showed the best accuracy (95.2 percent). Moreover, when the cutoff used for the criteria of Light et al was modified according to our own laboratory results, specificity rose to 93 percent with almost a similar accuracy (94 percent). Protein pleural fluid/serum ratio > 0.5 and pleural fluid cholesterol > 60 mg/dl showed equal specificity (91 percent), but the former had better sensitivity for exudates (88 percent vs 81 percent). CONCLUSIONS When the proportion of exudates included is 85 percent or more, as in the present series, the criteria of Light et al remain the method that offers the highest accuracy for segregating transudates from exudates.
Conversation in cardiology: Is there a need for clinical trials for the nonhyperemic pressure ratios?

In the last decade, coronary physiologic measurements in the cath lab have undergone dramatic advances in both techniques and outcomes for clinical practice. Moving from a dominant technique of fractional flow reserve (FFR) with its requirement for adenosine-induced hyperemia to a specific diastolic nonhyperemic pressure ratio (NHPR) during the wave-free period (WFP), called the instantaneous wave-free ratio (iFR), the field now enjoys at least five NHPRs (see Table 1 and Figure 1). Recall that in March 2017, the Coronary Revascularization Writing Group on behalf of the American College of Cardiology (ACC), American Association Thoracic Surgery (AATS), American Heart Association (AHA), American Society of Echocardiography (ASE), American Society of Nuclear Medicine (ASNC), Society of Cardiac Angiography and Intervention (SCAI), Society of Coronary Computer Tomography (SCCT), Society of Thoracic Surgery (STS), chaired by Patel et al, authored the 2017 Appropriate Use Criteria for Coronary Revascularization in Patients with Stable Ischemic Heart Disease, which changed the language from only iFR to more generic NHPRs, specifically, in page 2218, Section 3, “Assumptions,” “General Assumptions” added that
New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma

Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches.
A rare polyglycine type II‐like helix motif in naturally occurring proteins

Common structural elements in proteins such as α‐helices or β‐sheets are characterized by uniformly repeating, energetically favorable main chain conformations which additionally exhibit a completely saturated hydrogen‐bonding network of the main chain NH and CO groups. Although polyproline or polyglycine type II helices (PPII or PGII) are frequently found in proteins, they are not considered as equivalent secondary structure elements because they do not form a similar self‐contained hydrogen‐bonding network of the main chain atoms. In this context our finding of an unusual motif of glycine‐rich PGII‐like helices in the structure of the acetophenone carboxylase core complex is of relevance. These PGII‐like helices form hexagonal bundles which appear to fulfill the criterion of a (largely) saturated hydrogen‐bonding network of the main‐chain groups and therefore may be regarded in this sense as a new secondary structure element. It consists of a central PGII‐like helix surrounded by six nearly parallel PGII‐like helices in a hexagonal array, plus an additional PGII‐like helix extending the array outwards. Very related structural elements have previously been found in synthetic polyglycine fibers. In both cases, all main chain NH and CO groups of the central PGII‐helix are saturated by either intra‐ or intermolecular hydrogen‐bonds, resulting in a self‐contained hydrogen‐bonding network. Similar, but incomplete PGII‐helix patterns were also previously identified in a GTP‐binding protein and an antifreeze protein.
Predictors of N-acetyltransferase activity: should caffeine phenotyping and NAT2 genotyping be used interchangeably in epidemiological studies?

To determine whether NAT2 genotyping could be used interchangeably with caffeine phenotyping in assessing N-acetyltransferase activity in epidemiological studies, sources of interindividual variability in N-acetyltransferase activity were assessed among 90 subjects of various ethnic backgrounds in Hawaii. Forty-three subjects were patients with in situ colorectal cancer treated by polypectomy, and 47 were healthy population controls. Subjects were administered a lifestyle questionnaire and were evaluated for N-acetyltransferase activity by caffeine phenotyping. NAT2 genotype was also assessed by PCR amplification of peripheral leukocyte DNA for the M1, M2, and M3 variant alleles. Fifty-four % of the overall variation in acetylation activity was explained by the three genotype categories (homozygous variant, heterozygous, and homozygous wild-type). This proportion was reduced to 42% when genotype was modeled using only two categories ("slow" being homozygous variant; "rapid" being all others). Use of gout medications (probenecid or allopurinol), consumption of heavily browned fish, and P450IA2 activity (also measured by caffeine phenotyping), together explained another 11% of the variance. No association was found between acetylation activity and sex; race; age; education; smoking; physical activity; weight; consumption of coffee, alcohol, red meat, processed meat, and cruciferous vegetables; or use of menopausal estrogens, after taking genotype into account. Results were similar for colorectal cancer patients and controls. Considerable variation in acetylation activity was observed within the homozygous wild-type group. This study suggests that the use of genotyping, instead of phenotyping, to assess the association of acetylation with cancer risk is unlikely to introduce major misclassification or bias, especially when the three genotype categories are modeled and the sample size is large. However, when the rapid acetylation phenotype is the at-risk group (e.g., when studying colon career), phenotyping appears judicious given the variability in acetylation activity within this group.
The Enterochromaffin-like [ECL] Cell—Central in Gastric Physiology and Pathology

Background: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. Methods: This review is based upon literature research and personal knowledge. Results: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. Conclusions: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion.