Miracle-dz/UniFAR-FTUs huggingface dataset:
The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis

The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called “Brother of Regulator of Imprinted Sites” (BORIS) or “CTCF-like” (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint.
Functional analysis of aquaporin-2 mutants associated with nephrogenic diabetes insipidus by yeast expression.

Mutations of aquaporin-2 (AQP2) vasopressin water channel cause nephrogenic diabetes insipidus (NDI). It has been suggested that impaired routing of AQP2 mutants to the plasma membrane causes the disease; however, no determinations have been made of mutation-induced alterations of AQP2 channel water permeability. To address this issue, a series of AQP2 mutants were expressed in yeast, and the osmotic water permeability ( P f) of the isolated vesicles was measured. Wild-type and mutant AQP2 were expressed equally well in vesicles. P f of the vesicles containing wild-type AQP2 was 22 times greater than that of the control, which was sensitive to mercury and weakly dependent on the temperature. P fmeasurements and mercury inhibition examinations suggested that mutants L22V and P262L are fully functional, whereas mutants N68S, R187C, and S216P are partially functional. In contrast, mutants N123D, T125M, T126M, A147T, and C181W had very low water permeability. Our results suggest that the structure between the third and fifth hydrophilic loops is critical for the functional integrity of the AQP2 water channel and that disruption of AQP2 water permeability by mutations may cause NDI.
Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures.

In most cells, the ubiquitously expressed Na+/H+exchanger isoform 1 (NHE1) is thought to be a primary regulator of pH homeostasis, cell volume regulation, and the proliferative response to growth factor stimulation. To study the function of NHE1 during embryogenesis when these cellular processes are very active, we targeted the Nhe1 gene by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. NHE activity assays on isolated acinar cells indicated that the targeted allele is functionally null. Although the absence of NHE1 is compatible with embryogenesis, Nhe1 homozygous mutants (-/-) exhibit a decreased rate of postnatal growth that is first evident at 2 wk of age. At this time, Nhe1 -/- animals also begin to exhibit ataxia and epileptic-like seizures. Approximately 67% of the -/- mutants die before weaning. Postmortem examinations frequently revealed an accumulation of a waxy particulate material inside the ears, around the eyes and chin, and on the ventral surface of the paws. Histological analysis of adult tissues revealed a thickening of the lamina propria and a slightly atrophic glandular mucosa in the stomach.
Slot Synchronization of a WDM Packet-Switched Slotted Ring

In this paper, we present two different strategies of slot synchronization in wavelength-division-multiplexing (WDM) packet-switched slotted-ring networks. Emphasis is given to the architecture behind the WDM optical network demonstrator over rings (WONDER) project, which is based on tunable transmitters and fixed receivers. The WONDER experimental prototype is currently being developed at the laboratories of Politecnico di Torino. In the former strategy, a slot-synchronization signal is transmitted by the master station on a dedicated control wavelength; in the latter, slave nodes achieve slot synchronization aligning on data packets that are received from the master. The performance of both synchronization strategies, particularly in terms of packet-collision probability, was evaluated by simulation. The technique based on transmitting a timing signal on a dedicated control wavelength achieves better performance, although it is more expensive due to the need for an additional wavelength. However, the technique based on aligning data packets that are received from the master, despite attaining lower timing stability, still deserves further study, particularly if limiting the number of wavelengths and receivers is a major requirement. Some experimental results, which were measured on the WONDER prototype, are also shown. Measurement results, together with theoretical findings, demonstrate the good synchronization performance of the prototype.
The Association between Body Mass Index and Health-Related Quality of Life in Treatment-Seeking Arab Adults with Obesity

Few studies have thus far been carried out on Health-Related Quality of Life (HRQoL) and obesity in Arab-speaking countries, an issue that we therefore set out to investigate in this study. HRQoL was assessed by the validated Arabic version of the ORWELL 97 questionnaire in 129 treatment-seeking individuals with obesity referred to the Nutritional and Weight Management Outpatient Clinic at the Department of Nutrition and Dietetics of Beirut Arab University (BAU) in Lebanon, and 129 normal-weight participants of similar age and gender. Participants with obesity, regardless of gender, displayed higher total ORWELL 97 scores when compared with normal-weight controls, indicating that obesity is associated with lower HRQoL. Linear regression analysis showed that a higher body mass index (BMI) is associated with an increase in ORWELL 97 scores, but only among female, not male, participants with obesity (β = 2.89, 95% confidence interval (CI) = 1.43–4.53, p < 0.001). Moreover, logistic regression analysis showed that a one unit increase in BMI increases the odds of an ORWELL 97 score ≥ 71.75—considered indicative of a clinically significant impairment of HRQoL—by nearly 23% (odds ratio (OR), 95% CI = 1.23, 1.09–1.40, p < 0.05). If confirmed, our findings should prompt clinicians operating in Arab countries to encourage patients with obesity to initiate and persevere in weight-loss programs at the earliest opportunity.
Experimental Right Ventricular Hypertension Induces Regional β1‐Integrin–Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling

Background Development of right ventricular (RV) hypertension eventually contributes to RV and left ventricular (LV) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated. Methods and Results Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end‐diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin‐β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor‐β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α‐smooth muscle actin, integrin‐β1, transforming growth factor‐β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (BTT‐3033). Conclusions Experimentally induced RV hypertension triggers regional RV, hinge‐point, and LV integrin β1‐dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor‐β1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin‐mediated protective mechanism at the septal hinge points.
Low-cost Automatic Inpainting for Artifact Suppression in Facial Images

Facial images are often used in applications that need to recognize or identify persons. Many existing facial recognition tools have limitations with respect to facial image quality attributes such as resolution, face position, and artifacts present in the image. In this paper we describe a new low-cost framework for preprocessing low-quality facial images in order to render them suitable for automatic recognition. For this, we first detect artifacts based on the statistical difference between the target image and a set of pre-processed images in the database. Next, we eliminate artifacts by an inpainting method which combines information from the target image and similar images in our database. Our method has low computational cost and is simple to implement, which makes it attractive for usage in low-budget environments. We illustrate our method on several images taken from public surveillance databases, and compare our results with existing inpainting techniques.
Are Early Relapses in Advanced-Stage Ovarian Cancer Doomed to a Poor Prognosis?

Objective Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients. Study Design We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis. Results The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5). Conclusion ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters.
Compiling Exceptions Correctly (Extended Version)

Exceptions are an important feature of modern programming languages, but their compilation has traditionally been viewed as an advanced topic. In this article we show that the basic method of compiling exceptions using stack unwinding can be explained and verified both simply and precisely, using elementary functional programming techniques. In particular, we develop a compiler for a small language with exceptions, together with a proof of its correctness.
Nonalcoholic fatty liver disease: Is it time for combination treatment and a diabetes‐like approach?

Younossi et al. successfully summarized current and future therapeutic efforts for nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), an unmet medical need. We would like to express hereby our personal points of view. When planning clinical trials for NASH, it should be considered that multiple and diverse factors (“hits”) may contribute to its severity and progression. Based on this multiple-hit pathogenesis, we previously proposed a multiple-target management, thereby simultaneously targeting more than one of its pathogenetic hits: instead of targeting insulin resistance or obesity or dyslipidemia or oxidative stress or adipokine imbalance, we should target more than one of them. Nevertheless, there is currently limited evidence for combination treatment in NAFLD. For example, atorvastatin combined with antioxidants (vitamin E and vitamin C) effectively reduced hepatic steatosis. We have more recently shown that the combined low-dose spironolactone and vitamin E improved NAFLD liver fat score, an index of steatosis, more than vitamin E monotherapy; apart from the liver, spironolactone exhibits anti-fibrotic effects in cardiovascular and renal diseases. However, more and well-designed trials are needed before establishing the multiple-target NAFLD treatment. Moreover, based on the epidemiologic and pathogenetic similarities between type 2 diabetes mellitus (T2DM) and NAFLD, a diabetes-like management may be considered for NAFLD. The latest guidelines propose similar lifestyle recommendations for the management of T2DM and NAFLD. In this regard, similar targets for fasting glucose (<100 mg/dL), 2hour postprandial glucose (<140 mg/dL), serum lowdensity lipoprotein cholesterol (<100 mg/dL or <70 mg/dL depending on risk assessment for cardiovascular disease), systolic blood pressure (<130 mmHg) and diastolic blood pressure (<80 mmHg) may be considered for NAFLD patients. Importantly, when T2DM and NAFLD coexist, pioglitazone or glucagon-like peptide-1 analogs should be considered at the second step of T2DM treatment, i.e., when metformin monotherapy fails to adequately control T2DM, since they have been proved beneficial in NASH clinical trials. In conclusion, future clinical trials for NAFLD should be oriented towards the multiple pathogenetic “hits” of the disease. Until specific medications are approved for the hepatic component of the disease, mainly fibrosis, the optimal management of comorbidities is recommended.
Expression of multiple Na+/H+exchanger isoforms in rat parotid acinar and ductal cells.

Several members of the Na+/H+exchanger gene family (NHE1, NHE2, NHE3, and NHE4) with unique functional properties have been cloned from rat epithelial tissues. The present study examined the molecular and pharmacological properties of Na+/H+exchange in rat parotid salivary gland cells. In acinar cells superfused with a physiological salt solution (145 mM Na+), Na+/H+exchanger activity was inhibited by low concentrations of the amiloride derivative ethylisopropyl amiloride (EIPA; IC50 = 0.014 ± 0.005 μM), suggesting the expression of amiloride-sensitive isoforms NHE1 and/or NHE2. Semiquantitative RT-PCR confirmed that NHE1 transcripts are most abundant in this cell type. In contrast, the intermediate sensitivity of ductal cells to EIPA indicated that inhibitor-sensitive and -resistant Na+/H+exchanger isoforms are coexpressed. Ductal cells were about one order of magnitude more resistant to EIPA (IC50 = 0.754 ± 0.104 μM) than cell lines expressing NHE1 or NHE2 (IC50 = 0.076 ± 0.013 or 0.055 ± 0.015 μM, respectively). Conversely, ductal cells were nearly one order of magnitude more sensitive to EIPA than a cell line expressing the NHE3 isoform (IC50= 6.25 ± 1.89 μM). Semiquantitative RT-PCR demonstrated that both NHE1 and NHE3 transcripts are expressed in ducts. NHE1 was immunolocalized to the basolateral membranes of acinar and ductal cells, whereas NHE3 was exclusively seen in the apical membrane of ductal cells. Immunoblotting, immunolocalization, and semiquantitative RT-PCR experiments failed to detect NHE2 expression in either cell type. Taken together, our results demonstrate that NHE1 is the dominant functional Na+/H+exchanger in the plasma membrane of rat parotid acinar cells, whereas NHE1 and NHE3 act in concert to regulate the intracellular pH of ductal cells.
Ethanol modulation of intestinal epithelial tight junction barrier.

Previous studies have shown that high concentrations of ethanol (≥40%) cause functional damage of the gastrointestinal epithelial barrier by direct cytotoxic effect on the epithelial cells. The effects of lower noncytotoxic doses of ethanol on epithelial barrier function are unknown. A major function of gastrointestinal epithelial cells is to provide a barrier against the hostile substances in the gastrointestinal lumen. The apicolaterally located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent cells and act as a paracellular barrier. In this study, we investigated the effects of lower doses of ethanol on intestinal epithelial TJ barrier function using filter-grown Caco-2 intestinal epithelial monolayers. The Caco-2 TJ barrier function was assessed by measuring epithelial resistance or paracellular permeability of the filter-grown monolayers. Ethanol (0, 1, 2.5, 5, 7.5, and 10%) produced a dose-related drop in Caco-2 epithelial resistance and increase in paracellular permeability. Ethanol also produced a progressive disruption of TJ protein (ZO-1) with separation of ZO-1 proteins from the cellular junctions and formation of large gaps between the adjacent cells. Ethanol, at the doses used (≤10%), did not cause cytotoxicity (lactate dehydrogenase release) to the Caco-2 cells. Ethanol produced a disassembly and displacement of perijunctional actin and myosin filaments from the perijunctional areas. On ethanol removal, actin and myosin filaments rapidly reassembled at the cellular borders. Ethanol stimulated the Caco-2 myosin light chain kinase (MLCK) activity but did not affect the MLCK protein levels. Specific MLCK inhibitor ML-7 inhibited both ethanol increases in MLCK activity and TJ permeability without affecting the MLCK protein levels. Consistent with these findings, metabolic inhibitors sodium azide and 2,4-dinitrophenol significantly prevented ethanol-induced increase in Caco-2 TJ permeability, whereas cycloheximide or actinomycin D had no effect. The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK.
Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch.

Studies were performed to investigate the regulatory mechanism of bladder cyclooxygenase-2 (COX-2) expression after outlet obstruction. In situ hybridization of murine bladder tissues using COX-2-specific riboprobes demonstrated that COX-2 expression was induced predominantly in the bladder smooth muscle cells after outlet obstruction. To study the effect of increased mechanical stretch on COX isoform expression, cultured rat bladder smooth muscle cells were grown on silicone elastomer-bottomed plates coated with collagen type I and were subjected to continuous cycles of stretch/relaxation for variable duration. COX-1 mRNA levels did not change with stretch. COX-2 expression increased in a time-dependent manner after stretch, with maximal mRNA and protein levels occurring after 4 h. PGE2 levels increased more than 40-fold in the culture media after stretch, consistent with increased COX activity, and this was reduced to near completion in the presence of a COX-2 inhibitor, NS-398. Exposure to stretch over a 48-h period induced a 4.7 ± 0.6-fold increase in tritiated thymidine incorporation rate. This increase in DNA synthesis was markedly suppressed when the cells were stretched in the presence of NS-398. We conclude that in bladder obstruction COX-2 activation occurs predominantly in the smooth muscle cells in response to mechanical stretch. Our findings also suggest that stretch-activated COX-2 expression may participate in bladder smooth muscle cell proliferation and thereby play a role in pathological bladder wall thickening after obstruction.
Nonsaturable entry of neuropeptide Y into brain.

Neuropeptide Y (NPY) is found and is active both in the periphery and brain, but its crossing of the blood-brain barrier (BBB) in either direction has not been measured. We used multiple time-regression analysis to determine that radioactively labeled NPY injected intravenously entered the brain much faster than albumin, with an influx constant of 2.0 × 10-4ml ⋅ g ⋅ -1 ⋅ min-1. However, this rate of entry was not significantly changed by injection of 10 μg/mouse of excess NPY, by leptin, or by food deprivation. HPLC showed that most of the NPY entering the brain was intact, and capillary depletion with and without washout showed that the NPY did not remain bound to endothelial cells or associated with vascular elements. Perfusion in a blood-free solution eliminated binding to serum proteins as an explanation for the lack of saturation. Efflux of labeled NPY from the brain occurred at the same rate as albumin, reflecting the normal rate of reabsorption of cerebrospinal fluid. Thus NPY can readily enter the brain from blood by diffusion across the BBB.
BORABEY GÖLETİ'NİN TERMAL KATMANLAŞMA YAPISININ İNCELENMESİ

Eskisehir’de tarimsal sulama amacli olarak kullanilan yuzeysel su kaynaklarindan birisi olan Borabey Goleti, kapali bir havza yapisina sahip olmasi ve havzasindaki tarimcilik faaliyetleri nedeniyle gunumuzde kirlenme tehlikesi ile karsi karsiya kalma potansiyeli olan bir gol konumundadir. Tarimsal amacli suyun kalitesinin olumsuz duzeyde etkilenmesi ile karsi karsiya kalinmadan once gerekli onlemlerin alinmasi gereklidir. Bu kapsamda, Borabey Goleti’nin fiziko-hidrolojik sartlarinin belirlenmesi ve mevsimsel katmanlasma yapisinin incelenmesi gerekmektedir. Calisma kapsaminda golun batimetrik haritasinin cikartilmasi, golun sicaklik acisindan mevsimsel katmanlasma yapisinin incelenmesi gerceklestirilmistir. Batimetrik harita cikariminda RTK GPS kullanilarak yapilan arazi olcumleri ile akustik doppler akim profil cihazi (ADCP) kullanilarak elde edilen batimetrik harita verileri birlestirilerek yuksek cozunurluklu batimetri haritasi elde edilmistir. 2 yil boyunca gerceklestirilen monitorlama calismalarinda, Borabey Goleti’nin derinlige bagli sicaklik profili cikartilmistir. Ayrica, goldeki termal katmanlasma yapisinin belirlenmesi icin RTRM indisi kullanilmistir. Calisma sonucunda, Borabey Goleti'nin termal katmanlasma yapisina bagli olarak epilimniyon, metalimniyon, hipolimniyon tabaka hacimleri belirlenmistir. Ayrica golun monomiktik gol yapisina sahip oldugu ortaya cikarilmistir.