Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+ Channel (ENaC)

BACKGROUND: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively. METHODS: We generated kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) mice to examine whether renal AT1aR regulates Kir4.2 and Kir4.1. RESULTS: Ks-AT1aR-KO mice had a lower systolic blood pressure than Agtr1aflox/flox (control) mice. Ks-AT1aR-KO mice had a lower expression of NHE3 (Na+/H+-exchanger 3) and Kir4.2, a major Kir-channel in PT, than Agtr1aflox/flox mice. Whole-cell recording also demonstrated that the membrane potential in PT of Ks-AT1aR-KO mice was lesser negative than Agtr1aflox/flox mice. The expression of Kir4.1 and Kir5.1, Kir4.1/Kir5.1-mediated K+ currents of DCT and DCT membrane potential in Ks-AT1aR-KO mice, were similar to Agtr1aflox/flox mice. However, angiotensin II perfusion for 7 days hyperpolarized the membrane potential in PT and DCT of the control mice but not in Ks-AT1aR-KO mice, while angiotensin II perfusion did not change the expression of Kir4.1, Kir4.2, and Kir5.1. Deletion of AT1aR did not significantly affect the expression of αENaC (epithelial Na+ channel) and βENaC but increased cleaved γENaC expression. Patch-clamp experiments demonstrated that deletion of AT1aR increased amiloride-sensitive Na+-currents in the cortical-collecting duct but not in late-DCT. However, tertiapin-Q sensitive renal outer medullary potassium channel currents were similar in both genotypes. CONCLUSIONS: AT1aR determines the baseline membrane potential of PT by controlling Kir4.2 expression/activity but AT1aR is not required for determining the baseline membrane potential of the DCT and Kir4.1/Kir5.1 activity/expression. However, AT1aR is required for angiotensin II–induced hyperpolarization of basolateral membrane of PT and DCT. Deletion of AT1aR had no effect on baseline renal outer medullary potassium channel activity but increased ENaC activity in the CCD.
Clinically important effect sizes for clinical trials using infarct growth reduction as the primary outcome: a systematic review

Background Infarct growth on multimodal imaging is a common lead outcome in phase 2 proof-of-concept and dose-optimization neuroprotective agent stroke trials. However, the effect size in infarct growth reduction that correlates with clinically meaningful differences in clinical global disability outcomes has not been well delineated. Methods A systematic literature search identified all endovascular thrombectomy randomized trials reporting magnitude of treatment effect on both infarct growth reduction and increase in functional independence (modified Rankin Scale (mRS) 0–2). Data aggregation determined the size of infarct growth reductions salient to four types of clinically meaningful effect sizes of increase in functional independence: (1) the minimal clinically important difference (MCID)–outcome specific; (2) the MCID–practice changing; (3) the realistic target difference; and (4) the reasonable comparability effect size. Results A systematic search identified four trials enrolling 612 imaged participants. Across the trials, the amount of functional independence (mRS 0–2) increase associated with each 1 mL reduction in infarct growth was mean 2.3±0.6%. An infarct growth reduction of 0.57 mL correlated with the mRS 0–2 increase MCID of 1.3%. Infarct growth reductions of 2.27 mL, 4.35 mL, and 6.53 mL correlated with realistic effect and reasonable comparability effects sizes of mRS 0–2 increases of 5%, 10%, and 15%, respectively. Conclusion In formal meta-analysis of randomized treatment trials, every 1 mL reduction in infarct growth was associated with a 2.3% increase in functional independence (mRS 0–2) at 3 months. This conversion factor can inform selection of infarct growth effect size targets for phase 2 trials of neuroprotective agents.
Edinburgh Research Explorer Corporate culture and firm value

Based on the Competing Values Framework (CVF), we score 10-K text to measure company culture in four types (collaborative, controlling, competitive, and creative) and examine its role in ﬁrm stability. We ﬁnd that ﬁrms with higher controlling culture fared signiﬁcantly better during the 2008–09 crisis. Firms with stronger controlling culture experienced fewer layoffs, less negative asset growth, greater debt issuance, and increased access to credit-line facilities during the crisis. The positive effect of the controlling culture is stronger among the ﬁnancially-constrained ﬁrms. Overall, the controlling culture improves ﬁrm stability through greater support from capital providers.
Modelling Group Navigation: Dominance and Democracy in Homing Pigeons

During group navigation the information shared by group members may be complex, heterogeneous and may vary over time. Nevertheless, modelling approaches have demonstrated that even relatively simple interactions between individuals can produce complex collective outcomes. In such models each individual follows the same simple set of local rules, giving rise to differential outcomes of the navigational decision-making process depending on various parameters. However, inherent heterogeneity within groups means that some group members may emerge as more influential than others in navigational tasks and this underlying social structure may affect the ability of the group at large. Here, we present our preliminary modelling of group navigation specifically developed to include internal group structure. Building on existing models and recent experimental results we examine the role of individual influence on group navigation and its effects on group navigational ability. © The Royal Institute of Navigation 2008.
Regulation and function of alternative polyadenylation in development and differentiation

ABSTRACT Alternative processing of nascent mRNAs is widespread in eukaryotic organisms and greatly impacts the output of gene expression. Specifically, alternative cleavage and polyadenylation (APA) is a co-transcriptional molecular process that switches the polyadenylation site (PAS) at which a nascent mRNA is cleaved, resulting in mRNA isoforms with different 3’UTR length and content. APA can potentially affect mRNA translation efficiency, localization, stability, and mRNA seeded protein–protein interactions. APA naturally occurs during development and cellular differentiation, with around 70% of human genes displaying APA in particular tissues and cell types. For example, neurons tend to express mRNAs with long 3’UTRs due to preferential processing at PASs more distal than other PASs used in other cell types. In addition, changes in APA mark a variety of pathological states, including many types of cancer, in which mRNAs are preferentially cleaved at more proximal PASs, causing expression of mRNA isoforms with short 3’UTRs. Although APA has been widely reported, both the function of APA in development and the mechanisms that regulate the choice of 3’end cut sites in normal and pathogenic conditions are still poorly understood. In this review, we summarize current understanding of how APA is regulated during development and cellular differentiation and how the resulting change in 3’UTR content affects multiple aspects of gene expression. With APA being a widespread phenomenon, the advent of cutting-edge scientific techniques and the pressing need for in-vivo studies, there has never been a better time to delve into the intricate mechanisms of alternative cleavage and polyadenylation.
Involvement of endoplasmic reticulum and histone proteins in immunomodulation by TLR4-interacting SPA4 peptide against Escherichia coli

ABSTRACT Pulmonary host defense is critical for the control of lung infection and inflammation. An increased expression and activity of Toll-like receptor 4 (TLR4) induce phagocytic uptake/clearance and inflammation against Gram-negative bacteria. In this study, we addressed the mechanistic aspect of the immunomodulatory activity of the TLR4-interacting SPA4 peptide (amino acid sequence GDFRYSDGTPVNYTNWYRGE) against Escherichia coli. Binding of the SPA4 peptide to bacteria and direct anti-bacterial effects were investigated using flow cytometric, microscopic, and bacteriological methods. The bacterial uptake and inflammatory cytokine response were studied in dendritic cells expressing endogenous basal level of TLR4 or overexpressing TLR4. The subcellular distribution and co-localization of TLR4 and bacteria were investigated by immunocytochemistry. Furthermore, we studied the cellular expression and co-localization of endoplasmic reticulum (ER) molecules (calnexin and ER membrane protein complex subunit 1; EMC1) with lysosomal-associated membrane protein 1 (LAMP1) in cells infected with E. coli and treated with the SPA4 peptide. Simultaneously, the expression of histone H2A protein was quantitated by immunoblotting. Our results demonstrate no binding or direct killing of the bacteria by SPA4 peptide. Instead, it induces the uptake and localization of E. coli in the phagolysosomes for lysis and simultaneously suppresses the secreted levels of TNF-α. Overexpression of TLR4 further augments the pro-phagocytic and anti-inflammatory activity of SPA4 peptide. A time-dependent change in subcellular distribution of TLR4 and an increased co-localization of TLR4 with E. coli in SPA4 peptide-treated cells suggest an enhanced recognition and internalization of bacteria in conjugation with TLR4. Furthermore, an increased co-localization of calnexin and EMC1 with LAMP1 indicates the involvement of ER in pro-phagocytic activity of SPA4 peptide. Simultaneous reduction in secreted amounts of TNF-α coincides with suppressed histone H2A protein expression in the SPA4 peptide-treated cells. These results provide initial insights into the plausible role of ER and histones in the TLR4-immunomodulatory activity of SPA4 peptide against Gram-negative bacteria.
Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption–induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Asymptomatic parenchymal haemorrhage following endovascular treatment: Impact on functional outcome in patients with acute ischaemic stroke

In patients with acute ischaemic stroke (AIS), haemorrhagic transformation (HT) following endovascular treatment (EVT) is associated with poor functional outcome. However, the impact of asymptomatic HT, not linked to neurological deterioration in the acute phase, is unknown. We aimed to investigate the impact of asymptomatic PH1 (aPH1) and PH2 (aPH2) subtypes of HT on the functional outcome of patients treated with EVT.
Tilted implants for implant-supported fixed hybrid prostheses: retrospective review

Objectives This review assessed the performance of implant-supported fixed hybrid prostheses in 21 patients who received a total of 137 implants between 2003 and 2010. The implants were evaluated for marginal bone resorption, complications, success rate, and survival rate based on their vertical angularity, type of bone graft, and measured implant stability. Materials and Methods One-way ANOVA and chi-square tests were used to analyze the relationships among long-term evaluation factors and these variables. The mean initial bone resorption in the implant group with a vertical angle of more than 20° was 0.33 mm and mean final bone resorption was 0.76 mm. In contrast, the mean initial bone resorption in the implant group with a vertical angle of less than 10° was 1.19 mm and mean final bone resorption was 2.17 mm. Results The results showed that mean bone resorption decreased with an increase in the vertical placement angle of the implants used in fixed hybrid prostheses, as well as in the group without additional bone grafts and those with high implant stability. The success rate of implants placed after bone grafting was found to be higher than those placed simultaneously. Conclusion These results suggest that implant-supported fixed hybrid prostheses may be an effective treatment option for edentulous patients, and intentionally placing implants with high angularity may improve outcomes.
Sex differences in the age of childhood autism diagnosis and the impact of co‐occurring conditions

Sex differences in the age of autism diagnosis during childhood have been documented consistently but remain poorly understood. In this study, we used electronic health records data from a diverse, academic medical center to quantify differences in the age of autism diagnosis between boys and girls and identify associations between the age of diagnosis and co‐occurring neurodevelopmental, psychiatric, and medical conditions. An established computable phenotype was used to identify all autism diagnoses within the Duke University Health System between 2014 and 2021. Co‐occurring neurodevelopmental and psychiatric diagnoses as well as visits to specific medical and supportive services were identified in the 2 years prior to the autism diagnosis. Cox proportional hazards models were fitted to quantify associations between diagnosis age and sex with and without controlling for the presence of each co‐occurring diagnosis and visit type. Records from 1438 individuals (1142 boys and 296 girls) were included. Girls were more likely to be diagnosed either before age 3 ( χ2 = 497.720, p < 0.001) or after age 11 ( χ2 = 4.014, p = 0.047), whereas boys were more likely to be diagnosed between ages 3 and 11 ( χ2 = 5.532, p = 0.019). Visits for anxiety ( χ2 = 4.200, p = 0.040) and mood disorders ( χ2 = 7.033, p = 0.008) were more common in girls and associated with later autism diagnosis (HR = 0.615, p < 0.001; and HR = 0.493, p < 0.001). Visits for otolaryngology were more common in boys and associated with an earlier autism diagnosis (HR = 1.691, p < 0.001). After controlling for these conditions, associations between sex and diagnosis age were reduced and not statistically significant. These results show that the age of autism diagnosis differs in girls compared to boys, but these differences were neutralized when controlling for co‐occurring neurodevelopmental and psychiatric conditions prior to autism diagnosis. Understanding sex differences and the possible mediating role of other diagnoses may suggest targets for intervention to promote earlier and more equitable diagnosis.
Hydrological and nitrate modelling for the River Ic in Brittany (France) - Simulation results and pre-liminary scenario analysis Project acronym: AQUISAFE 1 Extension

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Revisiting the Prognostic Impact of Family History in Colorectal Cancer by Retrospective Propensity Score Matching

Background/Aim: Family history of colorectal cancer (CRC) is a known risk factor for CRC. However, its prognostic value in patients with CRC remains controversial. This study aimed to clarify the prognostic impact of a family history of CRC. Patients and Methods: We retrospectively reviewed the database from 1978 to 2018 and enrolled 3,655 consecutive patients with CRC. We investigated the clinicopathological factors of patients with CRC with and without a family history. After propensity score matching, we performed a survival analysis of patients with CRC with and without a family history. Results: Patients with CRC with a family history of CRC had a young onset (63.2 and 65.9; p<0.001), were more likely to be female (54.3% and 49.7%; p=0.042), had less symptomatic disease (76.9% and 80.8%; p=0.008), were more likely to have right-sided colon cancer (27.5% and 26.1%), and had less distant metastases (11.3% and 14.9%; p=0.023) and multiple CRCs (10.2% and 7.8%) compared with those without a family history of CRC. Prior to propensity score matching, CRC-specific survival analysis showed that a family history of CRC was a good prognostic factor (p=0.022). After propensity score matching, survival curves overlapped between the two groups. Conclusion: Patients with CRC with a family history of CRC had specific clinicopathological features including younger onset, female sex, proximal colon location, fewer symptoms, smaller number of distant metastases, likelihood of multiple diseases, and earlier cancer stage. Family history of CRC in patients with CRC was not a prognostic factor.
Beyond geography's visible worlds: a cultural politics of music

Within human geography, the meeting between art matters and cultural politics has been a predominantly visual affair. However, this article argues that sound is as important as sight for the project of geography, and that music has as secure a place as the visual arts in the study of social life. For example, while cultural studies of Renaissance Italy have focused on the way that landscape painting encapsulates the political economy of the period, I consider why the ‘truths’ of the time were nurtured as much by filling space with sound as by depicting place on canvas. Similarly, although painters are able vividly to depict the impact of industrialization on the English landscape, by exploring the spaces of music – a more neglected route into the historical geography of modern Britain – I suggest there is more to the link between art and industrialism than first meets the eye. Finally, building on maps of race and racism drawn up from ethnography, narrative and visual representation, I tease out the contested terrain of music, and identify it as a medium through which those whose condition society tries its best not to see can begin to make themselves heard.
Ambient noise levels in north central Italy

The characteristics of background seismic noise in north central Italy have been investigated by means of velocity power spectral analysis within the frequency range 0.1–15 Hz. The method proposed by McNamara and Buland (2004) has been applied to estimate the probability density function (PDF) of power spectra computed for ten different stations. Since the target region is the most industrialized area of Italy, a large variability among the power spectra for different sites is observed in the frequency range 1–15 Hz, with the noise levels at two stations exceeding the New High Noise Model (NHNM) of Peterson (1993). The 95th percentile of the PDF varies from −165 to −125 dB (relative to (m/s)2/Hz). This variability could significantly affect the detection capabilities of a network installed for recording the small to moderate size seismicity occurring in north central Italy. We also observed that the dispersion of the powers, estimated at each site as the difference between the 95th and the 5th percentiles, shows a positive trend with frequency that can be ascribed to the diurnal variation of the background noise levels. In the frequency range 0.1–1 Hz, the dominant feature is the double frequency (DF) peak of microseisms generated by oceanic storms. At one of the considered stations, the seasonal variability of the maximum amplitude of the DF peak has been observed in the period from April 2004 to December 2005. Considering the barometric maps provided by the UK Meteorological Office, we observed that the strongest powers in the range 0.10–0.25 Hz occur when intense storms are present over the North Atlantic Ocean, whereas the measurements of the height, frequency, and azimuth of the sea waves at two buoys of the Rete Ondametrica Italiana deployed in the Adriatic and Tyrrhenian seas suggest that the DF microseisms in the frequency range 0.25–0.50 Hz are generated by storms over the Mediterranean Sea. Finally, the analyzed region is characterized by two large‐scale geologic features, namely, the Po Plain and the Alps. The impedance contrast between these two units causes a noise reduction of about 10 dB in the frequency range 0.2–0.6 Hz.
Value of circulating neutrophil elastase for detecting recurrence of differentiated thyroid cancer

Objective The inflammatory microenvironment has been implicated in differentiated thyroid cancer (DTC). Inflammatory stimuli induce the release of components of neutrophils into extracellular space, leading to formation of neutrophil extracellular trap (NET), which can stimulate growth and progression of cancer. Generation of activated factor XII and thrombin is also involved in cancer progression. This study attempted to determine whether the level of circulating markers of NET, activated factor XII, and endogenous thrombin potential may be useful for detecting the recurrence of DTC. Methods A total of 122 patients with DTC were recruited during the postoperative follow-up period. Measurement of the levels of circulating markers of NET (neutrophil elastase, histone–DNA complex, cell-free dsDNA), activated factor XII, and endogenous thrombin potential was performed. Results A significantly elevated level of neutrophil elastase was detected in patients with recurrence (n = 12) compared to those without recurrence (n = 110), while significant elevation of the levels of other markers was not observed. The value for area under the curve (0.717, P = 0.018) of neutrophil elastase for detecting recurrence of DTC was superior to that (0.661, P = 0.051) of serum thyroglobulin. An elevated level of neutrophil elastase was significantly associated with recurrence of DTC independent of serum thyroglobulin. Conclusions Because an elevated level of neutrophil elastase was detected in patients with recurrence of DTC and showed a significant association with recurrence of DTC, it can be proposed as a novel biomarker for use in detecting recurrence of DTC along with other tests.