Miracle-dz/UniFAR-FTUs huggingface dataset:
Escherichia coli Leucine-Responsive Regulatory Protein Bridges DNA In Vivo and Tunably Dissociates in the Presence of Exogenous Leucine

Leucine-responsive regulatory protein (Lrp) is one of the most impactful regulators in E. coli and other bacteria. Lrp senses nutrient conditions and responds by controlling strategies for virulence, cellular motility, and nutrient acquisition. ABSTRACT Feast-famine response proteins are a widely conserved class of global regulators in prokaryotes, the most highly studied of which is the Escherichia coli leucine-responsive regulatory protein (Lrp). Lrp senses the environmental nutrition status and subsequently regulates up to one-third of the genes in E. coli, either directly or indirectly. Lrp exists predominantly as octamers and hexadecamers (16mers), where leucine is believed to shift the equilibrium toward the octameric state. In this study, we analyzed the effects of three oligomerization state mutants of Lrp in terms of their ability to bind to DNA and regulate gene expression in response to exogenous leucine. We find that oligomerization beyond dimers is required for Lrp’s regulatory activity and that, contrary to previous speculation, exogenous leucine modulates Lrp activity at its target promoters exclusively by inhibiting Lrp binding to DNA. We also show evidence that Lrp binding bridges DNA over length scales of multiple kilobases, revealing a new range of mechanisms for Lrp-mediated transcriptional regulation. IMPORTANCE Leucine-responsive regulatory protein (Lrp) is one of the most impactful regulators in E. coli and other bacteria. Lrp senses nutrient conditions and responds by controlling strategies for virulence, cellular motility, and nutrient acquisition. Despite its importance and being evolutionarily highly conserved across bacteria and archaea, several mysteries remain regarding Lrp, including how it actually responds to leucine to change its regulation of targets. Previous studies have led to the hypothesis that Lrp switches between two states, an octamer (8 Lrp molecules together) and a hexadecamer (16 Lrp molecules together), upon exposure to leucine; these are referred to as different oligomerization states. Here, we show that contrary to previous expectations, it is Lrp’s propensity to bind DNA, rather than its oligomerization state, that is directly affected by leucine in the cell’s environment. Our new understanding of Lrp activity will aid in identifying and disrupting pathways used by bacteria to cause disease.
Functional analysis of the Candida albicans ECE1 Promoter

In recent years it was shown that secretion of the toxic peptide candidalysin from hyphae of the major human fungal pathogen Candida albicans contributes heavily to its virulence. The peptide is derived from a precursor protein which is encoded by the ECE1 gene whose transcription is known to be closely associated with formation of hyphae. ABSTRACT The formation of hyphae is a key virulence attribute of Candida albicans as they are required for adhesion to and invasion of host cells, and ultimately deep-tissue dissemination. Hyphae also secrete the peptide toxin candidalysin, which is crucial for destruction of host cell membranes. The peptide is derived from a precursor protein encoded by the gene ECE1 which is strongly induced during hyphal growth. Previous studies revealed a very complex regulation of this gene involving several transcription factors. However, the promoter of the gene is still not characterized. Here, we present a functional analysis of the intergenic region upstream of the ECE1 gene. Rapid amplification of cDNA ends (RACE)-PCR was performed to identify the 5′ untranslated region, which has a size of 49 bp regardless of the hyphae-inducing condition. By using green fluorescent protein (GFP) reporter constructs we further defined a minimal promoter length of 1,500 bp which was verified by RT-qPCR. Finally, we identified the TATA element required for the expression of the gene. It is located 106 to 109 bp upstream of the ECE1 start codon. Our results illustrate that despite a very short 5′ UTR, a relatively long promoter is required to secure ECE1 transcription, indicating a complex regulatory machinery tightly controlling the expression of the gene. IMPORTANCE In recent years it was shown that secretion of the toxic peptide candidalysin from hyphae of the major human fungal pathogen Candida albicans contributes heavily to its virulence. The peptide is derived from a precursor protein which is encoded by the ECE1 gene whose transcription is known to be closely associated with formation of hyphae. Here, we used a GFP reporter system to determine the length of the ECE1 promoter and were able to show that it has a minimal size of 1,500 bp. Surprisingly, the gene has a very short 5′ UTR of only 49 bp. In accordance with this, the TATA element required for transcription is located 106 to 109 bp upstream of the start codon. This indicates that ECE1 expression is controlled by a very long promoter allowing a complex network of transcription factors to contribute to the gene’s regulation.
Mistreatment in health care among women in Appalachia

Abstract Good quality patient care requires health care providers to respect the humanity and autonomy of their patients. However, this is not achieved in all settings. This study used cross-sectional survey data including open-ended text responses to explore negative experiences with health care providers among women in Appalachia. We used the Heath Stigma & Discrimination Framework (HSDF) to identify how stigma is created and perpetuated through interactions with health care providers. Survey data from 628 women collected through purposive sampling identified that two out of three participants had had a bad encounter with a provider that made them not want to return for care. One in six participants had a negative experience specifically while seeking contraception. Using the domains of the HSDF framework, qualitative answers to open-ended questions illuminated how health care providers, influenced by social and cultural norms related to religiosity, patriarchal views, poverty, poor health infrastructure, and the opioid crisis, created and perpetuated stigma through dehumanising treatment, low-quality care, and health care misogyny. Because stigma is a driver of health inequity, these findings highlight the important and sometimes problematic role that health care providers can play when they create a barrier to future care through poor treatment of patients.
Commentary: Plaque burden estimated from optical coherence tomography with Deep Learning: In‐vivo validation using coregistered intravascular ultrasound

Catheter Cardiovasc Interv. 2023;101:297–298. wileyonlinelibrary.com/journal/ccd © 2023 Wiley Periodicals LLC. | 297 Key Points • Visibility of the media poses a challenge to accurate evaluation of plaque by conventional optical coherence tomography (OCT). • Deep Learning algorithms are reliable for the assessment of plaque burden using OCT. • Larger studies are necessary to validate such algorithms.
Body fat and muscle in relation to heart rate variability in young-to-middle age men: a cross sectional study

Abstract Background While obesity is recognisably associated with changes in heart rate variability (HRV), the association between skeletal muscle mass and HRV is less clear. Aims In this cross sectional study, we analysed the association of body fat (four parameters) and muscle mass (five parameters) with indicators of HRV activity. Subjects and methods Assessment of body composition and HRV was performed in n = 180 young-to-middle age healthy men exposed to high occupational physical activity, using the multi-frequency bioelectrical impedance device and the PPG-StressFlow® HRV photoplethysmography device, respectively. Results Mean values of parameters of fat tissue were above normal/reference values. Muscle tissue indicators were higher or within the reference ranges. Fat tissue parameters were significantly higher in participants with lower parasympathetic nervous system (PNS) indicators. Weight-adjusted skeletal muscle index (wSMI) was significantly lower in men with reduced PNS parameters. Fat tissue parameters were negatively correlated with PNS parameters, while wSMI was positively correlated with PNS parameters. Conclusions Participants with higher fat mass and lower muscle mass had poorer parasympathetic activity. Since mean values of HRV parameters indicated mild parasympathetic dominance, we conclude that physical activity and consequently good muscle mass potentially compensated for the negative interaction between fat tissue and HRV.
Differential Effects of Rhodococcus equi Virulence-Associated Proteins on Macrophages and Artificial Lipid Membranes

Rhodococcus equi is a major cause of life-threatening pneumonia in foals and occasionally in immunocompromised persons. Virulence-associated protein A (VapA) promotes R. equi multiplication in lung macrophages, which are the major host cells during foal infection. ABSTRACT Virulence-associated protein A (VapA) of Rhodococcus equi is a pathogenicity factor required for the multiplication of virulent R. equi strains within spacious macrophage vacuoles. The production of VapA is characteristic for R. equi isolates from pneumonic foals. VapB and VapN proteins in R. equi isolates from infected pig (VapB) and cattle (VapN) have amino acid sequences very similar to VapA and consequently have been assumed to be its functional correlates. Using model membrane experiments, phagosome pH acidification analysis, lysosome size measurements, protein partitioning, and degradation assays, we provide support for the view that VapA and VapN promote intracellular multiplication of R. equi by neutralizing the pH of the R. equi-containing vacuole. VapB does not neutralize vacuole pH, is not as membrane active as VapA, and does not support intracellular multiplication. This study also shows that the size of the sometimes enormous R. equi-containing vacuoles or the partitioning of purified Vaps into organic phases are not features that have predictive value for virulence of R. equi, whereas the ability of Vaps to increase phagosome pH is coupled to virulence. IMPORTANCE Rhodococcus equi is a major cause of life-threatening pneumonia in foals and occasionally in immunocompromised persons. Virulence-associated protein A (VapA) promotes R. equi multiplication in lung macrophages, which are the major host cells during foal infection. In this study, we compare cellular, biochemical, and biophysical phenotypes associated with VapA to those of VapB (typically produced by isolates from pigs) or VapN (isolates from cattle). Our data support the hypothesis that only some Vaps support multiplication in macrophages by pH neutralization of the phagosomes that R. equi inhabit.
Cloud transition across the daily cycle illuminates model responses of trade cumuli to warming

Significance The response of trade-wind clouds to warming has long been a major source of uncertainty for climate change projections. By analyzing a set of climate models, we identify two contrasting types of model behaviors, which are evident both at the daily timescale and under global warming. These opposing behaviors depend on whether models can simulate cloud transitions—between very shallow and deeper cumuli—in response to changes in the convective mass flux. We show that the daily cycle can be used as a laboratory for assessing the physical credibility of trade cumulus responses to warming as simulated by climate models relative to observed cloud variations and processes. Our findings can also help guide future model development using observational benchmarking.
DNA-methylation and immunological response in medication overuse headache

Objective To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. Methods We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. Results We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1–11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041). Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. Conclusion This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches. ClinicalTrials.gov Identifier: NCT02993289
The Differential Relation of Emotional, Physical, and Sexual Abuse Histories to Antidepressant Treatment Remission and Persistence of Anhedonia in Major Depression: A CAN-BIND-1 Report

Objective Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories. Methods In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale. Results Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8. Conclusions We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.
Transport of a multiple-ion species plasma in the Pfirsch-Schlüter regime

The classical parallel friction coefficients, which relate the collisional friction forces to the flow of particles and heat along the magnetic field, are calculated for a multiple ion species plasma. In the short mean‐free‐path regime, the neoclassical Pfirsch–Schluter transport coefficients for a toroidally confined multispecies plasma are computed in terms of the classical friction coefficients. The dependence of the neoclassical cross‐field transport on the equilibration of the parallel ion temperature profiles is determined.
Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution

Abstract Background: To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution. Methods: This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS). Results: During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan–Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P = 0.025 and P = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4–99.8%) and 95.2% (95% CI: 89.0–100.0%), respectively, and 80.5% (95% CI: 69.3–93.6%) and 90.5% (95% CI: 52.8–99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01–0.88) and 0.042 (HR: 0.19; 95% CI: 0.04–0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups. Conclusion: Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.
Collisionless transport of energetic electrons in the solar corona at current-free double layers

Context. Impinging electron beams in the solar chromosphere generate hard X-ray radiation (HXR) through the collisional Bremstrahlung thick target model. The deduced electron distributions usually exhibit a broken-power-law. Assuming that the initial distribution function was a drift-Maxwellian, this indicates that the distribution of energetic electrons changes in the course of their propagation, from the looptop acceleration site to the high density chromosphere, via a collisionless scattering mechanism. Aims. The formation of a broken-power-law spectrum via the particle interaction with the current-free weak double layers (DLs) in a reverse current beam plasma system. Methods. The unstable waves generated in current-free coronal plasmas are first studied by means of a linear instability analysis. For most probable coronal plasma parameters, a one-dimensional electrostatic Vlasov-code simulation is performed to understand the nonlinear evolution of the instabilities and their influences on the electron distribution. Results. DL structures cause a dissipation of low energy beam electrons and a stagnation of return-current electrons. Fast electron holes are formed, a secondary two-stream instability, caused by the DL-accelerated electrons. Electron and ion heating by DLs also takes place. Conclusions. The plasma distributions of energetic electrons in the solar corona evolve via their interactions with nonlinear largeamplitude phase-space structures. At the late stage of evolution, the low-energy electrons are slowed down while the high energy part stays uninfluenced after the appearance of DLs. A major part of the return-current electrons change their direction to that of the injected beam. As a result the distribution becomes a broken-power-law as observed by chromospheric HXR radiation.
The potato StMKK5‐StSIPK module enhances resistance to Phytophthora pathogens through activating the salicylic acid and ethylene signalling pathways

Abstract Mitogen‐activated protein kinase (MAPK) cascades play pivotal roles in plant responses to both biotic and abiotic stress. A screen of a Nicotiana benthamiana cDNA virus‐induced gene silencing (VIGS) library for altered plant responses to inoculation with Phytophthora infestans previously identified an NbMKK gene, encoding a clade D MAPKK that we renamed as NbMKK5, which is involved in immunity to P. infestans. To study the role of the potato orthologous gene, referred to as StMKK5, in the response to P. infestans, we transiently overexpressed StMKK5 in N. benthamiana and observed that cell death occurred at 2 days postinfiltration. Silencing of the highly conserved eukaryotic protein SGT1 delayed the StMKK5‐induced cell death, whereas silencing of the MAPK‐encoding gene NbSIPK completely abolished the cell death response. Further investigations showed that StMKK5 interacts with, and directly phosphorylates, StSIPK. Furthermore, both StMKK5 and StSIPK trigger salicylic acid (SA)‐ and ethylene (Eth)‐related gene expression, and co‐expression of the salicylate hydroxylase NahG with the negative regulator of Eth signalling CTR1 hampers StSIPK‐triggered cell death. This observation indicates that the cell death triggered by StMKK5‐StSIPK is dependent on the combination of SA‐ and Eth‐signalling. By introducing point mutations, we showed that the kinase activity of both StMKK5 and StSIPK is required for triggering cell death. Genetic analysis showed that StMKK5 depends on StSIPK to trigger plant resistance. Thus, our results define a potato StMKK5‐SIPK module that positively regulates immunity to P. infestans via activation of both the SA and Eth signalling pathways.
THE EVOLUTION OF 1 AU EQUATORIAL SOLAR WIND AND ITS ASSOCIATION WITH THE MORPHOLOGY OF THE HELIOSPHERIC CURRENT SHEET FROM SOLAR CYCLES 23 TO 24

The solar wind can be categorized into three types based on its “freeze-in” temperature (Tfreeze-in) in the coronal source: low Tfreeze-in wind mostly from coronal holes, high Tfreeze-in wind mostly from regions outside of coronal holes, including streamers (helmet streamer and pseudostreamer), active regions, etc., and transient interplanetary coronal mass ejections (ICMEs) usually possessing the hottest Tfreeze-in. The global distribution of these three types of wind has been investigated by examining the most effective Tfreeze-in indicator, the O7 +/O6 + ratio, as measured by the Solar Wind Ion Composition Spectrometer on board the Advanced Composition Explorer (ACE) during 1998–2008 by Zhao et al. In this study, we extend the previous investigation to 2011 June, covering the unusual solar minimum between solar cycles 23 and 24 (2007–2010) and the beginning of solar cycle 24. We find that during the entire solar cycle, from the ascending phase of cycle 23 in 1998 to the ascending phase of cycle 24 in 2011, the average fractions of the low O7 +/O6 + ratio (LOR) wind, the high O7 +/O6 + ratio (HOR) wind, and ICMEs at 1 AU are 50.3%, 39.4%, and 10.3%, respectively; the contributions of the three types of wind evolve with time in very different ways. In addition, we compare the evolution of the HOR wind with two heliospheric current sheet (HCS) parameters, which indicate the latitudinal standard deviation (SD) and the slope (SL) of the HCS on the synoptic Carrington maps at 2.5 solar radii surface. We find that the fraction of HOR wind correlates with SD and SL very well (slightly better with SL than with SD), especially after 2005. This result verifies the link between the production of HOR wind and the morphology of the HCS, implying that at least one of the major sources of the HOR wind must be associated with the HCS.