Miracle-dz/UniFAR-FTUs huggingface dataset:
Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages

The emergence of Plasmodium falciparum parasite resistance to dihydroartemisinin + piperaquine (PPQ) in Southeast Asia threatens plans to increase the global use of this first-line antimalarial combination. High-level PPQ resistance appears to be mediated primarily by novel mutations in the P. falciparum chloroquine resistance transporter (PfCRT), which enhance parasite survival at high PPQ concentrations in vitro and increase the risk of dihydroartemisinin + PPQ treatment failure in patients. Using isogenic Dd2 parasites expressing contemporary pfcrt alleles with differential in vitro PPQ susceptibilities, we herein characterize the molecular and physiological adaptations that define PPQ resistance in vitro. Using drug uptake and cellular heme fractionation assays we report that the F145I, M343L, and G353V PfCRT mutations differentially impact PPQ and chloroquine efflux. These mutations also modulate proteolytic degradation of host hemoglobin and the chemical inactivation of reactive heme species. Peptidomic analyses reveal significantly higher accumulation of putative hemoglobin-derived peptides in the PPQ-resistant mutant PfCRT isoforms compared to parental PPQ-sensitive Dd2. Joint transcriptomic and metabolomic profiling of late trophozoites from PPQ-resistant or -sensitive isogenic lines reveals differential expression of genes involved in protein translation and cellular metabolism. PPQ-resistant parasites also show increased susceptibility to an inhibitor of the P. falciparum M17 aminopeptidase that operates on short globin-derived peptides. These results reveal unique physiological changes caused by the gain of PPQ resistance and highlight the potential therapeutic value of targeting peptide metabolism in P. falciparum.
Cell-cell contacts via N-cadherin induce a regulatory renin secretory phenotype in As4.1 cells

The lack of a clonal renin-secreting cell line has greatly hindered the investigation of the regulatory mechanisms of renin secretion at the cellular, biochemical, and molecular levels. In the present study, we investigated whether it was possible to induce phenotypic switching of the renin-expressing clonal cell line As4.1 from constitutive inactive renin secretion to regulated active renin secretion. When grown to postconfluence for at least two days in media containing fetal bovine serum or insulin-like growth factor-1, the formation of cell-cell contacts via N-cadherin triggered downstream cellular signaling cascades and activated smooth muscle-specific genes, culminating in phenotypic switching to a regulated active renin secretion phenotype, including responding to the key stimuli of active renin secretion. With the use of phenotype-switched As4.1 cells, we provide the first evidence that active renin secretion via exocytosis is regulated by phosphorylation/dephosphorylation of the 20 kDa myosin light chain. The molecular mechanism of phenotypic switching in As4.1 cells described here could serve as a working model for full phenotypic modulation of other secretory cell lines with incomplete phenotypes.
What happens in the long term: Uptake of cancer surveillance and prevention strategies among at‐risk relatives with pathogenic variants detected via cascade testing

Cascade genetic testing for hereditary cancer syndromes offers affected relatives the opportunity to pursue cancer screening and risk‐reducing surgery and thus reduces morbidity and mortality. The purpose of this study was to measure the long‐term utilization of targeted cancer prevention and quality of life among at‐risk relatives offered clinician‐facilitated cascade genetic testing.
LGD‐4033 and MK‐677 use impacts body composition, circulating biomarkers, and skeletal muscle androgenic hormone and receptor content: A case report

What is the main observation in this case? Co‐administration of LGD‐4033 and MK‐677 increased body mass, lean mass and fat mass, while negatively impacting bone, serum lipids, liver enzymes, testosterone (total and free) and, probably, follicle‐stimulating hormone. What insights does it reveal? Our cross‐sectional data imply that these compounds might alter intramuscular androgenic hormone and receptor concentrations along with promoting muscular strength, when compared with previously published data from trained males.
An evaluation of value-based outcomes for women admitted to a dialectical behaviour therapy integrated practice unit: a follow-up study

Abstract Background: An earlier evaluation (Fox et al., 2014) highlighted reductions in risk behaviours and restrictive practices for women admitted to low secure dialectical behaviour therapy (DBT) unit. Since then, a value-based healthcare model has been adopted. Aims: To explore changes in health, social and psychological functioning, risk, quality of life, and in incidents of violence and restrictive practices, over the initial 12-month period of admission to a specialist DBT service. Method: Data were extracted from electronic clinical records for 41 women with emotionally unstable personality disorder admitted to a specialist integrated practice unit (IPU) providing a comprehensive DBT programme. Secondary analysis was conducted on an anonymous dataset of routinely collected outcome measures at baseline admission, and 6 and 12 months post-admission. ANOVAs and pairwise post hoc comparisons, and non-parametric equivalents, were conducted to examine changes in outcomes. Results: Findings showed statistically significant improvements in mental health scores on the ReQOL (p<.01), global, wellbeing, problems, functioning and risk scores on the COREOM (all p<.01), and severe disturbance, emotional wellbeing, socioeconomic status, risk and need scores on the HoNOS-Secure (all p<.05). Significant reductions in risk behaviours (p<.01) and restrictive practices (p<.01) were also apparent. The most substantiative improvements were largely demonstrated over a 12-month admission period. Conclusions: Admission to the DBT IPU yielded significant improvements on outcomes pertaining to quality of life, psychological distress, and risk. Importantly, these are outcomes that aligned with patients’ perceptions of recovery.
The WNT/Ca2+ pathway promotes atrial natriuretic peptide secretion by activating protein kinase C/transforming growth factor-β activated kinase 1/activating transcription factor 2 signaling in isolated beating rat atria

WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) β and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-β activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC–TAK1–ATF2–TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT–ANP signaling is implicated in cardiac physiology and pathophysiology.
Possible case of polyarteritis nodosa with epididymitis following COVID-19 vaccination: A case report and review of the literature.

Abstract The global outbreak of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 has prompted the rapid spread and development of vaccines to prevent the spread of the disease. COVID-19 vaccine has demonstrated excellent efficacy in reducing morbidity and severity of the disease, and most adverse reactions are very minor. However, some patients have been reported to develop autoimmune diseases, such as rheumatoid arthritis, myocarditis, Guillain-Barre syndrome, and vasculitis, following COVID-19 vaccination. Herein, we present a case of polyarteritis nodosa with epididymitis following COVID-19 mRNA vaccination. The patient’s initial symptoms were fever and testicular pain, and magnetic resonance imaging showed epididymitis. He was diagnosed as having polyarteritis nodosa with epididymitis and treated with high-dose prednisolone, with a good clinical outcome.
A SEROLOGIC SURVEY OF FRANCISELLA TULARENSIS EXPOSURE IN WILDLIFE ON THE ARCTIC COASTAL PLAIN OF ALASKA, USA

Abstract: Tularemia is an infectious zoonotic disease caused by one of several subspecies of Francisella tularensis bacteria. Infections by F. tularensis are common throughout the northern hemisphere and have been detected in more than 250 wildlife species. In Alaska, US, where the pathogen was first identified in 1938, studies have identified F. tularensis antibodies in a diverse suite of taxa, including insects, birds, and mammals. However, few such investigations have been conducted recently and knowledge about the current distribution and disease ecology of F. tularensis is limited, particularly in Arctic Alaska, an area undergoing rapid environmental changes from climate warming. To help address these information gaps and provide insights about patterns of exposure among wildlife, we assessed the seroprevalence of F. tularensis antibodies in mammals and tundra-nesting geese from the Arctic Coastal Plain of Alaska, 2014–17. With a commercially available slide agglutination test, we detected antibodies in 14.7% of all individuals sampled (n=722), with titers ranging from 1:20 to 1:320. We detected significant differences in seroprevalence between family groups, with Canidae (foxes, Vulpes spp.) and Sciuridae (Arctic ground squirrel, Spermophilus parryii) having the highest seroprevalence at 21.5% and 33.3%, respectively. Mean seroprevalence for Ursidae (polar bears, Ursus maritimus) was 13.3%, whereas Cervidae (caribou, Rangifer tarandus) had comparatively low seroprevalence at 6.5%. Antibodies were detected in all Anatidae species sampled, with Black Brant (Branta bernicla nigricans) having the highest seroprevalence at 13.6%. The detection of F. tularensis antibodies across multiple taxa from the Arctic Coastal Plain and its nearshore marine region provides evidence of exposure to this pathogen throughout the region and highlights the need for renewed surveillance in Alaska.
Molecular Surveillance for Lymphoproliferative Disease Virus and Reticuloendotheliosis Virus in Rio Grande Wild Turkeys (Meleagris gallopavo intermedia) in Texas, USA

Abstract: Reticuloendotheliosis virus (REV) and lymphoproliferative disease virus (LPDV) are avian retroviruses that can cause neoplastic disease and present with similar pathologies. Lymphoproliferative disease virus has been reported in the Eastern US and states bordering Texas, USA, but has not been previously detected within the state. In a prior study, we detected REV in native Rio Grande Wild Turkeys (Meleagris gallopavo intermedia) and an Eastern Wild Turkey (Meleagris gallopavo silvestris) originating from West Virginia. Given LPDV detection in states bordering Texas and our finding of an REV-positive Eastern Wild Turkey imported from a LPDV endemic region, we sought to determine LPDV prevalence in Texas and continue surveillance for REV. During 2018–20, dried blood spots from 373 individual Rio Grande Wild Turkeys from 20 different counties were tested for the presence of proviral REV or LPDV DNA. In affected counties, approximately 4% of individuals were infected with REV (7/197) or LPDV (10/273) and one bird was coinfected with both viruses. Phylogenetic analysis indicated a close relationship of the LPDV isolates to variants from other Southern and Central states. This study provides molecular evidence of LPDV in Texas, and continued surveillance is necessary to determine the potential effects of the virus on reproductive success, coinfections, and overall health of Wild Turkey populations.
Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome

Significance Statement Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, which encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). A subset of patients with Gitelman syndrome has only one specific pathogenic variant identified. In this study, long-read sequencing identified 46 previously undetected variants in 95 patients with suspected Gitelman syndrome. A midigene splice assay confirmed the pathogenicity of intronic variants. The data show that both intronic and exonic variants were missed previously and that former detection of one SLC12A3 variant predicts identification of an additional variant. The findings advocate long-read sequencing, complemented with a midigene splice assay, for intronic variants, as a second-tier diagnostic test in patients with one pathogenic SLC12A3 variant. Background Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3, which encodes the Na+-Cl− cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield. Methods Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants. Results A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns. Conclusion Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.
Symbol, Surface operators and $S$-duality

We study rigid surface operators in the $N=4$ supersymmetric Yang-Mills theories with gauge groups $SO(n)$ and $Sp(2n)$. Using maps $X_S$ and $Y_S$ between these two theories, Wyllard made explicit proposals for how the $S$-duality map should act on certain subclasses of surface operators. We study the maps $X_S$ and $Y_S$ further and simplify the construction of symbol invariant of rigid surface operators by a convenient trick. By consistency checks, we recover and extend the $S$-duality maps proposed by Wyllard. We find new subclasses of rigid surface operators related by $S$-duality. We try to explain the exceptions of $S$-duality maps. We also discuss the extension of the techniques used in the $B_n/C_n$ theories to the $D_n$ theories.
Distress and Satisfaction in Women Who Perceive that Their Male Partners Use Pornography: The Roles of Attitude, Religious Commitment and Conservative Religiosity

ABSTRACT Qualitative studies suggest that women’s attitudes and religiosity have an important role in their experience of their male partners’ pornography use, but these factors have not been adequately studied. The present study examined the contributions of perceived frequency of male partners’ solitary pornography use (PFREQ), women’s attitudes toward their partners’ pornography use, conservative religiosity, and religious commitment to women’s pornography-related distress, relationship satisfaction, and sexual satisfaction in women who reported they were married to or cohabitating with men who had used pornography in the prior 3 months (median frequency = 1–2 times/week). Participants were online research panel participants (n = 625), age mean = 44[SD = 13], diverse SES, 86% White. Partial correlations and multiple regressions, controlling for demographic variables and COVID-19-related stress, indicated that higher PFREQ and negative attitudes toward pornography were significantly associated with women’s higher pornography-related distress, lower relationship satisfaction, and lower sexual satisfaction. Moderation analyses found that negative attitude amplified the negative association between PFREQ and relationship satisfaction, and conservative religiosity amplified the positive association between PFREQ and pornography-related distress. Neither attitude nor religious factors moderated the negative association between PFREQ and sexual satisfaction. Findings suggest that attitude, religious factors, and PFREQ are each important to consider in research and clinical contexts.
Detection of a new methylamine (CH3NH2) source: Candidate for future glycine surveys

Interstellar glycine (NH2CH2COOH), the simplest amino acid, has long been sought in studying a possible relation between the Universe and origin of life. In the last 40 or so years all surveys of glycine have failed; an alternative strategy would be to search for precursor(s) to glycine. Such studies of precursors would be crucial prior to conducting sensitive surveys with ALMA. Laboratory studies have suggested that CH3NH2 is a possible precursor to glycine. Further theoretical study also suggests that the CH2NH2 radical that can be formed from CH3NH2 through photodissociation can be a good precursor to glycine. Thus, we have looked for CH3NH2 towards several hot core sources using the Nobeyama 45 m radio telescope, and succeeded in finding a new CH3NH2 source, G10.47+0.03, with a fractional abundance of 1.5 ± 1.1 × 10−8; at the time of writing, this source is the most abundant source of CH3NH2 ever known. We found that the observed abundance of CH3NH2 agrees fairly well with the theoretical value predicted by R. T. Garrod (2013, ApJ, 765, 60). The detectability of interstellar glycine is discussed.
Antifungal Compounds from the Leaves of Rhynchosia minima

Rhynchosia minima, commonly known as jumby bean, is used as a remedy for respiratory ailments in various parts of the world. It is also used by South African traditional healers to treat heart or chest pain. This study aimed to investigate the bioactive constituents of the leaf extracts of R. minima against selected fungal isolates that have been identified as risk factors in respiratory illness. Rhynchosia minima leaves were extracted sequentially using hexane, dichloromethane, ethyl acetate and methanol in increasing order of polarity. The extracts were subjected to repeated chromatographic techniques, for phytochemical isolation. The extracts and isolated compounds were screened against Candida albicans and Cryptococcus neoformans by determining the minimum concentration that inhibited fungal growth. Six flavonoids, one norisoprenoid and one cyclitol were isolated and characterized by 1D and 2D NMR and HR‐ESI‐MS. The extracts obtained in the study had moderate to weak antifungal activities, with MICs ranging from 312.5 to 1250.0 μg/mL against both fungi. Four isolated compounds were also screened, with two of them exhibiting activity against C. albicans (MIC=6.25 μg/mL) that was comparable to amphotericin B, the positive control. These two compounds also had better antifungal potential against C. neoformans with an MIC=6.25 μg/mL, compared to the MIC of 12.5 μg/mL of amphotericin B. Seven of the eight isolated compounds were obtained from the extracts of Rhynchosia minima for the first time. Two of the isolated compounds demonstrated activity comparable or superior to amphotericin B activity. The notable potency displayed by these compounds warrants further investigation on their development as antifungal agents.
O GPS e a velocidade constante da luz

The Lorentz transformations and special relativity are unable to provide a realistic physical explanation of the behavior of matter and light. We will show that all these phenomena can be explained using Newton's physics and mass-energy conservation, without space contraction or time dilation. We have seen previously that the principle of mass-energy conservation requires that clocks run at a slower rate in a moving frame, and physical bodies become longer because of the increase of the Bohr radius. These results allow us to answer the question: With respect to what does light travel? For example, when we move away at velocity v from a source emitting light at velocity c, the relative motion of the radiation is observed from the Doppler shift. How can we explain logically that these photons appear to reach us at velocity c and not (c-v)? The conventional explanation relies on special relativity, but it implies an esoteric space-time distortion, which is not compatible with logic. This paper gives a physical explanation how the velocity of light is really (c-v) with respect to the observer, even if the observer's tools always measure a velocity represented by the number c. We explain how this problem is crucial in the Global Positioning System (GPS) and in clock synchronization. The Lorentz' transformations become quite useless. This apparent constant velocity of light with respect to a moving frame is the most fascinating illusion in science.
Crossover Patient Outcomes for Targeted Lung Denervation in Moderate to Severe Chronic Obstructive Pulmonary Disease: AIRFLOW-2

Background: Targeted Lung Denervation (TLD) is a potential new therapy for COPD. Radiofrequency energy is bronchoscopically delivered to the airways to disrupt pulmonary parasympathetic nerves, to reduce bronchoconstriction, mucus hypersecretion, and bronchial hyperreactivity. Objectives: This work assesses the effect of TLD on COPD exacerbations (AECOPD) in crossover subjects in the AIRFLOW-2 trial. Method: The AIRFLOW-2 trial is a multicentre, randomized, double-blind, sham-controlled crossover trial of TLD in COPD. Patients with symptomatic COPD on optimal medical therapy with an FEV1 of 30–60% predicted received either TLD or sham bronchoscopy in a 1:1 randomization. Those in the sham arm had the opportunity to cross into the treatment arm after 12 months. The primary end point was rate of respiratory adverse events. Secondary end points included adverse events, changes in lung function and health-related quality of life and symptom scores. Results: Twenty patients were treated with TLD in the crossover phase and were subsequently followed up for 12 months (50% female, mean age 64.1 ± 6.9 years). After TLD, there was a trend towards a reduction in time to first AECOPD (hazard ratio 0.65, p = 0.28, not statistically significant) in comparison to sham follow-up period. There was also a reduction in time to first severe AECOPD in the crossover period (hazard ratio 0.38, p = 0.227, not statistically significant). Symptom scores and lung function showed stability. Conclusions: AIRFLOW-2 crossover data support that of the randomization phase, showing trends towards reduction in COPD exacerbations with TLD.