Miracle-dz/UniFAR-FTUs huggingface dataset:
Modification of pfap2μ and pfubp1 Markedly Reduces Ring-Stage Susceptibility of Plasmodium falciparum to Artemisinin In Vitro

Management of uncomplicated malaria worldwide is threatened by the emergence in Asia of Plasmodium falciparum carrying variants of the pfk13 locus and exhibiting reduced susceptibility to artemisinin. Mutations in two other genes, ubp1 and ap2μ, are associated with artemisinin resistance in rodent malaria and with clinical failure of combination therapy in African malaria patients. ABSTRACT Management of uncomplicated malaria worldwide is threatened by the emergence in Asia of Plasmodium falciparum carrying variants of the pfk13 locus and exhibiting reduced susceptibility to artemisinin. Mutations in two other genes, ubp1 and ap2μ, are associated with artemisinin resistance in rodent malaria and with clinical failure of combination therapy in African malaria patients. Transgenic P. falciparum clones, each carrying orthologues of mutations in pfap2μ and pfubp1 associated with artemisinin resistance in Plasmodium chabaudi, were derived by Cas9 gene editing. Susceptibility to artemisinin and other antimalarial drugs was determined. Following exposure to 700 nM dihydroartemisinin in the ring-stage survival assay, we found strong evidence that transgenic parasites expressing the I592T variant (11% survival), but not the S160N variant (1% survival), of the AP2μ adaptin subunit were significantly less susceptible than the parental wild-type parasite population. The V3275F variant of UBP1, but not the V3306F variant, also displayed reduced susceptibility to dihydroartemisinin (8.5% survival versus 0.5% survival). AP2μ and UBP1 variants did not elicit reduced susceptibility to 48 h of exposure to artemisinin or to other antimalarial drugs. Therefore, variants of the AP2 adaptor complex μ-subunit and of the ubiquitin hydrolase UBP1 reduce in vitro artemisinin susceptibility at the early ring stage in P. falciparum. These findings confirm the existence of multiple pathways to perturbation of either the mode of action of artemisinin, the parasite’s adaptive mechanisms of resistance, or both. The cellular role of UBP1 and AP2μ in Plasmodium parasites should now be elucidated.
An Updated Nomogram for Predicting Invasiveness in Preoperative Ductal Carcinoma In Situ of the Breast

Purpose To validate and update a nomogram for predicting ductal carcinoma in situ (DCIS) upstaging in preoperative biopsy. Materials and Methods Medical records of 444 preoperative DCIS patients were evaluated and used to validate a previous version of the Severance nomogram for predicting DCIS upstaging in preoperative biopsy. Patients were divided into two groups according to the final postoperative pathology. Univariate and multivariate analyses with the chi-square test, Student's t-test, and binary logistic regression method identified new significant variables. The updated nomogram was evaluated with the C-index and Hosmer—Lemeshow goodness of fit test. Results The area under a receiver operating characteristic curve for comparison with the previous nomogram was 0.48. In postoperative pathology, the pure DCIS and invasive cancer groups comprised 345 and 99 cases, respectively. Approximately 22.3% of patients preoperatively diagnosed with DCIS were upstaged to invasive cancer. Significant variables in the univariate analysis were operation type, human epidermal growth factor receptor 2 overexpression, comedo necrosis, sonographic mass, mammographic mass, preoperative biopsy method, and suspicious microinvasion in preoperative biopsy. In multivariate analysis, operation type, sonographic mass, mammographic mass, and suspicious microinvasion were risk factors for upstaging. The updated model with these variables showed moderate discrimination and was appropriate in the calibration test. Conclusion The previous nomogram did not effectively discriminate upstaging of preoperative DCIS in an independent cohort. An updated version of the nomogram appears to provide more accurate information for predicting preoperative DCIS upstaging.
Prevalence and adverse obstetric outcomes of female genital mutilation among women in rural Northern Ghana.

BACKGROUND Female genital mutilation (FGM) is commonly practiced in sub-Saharan Africa and results in adverse pregnancy outcomes among affected women. This paper assessed the prevalence and effects of FGM on pregnancy outcomes in a rural Ghanaian setting. METHODS We analyzed 9306 delivery records between 2003 and 2013 from the Navrongo War Memorial Hospital. Multivariable logistic regression analyses were used to determine the effects of FGM on pregnancy outcomes such as stillbirth, birth weight, postpartum haemorrhage, caesarean and instrumental delivery. We also assessed differences in the duration of stay in the hospital by FGM status. RESULTS A greater proportion of mothers with FGM (24.7%) were older than 35 years compared with those without FGM (7.6%). FGM declined progressively from 28.4% in 2003 to 0.6% in 2013. Mothers with FGM were nearly twice as likely to have caesarean delivery (adjusted odds ratios = 1.85 with 95%CI [1.72, 1.99]) and stillbirths (1.60 [1.21, 2.11]) compared with those without. Similarly, they had a 4-fold increased risk of post-partum haemorrhage (4.69 [3.74, 5.88]) and more than 2-fold risk lacerations/episiotomy (2.57 [1.86, 3.21]) during delivery. Average duration of stay in the hospital was higher for mothers with FGM from 2003 to 2007. CONCLUSIONS Despite significant decline in prevalence of FGM, adverse obstetric outcomes are still high among affected women. Increased public health education of circumcised women on these outcomes would help improve institutional deliveries and heighten awareness and prompt clinical decisions among healthcare workers. Further scale-up of community level interventions are required to completely eliminate FGM.
Key characteristics of 86 agents known to cause cancer in humans

ABSTRACT Since the inception of the International Agency for Research on Cancer (IARC) in the early 1970s, the IARC Monographs Programme has evaluated more than 1000 agents with respect to carcinogenic hazard; of these, up to and including Volume 119 of the IARC Monographs, 120 agents met the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs provided a review and update of Group 1 carcinogens. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers, and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. Data on biological mechanisms of action (MOA) were extracted from the Monographs to assemble a database on the basis of ten key characteristics attributed to human carcinogens. After some grouping of similar agents, the characteristic profiles were examined for 86 Group 1 agents for which mechanistic information was available in the IARC Monographs up to and including Volume 106, based upon data derived from human in vivo, human in vitro, animal in vivo, and animal in vitro studies. The most prevalent key characteristic was “is genotoxic”, followed by “alters cell proliferation, cell death, or nutrient supply” and “induces oxidative stress”. Most agents exhibited several of the ten key characteristics, with an average of four characteristics per agent, a finding consistent with the notion that cancer development in humans involves multiple pathways. Information on the key characteristics was often available from multiple sources, with many agents demonstrating concordance between human and animal sources, particularly with respect to genotoxicity. Although a detailed comparison of the characteristics of different types of agents was not attempted here, the overall characteristic profiles for pharmaceutical agents and for chemical agents and related occupations appeared similar. Further in-depth analyses of this rich database of characteristics of human carcinogens are expected to provide additional insights into the MOA of human cancer development.
MKL1 mediates TGF‐β‐induced CTGF transcription to promote renal fibrosis

Aberrant fibrogenesis impairs the architectural and functional homeostasis of the kidneys. It also predicts poor diagnosis in patients with end‐stage renal disease (ESRD). Renal tubular epithelial cells (RTEC) can trans‐differentiate into myofibroblasts to produce extracellular matrix proteins and contribute to renal fibrosis. Connective tissue growth factor (CTGF) is a cytokine upregulated in RTECs during renal fibrosis. In the present study, we investigated the regulation of CTGF transcription by megakaryocytic leukemia 1 (MKL1). Genetic deletion or pharmaceutical inhibition of MKL1 in mice mitigated renal fibrosis following the unilateral ureteral obstruction procedure. Notably, MKL1 deficiency in mice downregulated CTGF expression in the kidneys. Likewise, MKL1 knockdown or inhibition in RTEs blunted TGF‐β induced CTGF expression. Further, it was discovered that MKL1 bound directly to the CTGF promoter by interacting with SMAD3 to activate CTGF transcription. In addition, MKL1 mediated the interplay between p300 and WDR5 to regulate CTGF transcription. CTGF knockdown dampened TGF‐β induced pro‐fibrogenic response in RTEs. MKL1 activity was reciprocally regulated by CTGF. In conclusion, we propose that targeting the MKL1–CTGF axis may generate novel therapeutic solutions against aberrant renal fibrogenesis.
Cytomegalovirus (CMV)-Vectored vaccines for HIV and other pathogens.

: The use of cytomegalovirus (CMV) as a vaccine vector to express antigens against multiple infectious diseases, including simian immunodeficiency virus, Ebola virus, plasmodium, and mycobacterium tuberculosis, in rhesus macaques has generated extraordinary levels of protective immunity against subsequent pathogenic challenge. Moreover, the mechanisms of immune protection have altered paradigms about viral vector-mediated immunity against ectopically expressed vaccine antigens. Further optimization of CMV-vectored vaccines, particularly as this approach moves to human clinical trials will be augmented by a more complete understanding of how CMV engenders mechanisms of immune protection. This review summarizes the particulars of the specific CMV vaccine vector that has been used to date (rhesus CMV strain 68-1) in relation to CMV natural history.
Radiotherapy for the Palliation of Advanced Sarcomas—The Effectiveness of Radiotherapy in Providing Symptomatic Improvement for Advanced Sarcomas in a Single Centre Cohort

Background: Sarcomas are rare and heterogeneous tumours with a large proportion of patients requiring palliative intervention. They are regarded as relatively radioresistant and therefore achieving good palliation with radiation may require larger doses than for more common solid tumour types. Limited data is available regarding appropriate palliative radiotherapy dose fractionation. This case series aims to assess the effectiveness of radiotherapy in providing symptomatic improvement for advanced sarcomas. Method: Data was retrospectively collected for patients treated with palliative radiotherapy between July 2010 and April 2019 at one institution. The primary outcome was documented symptomatic improvement following radiotherapy. Secondary outcome was overall survival. Results: One hundred and five patients had a total of 137 sites treated using 25 different dose fractionation schedules. The median patient age was 54 (range 8–90) years. Treated sites included 114 soft tissue and 23 bone sarcomas. Data on symptomatic improvement was available in 56% and 67% of cases respectively. A total of 70% of soft tissue and 55% of bone sarcoma patients reported symptomatic improvement. Symptomatic response rates appeared to increase to a biological effective dose (BED) of 50Grey4 (Gy4) (alpha beta ratio (α/β) = 4 for tumour) but did not continue to improve with further rises in dose beyond this. Conclusion: Palliative radiotherapy offers symptomatic improvement for sarcoma patients with two-thirds of patients reporting reduction in symptoms. These results are limited by the heterogeneous study population including different sarcoma subtypes each with a probable different radio-sensitivity, treated with different radiotherapy schedules. Further prospective data collection is needed considering sarcoma subtype radio-sensitivity, to determine appropriate palliative dose fractionation schedules.
Sexual Harassment of College and University Students: A Systematic Review

Increased attention to Title IX and the #MeToo movement has led to more interest in developing strategies to prevent forms of gender-based violence beyond acquaintance rape, including sexual harassment (SH). This study reviewed the extant literature published since 2000 on SH of college/university students (n = 24) to determine (a) study methods, (b) sample sociodemographic characteristics, (c) prevalence, (d) risk and protective factors, and (e) consequences of campus SH. These studies shared the view that overall SH rates are high, but their findings were difficult to cross-evaluate due to variations in their study designs. Generally, unwanted sexual attention and gender harassment were more commonly experienced in campus SH occurrences than sexual coercion. Findings indicated that being White, a woman, or a sexual minority increased a student’s likelihood of experiencing SH while at a college/university. Student SH survivors rarely filed official reports but often faced a variety of mental and physical health consequences. Women of color experienced lower rates of SH but more severe consequences in the aftermath. This review concludes by detailing several implications for future research, as well as possible campus SH prevention, intervention, and policy protocols.
The benefits differential equations bring to limb development

Systems biology is a large field, offering a number of advantages to a variety of biological disciplines. In limb development, differential‐equation based models can provide insightful hypotheses about the gene/protein interactions and tissue differentiation events that form the core of limb development research. Differential equations are like any other communicative tool, with misuse and limitations that can come along with their advantages. Every theory should be critically analyzed to best ascertain whether they reflect the reality in biology as well they claim. Differential equation‐based models have consistent features which researchers have drawn upon to aid in more realistic descriptions and hypotheses. Nine features are described that highlight these trade‐offs. The advantages range from more detailed descriptions of gene interactions and their consequence and the capacity to model robustness to the incorporation of tissue size and shape. The drawbacks come with the added complication that additional genes and signaling pathways that require additional terms within the mathematical model. They also come in the translation between the mathematical terms of the model, values and matrices, to the real world of genes, proteins, and tissues that constitute limb development. A critical analysis is necessary to ensure that these models effectively expand the understanding of the origins of a diversity of limb anatomy, from evolution to teratology.
Exuberant Ductolobular Hyperplasia as the Primary Histological Finding in a Patient with Idiopathic Gigantomasita

Gigantomastia is a rare, debilitating condition defined as an excess of greater than 1500 g of breast tissue per breast.1, 2 Although the majority of cases are attributed to hormonal changes that occur in juvenile and pregnant populations, only 10 cases of idiopathic gigantomastia unrelated to hormonal changes or autoimmune disease have been reported in the literature.1, 3 Treatment of gigantomastia is variable as no definitive guidelines are available because of its rarity, and no suggestions have been made considering histologically guided therapies of the disease. We present a case of a 36-year-old female with a 16 months history of bilateral breast enlargement. Per patient history, her breasts enlarged at a rate of four cup sizes over approximately one year, then began to enlarge more rapidly at a rate of three cup sizes over six months (Fig. 1A). Thyroid function studies revealed findings consistent with the patient’s history of Hashimoto’s thyroiditis, well controlled with Levothyrox 25 mg for many years. Prolactin studies revealed no ab-
Figures of the dead: A decade of tuberculosis mortality registrations in South Africa.

South Africa (SA) is committed to reducing tuberculosis (TB) mortality rates in line with the World Health Organization's End TB Strategy and the Sustainable Development Goal (SDG) targets. From mortality reports released by Statistics South Africa, this study analysed reported TB mortality in SA from 2006 to 2016 to inform our understanding of TB mortality and the development of strategies needed to attain the SDG targets. TB mortality includes all deaths reported to the Department of Home Affairs with TB reported as the underlying cause of death based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) definition. Although TB remains the leading cause of death, TB mortality rates in SA have fallen substantially in the past decade. From 2006 to 2016, the number of deaths due to TB plummeted from 76 881 to 29 399 and the proportion of all-cause mortality due to TB more than halved from 13% to <6%. Furthermore, the profile of people dying from TB has changed, with a decrease in the proportion of children aged <15 years, adults of reproductive age (15 - 49) and women, and an increase in the proportion aged ≥50. This change has largely mirrored the overall pattern of deaths in SA, with large decreases in deaths in adults aged 15 - 49, especially women, thought to be because of the scale-up of the antiretroviral treatment programme for HIV. The End TB Strategy target of a 95% reduction in TB mortality by 2035 is achievable in SA. However, sustained effort in high-risk groups together with improved vital registration data are needed to ensure attainment of the target.
miRNA-183-5p.1 promotes the migration and invasion of gastric cancer AGS cells by targeting TPM1

MicroRNA-183 (miR-183) is a small, non-coding RNA that is involved in post-transcriptional processes, is upregulated in gastric cancer and acts as an oncogene in cancer migration. Although fragmentary reports have demonstrated the importance of miR-183 in gastric cancer, its biofunctions and regulatory effects are still unknown. In the present study, the gene and protein expression levels were determined by reverse transcription-quantitative PCR and western blot analysis. The connection between miR-183-5p.1 and tropomyosin 1 (TPM1) was tested through luciferase reporter experiments. Cell viability, apoptosis and related proteins were detected by MTT assay, flow cytometry, immunofluorescence and western blotting, respectively. The migration and invasion of AGS cells modulated by miR-183-5p.1 were analyzed by Transwell assay. TPM1 expression was found to be decreased in gastric cancer tissues and cell lines when compared with normal and adjacent tissues and gastric epithelial cells, and was regulated by miR-183-5p.1 targeting TPM1. miR-183-5p.1 overexpression facilitated the growth and suppressed the death of AGS cells through Bcl-2 and P53 proteins. In addition, miR-183-5p.1 restricted TPM1, TPM2 and TPM3 protein expression in AGS cells. The excessive levels of miR-183-5p.1 promoted the migration and invasion of AGS cells, and inhibited the apoptosis of AGS cells. However, the knockdown of miR-183-5p.1 induced the opposite in AGS cells. In conclusion, miR-183-5p.1 promotes cell proliferation, migration and invasion by downregulating TPM1 and deactivating the Bcl-2/P53 signaling pathways in gastric cancer, indicating that miR-183-5p.1 and TPM1 may be potential targets for the diagnosis or therapy of gastric cancer in the future.
Effect of the Combination of Creatine Monohydrate Plus HMB Supplementation on Sports Performance, Body Composition, Markers of Muscle Damage and Hormone Status: A Systematic Review

Although there are many studies showing the isolated effect of creatine monohydrate (CrM) and β-hydroxy β-methylbutyrate (HMB), it is not clear what effect they have when they are combined. The main purpose of this systematic review was to determine the efficacy of mixing CrM plus HMB in comparison with their isolated effects on sports performance, body composition, exercise induced markers of muscle damage, and anabolic-catabolic hormones. This systematic review was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement guidelines and the PICOS model, for the definition of the inclusion criteria. Studies were found by searching PubMed/MEDLINE, Web of Science (WOS), and Scopus electronic databases from inception to July 3rd 2019. Methodological quality and risk of bias were assessed by two authors independently, and disagreements were resolved by third-party evaluation, in accordance with the Cochrane Collaboration Guidelines samples. The literature was examined regarding the effects of the combination of CrM plus HMB on sport performance using several outcome variables (athletic performance, body composition, markers of muscle damage, and hormone status). This systematic review included six articles that investigated the effects of CrM plus HMB on sport performance (two on strength performance, showing improvements in one of them; three on anaerobic performance, presenting enhancements in two of them; and one on aerobic performance, not presenting improvements), body composition (three on body mass, showing improvements in one of them; two on fat free mass, presenting increases in one of them; and two on fat mass, showing decreases in one of them) and markers of muscle damage and hormone status (four on markers of muscle damage and one on anabolic-catabolic hormones, not showing benefits in any of them). In summary, the combination of 3–10 g/day of CrM plus 3 g/day of HMB for 1–6 weeks could produce potential positive effects on sport performance (strength and anaerobic performance) and for 4 weeks on body composition (increasing fat free mass and decreasing fat mass). However, this combination seems to not show positive effects relating to markers of exercise-induced muscle damage and anabolic-catabolic hormones.