Miracle-dz/UniFAR-FTUs huggingface dataset:
Producing Gram-Scale Unnatural Rosavin Analogues from Glucose by Engineered Escherichia Coli.

Cinnamyl alcohol glycosides (CAGs) are key active ingredients of the precious medicinal plant Rhodiola rosea L, which has diverse pharmacological activities. The quality of R. rosea extracts is standardized to the contents of rosavin, a cinnamyl alcohol disaccharide, along with salidroside. The supply of rosavin and analogues is limited by both the inefficiency of chemical synthesis methods and the shortage of natural resources. Herein, we achieved de novo synthesis of a series of rosavin analogues by engineered Escherichia coli strains. First, cinnamyl alcohol was synthesized by expression of phenylalanine ammonia-lyase (PAL), hydroxycinnamate:CoA ligase, and cinnamyl-CoA reductase in a phenylalanine high-producing strain. UGT73C5 from Arabidopsis thaliana and a sugar chain elongating glycosyltransferase from Catharanthus roseus, CaUGT3 sequentially catalyzed the formation of an unnatural cinnamyl alcohol diglucoside, named rosavin B. Then, these biosynthetic enzymes were transformed into a tyrosine high-producing strain, except that PAL was replaced by a tyrosine ammonia-lyase, and synthesis of mono- and di- glucosides of p-coumaryl alcohol with sugars attached to aliphatic or phenolic hydroxyl position was achieved. Finally, fed-batch fermentation was conducted for the strain producing rosavin B, and the titer reached 4.7 g/L. Tri- and tetra- glucosides of cinnamyl alcohol were also produced by fed-batch fermentation. In summary, seven rosavin analogues including six unnatural compounds were produced from glucose by microorganism. This work expanded the structural diversity of CAGs, which holds promise to discover new analogues with improved pharmaceutical properties. The study also paves the way for producing CAGs in a sustainable and cheap way.
Autonomic modulation of the electrical substrate in mice haploinsufficient for cardiac sodium channels: a model of the Brugada syndrome.

A murine line with a haploinsufficiency in SCN5A has been used to model human Brugada syndrome: a disease causing sudden cardiac death due to lethal ventricular arrhythmias. We explored the effects of cholinergic tone on electrophysiological parameters in wild type and genetically modified, heterozygous, Scn5a+/- knockout mice. Scn5a+/-, ventricular slices showed longer refractory periods than wild-type both at baseline (Scn5a+/- 79±4 vs WT 63±4 ms, p <0.001) and during isoprenaline challenge. Scn5a+/- hearts also showed lower conduction velocities than did WT at baseline (0.27±0.04 vs 0.47±0.11 m/s, p=0.01) and blunted responses to isoprenaline challenge. Carbachol exerted limited effects but reversed the effects of isoprenaline with co-application. Scn5a+/- mice showed a reduction in conduction reserve in that isoprenaline no longer increased conduction velocity and this was not antagonised by muscarinic agonists.
Equal tibial component fixation of a mobile-bearing and fixed-bearing medial unicompartmental knee arthroplasty: a randomized controlled RSA study with 2-year follow-up

Background and purpose — Differences in stress distribution in a mobile-bearing and fixed-bearing unicompartmental knee arthroplasty (UKA) design might lead to a difference in fixation of the tibial component. We compared tibial component migration of a mobile-bearing (MB) UKA and a fixed-bearing (FB) UKA using radiostereometric analysis. Patients and methods — In a randomized, patient-blinded clinical trial 62 patients received either the MB Oxford UKA or the FB Sigma UKA. The patients were followed for 24 months with radiostereometric analysis. Clinical outcome was assessed with Oxford Knee Score (OKS), RAND-36 and leg extension power. Results — Migration of the tibial components was similar between groups throughout follow-up. At 12 months, MTPM of the tibial component was 0.44 mm (95% CI 0.34–0.55) for the MB group and 0.40 mm (CI 0.31–0.50) for the FB group. Between 12 and 24 months, the tibial components migrated with a median MTPM increase of 0.03 mm (CI –0.02 to 0.08) in the MB group and 0.03 mm (CI –0.02 to 0.07) in the FB group. Continuous migration of the tibial component was found for 1 MB UKA and 2 FB UKAs. Both groups showed similar and clinically relevant improvement in clinical outcome. Interpretation — MB and FB tibial components had similar good fixation and clinical improvement until 2 years. Based on this study, a low 5- to 10-year revision rate can be expected for both implants. Trial registration: ClinicalTrials.gov identifier: NCT03434600.
Survivors’ Social Construction of Intimate Partner Violence in Cebu City, Philippines

Intimate partner violence (IPV) is a worldwide social issue perpetrated by intimate male partners against their wives. Studies on IPV have generated accurate comparative information since the 1993 World Conference on Human Rights and the Declaration on the Elimination of Violence Against Women to guide strategy and track progress in attempts to comprehend the IPV issues. In many attempts to understand violence against women, the social construction of IPV was not well documented in the literature. This article aims to explore IPV survivors’ social construction of IPV by analyzing the experiential narratives of IPV survivors. To address the objective, this article used the phenomenological approach by examining the lived experiences of 15 IPV survivors. Our study finds that IPV made IPV survivors empowered, and with this social construction, survivors were able to overcome violence perpetrated by their intimate partners. The findings further proved that giving preferential attention to the needs of IPV victims could lead to victim empowerment, a factor needed in the elimination of violence against women and children in all forms. It is suggested for any intervention activities to (a) ultimately address the empowerment of individuals and (b) respond to the needs of individuals because what may work for one victim may not work for another.
Perceptions of barriers to effective obesity management in Canada: Results from the ACTION study

Obesity is a chronic disease with a significant and growing impact on Canadians. The “Awareness, Care and Treatment In Obesity MaNagement” (ACTION) Study investigated perceptions, attitudes and perceived barriers to obesity management among Canadian people with obesity (PwO), healthcare providers (HCPs) and employers. In this study adult PwO (body mass index ≥30 kg/m2, based on self‐reported height/weight), HCPs (physicians and allied HCPs managing PwO) and employers (≥20 employees; offering health insurance), completed online surveys between 3 August and 11 October 2017 in a cross‐sectional design. Survey respondents (N = 2545) included 2000 PwO, 395 HCPs and 150 employers. Obesity was viewed as a “chronic medical condition” by most PwO (60%), HCPs (94%) and employers (71%) and deemed to have a large impact on overall health (74%, 78%, 81%, respectively). Many PwO (74%) believed weight management was their own responsibility. While PwO (55%) reportedly knew how to manage their weight, only 10% reported maintaining ≥10% weight reduction for >1 year. Despite low success rates, the most commonly reported effective long‐term weight loss methods tried and/or recommended were “improvements in eating habits” (PwO 38%; HCP 63%) and “being more active” (PwO 39%; HCP 54%). PwO and HCPs reported very different perceptions of the quality and content of their interaction during obesity management discussions. These findings highlight the communication gaps and misunderstanding between PwO, HCPs and employers. This underscores the importance of, and need for, evidence‐based management of obesity and a collaborative approach and understanding of the complex nature of this chronic disease.
Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis

Significance Craniosynostosis (CS) is a frequent congenital malformation featuring premature fusion of cranial sutures; 15% of these children have syndromic disease, often due to rare mutations with large effect. While many genes causing Mendelian forms of syndromic CS have been identified, clinical sequencing often fails to identify a likely causative mutation. We performed whole-exome sequencing of 12 case-parent trios with previously negative genetic evaluations. The results identified likely pathogenic mutations in TFAP2B, KAT6A, GLI2, SOX11, CTNNA1, and GPC4 in these families, adding several loci to those known to cause syndromic CS. The findings have implications for determining risk of disease in subsequent offspring and demonstrate that unexplained syndromic CS cases are a particularly rich vein for discovery of CS loci. Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10−8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10−12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.
Does student orientation improve nursing image and positively influence the enrolment of nursing students in the University? An observational study

Background and aim of the study: Nursing has not yet received full social recognition and in general the public opinion does not have a completely positive perception of it, which regards it as an auxiliary profession to the medical profession. This study aims to investigate the image of the nurse among year 4 and 5 high school students. Methods: Two groups of students were interviewed, one at their institution without any previous orientation (n = 102) and one at the University of Bologna during orientation day (n = 388). A validated questionnaire (Nursing Attitude Questionnaire) of 30 items was delivered. Two additional questions were added to explore the possibility of advising relatives and acquaintances to become a nurse and therefore to choose the nursing degree course. Results: All areas of the NAQ scored significantly higher in the group where students attended the orientation day, especially the ones related to the professional role, stereotypes and professional value items. Female students ≥ 21 had a more positive image of the nurse. Both groups recognized that nurses are important figures for patients and that they are intelligent people, who must have a degree in order to carry out their work duties. Differences between the groups were recorded. Students in group 1 did not accept nursing autonomy while students in group 2 understood differences between nursing and medical careers, attributing to them the same value. A positive correlation between the positive image of the nursing profession and the interest in becoming nurses or advising others to undertake the nursing course was found. In conclusion, orientation is effective in helping high school students in the choice of their university courses. Regarding nursing, strategies to improve the image of the nurse and enrollment should be combined during orientation day with current up to date communication and learning tools, such as social media and simulation laboratories. Furthermore, it appears increasingly important to extend orientation and tutoring activities to junior high school students, families and teachers. (www.actabiomedica.it)
High Prevalence of Autoimmune Gastritis in Patients with Nonalcoholic Steatohepatitis

Objective To evaluate the prevalence of autoimmune gastritis in patients with histologically proven nonalcoholic steatohepatitis (NASH). Methods A total of 33 patients with NASH and 143 patients with chronic liver disease (66, 24, 22, 10, 1, and 21 patients with hepatitis C, hepatitis B, autoimmune hepatitis/primary biliary cholangitis, non-B/non-C hepatitis, fatty liver, and alcoholic disease, respectively) who underwent upper gastrointestinal endoscopy between January 2013 and August 2016 were retrospectively assessed to determine the prevalence of autoimmune gastritis. The clinical characteristics of these patients with NASH and autoimmune gastritis were examined, and the clinical characteristic and biomarkers were compared between patients with NASH with and without autoimmune gastritis. Results Six of the 33 patients with NASH (19.4%) were diagnosed with autoimmune gastritis. The prevalence of autoimmune gastritis was higher in patients with NASH than in those with other chronic liver diseases [4/143 (2.8%), p=0.002]. All six patients with NASH and autoimmune gastritis exhibited high serum gastrin levels; five of the patients were positive for anti-parietal cell antibodies, and one was negative for anti-parietal cell antibodies but positive for intrinsic factor antibody. Furthermore, 1 patient presented with iron-deficiency anemia (hemoglobin <11 g/dL), but none developed pernicious anemia. Endocrine cell micronests were found in four patients. Patients with NASH and autoimmune gastritis tended to be older with lower ferritin levels than the other patients. Conclusion The prevalence of NASH with concomitant autoimmune gastritis was high, highlighting the need for upper endoscopy for the diagnosis of autoimmune gastritis and gastric malignancies.
Pattern and scale: evaluating generalities in crab distributions and marsh dynamics from small plots to a national scale.

The generality of ecological patterns depends inextricably on the scale at which they are examined. We investigated patterns of crab distribution and the relationship between crabs and vegetation in salt marshes at multiple scales. By using consistent monitoring protocols across 15 US National Estuarine Research Reserves, we were able to synthesize patterns from the scale of quadrats to the entire marsh landscape to regional and national scales. Some generalities emerged across marshes from our overall models, and these are useful for informing broad coastal management policy. We found that crab burrow distribution within a marsh could be predicted by marsh elevation, distance to creek and soil compressibility. While these physical factors also affected marsh vegetation cover, we did not find a strong or consistent overall effect of crabs at a broad scale in our multivariate model, though regressions conducted separately for each site revealed that crab burrows were negatively correlated with vegetation cover at 4/15 sites. This contrasts with recent smaller-scale studies and meta-analyses synthesizing such studies that detected strong negative effects of crabs on marshes, likely because we sampled across the entire marsh landscape, while targeted studies are typically limited to low-lying areas near creeks, where crab burrow densities are highest. Our results suggest that sea-level rise generally poses a bigger threat to marshes than crabs, but there will likely be interactions between these physical and biological factors. Beyond these generalities across marshes, we detected some regional differences in crab community composition, richness and abundance. However, we found striking differences among sites within regions, and within sites, in terms of crab abundance and relationships to marsh integrity. Although generalities are broadly useful, our findings indicate that local managers cannot rely on data from other nearby systems, but rather need local information for developing salt marsh management strategies. This article is protected by copyright. All rights reserved.
Pan-Cancer Analysis of CDK12 Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype.

BACKGROUND CDK12 loss-of-function (LOF) genomic alterations are associated with focal tandem duplications (FTDs) in ovarian and prostate cancers. Because these FTDs may produce fusion-induced neoantigens (FINAs), CDK12 alteration is a candidate biomarker for immune checkpoint inhibitor sensitivity. Here we determine the prevalence of CDK12-LOF alterations and their association with FTDs across diverse tumor types. MATERIALS AND METHODS A total of 142,133 tumor samples comprising 379 cancer types were sequenced (August 2014 to April 2018) by hybrid capture-based comprehensive genomic profiling (Foundation Medicine, Cambridge, MA) as part of routine clinical care. Results were analyzed for base substitutions, short insertions/deletions, rearrangements, and copy number alterations. CDK12-LOF genomic alterations were assessed for zygosity status and association with FTDs/focal copy number gain. RESULTS CDK12 genomic alterations were detected in 1.1% of all cases, most frequently in prostate cancer (5.6%), but were also observed at >1% frequency in 11 cancer types. Across multiple cancer types, including prostate, gastric/esophageal, ovarian, breast, and endometrial cancer, the number of FTDs was significantly increased in CDK12-LOF versus CDK12 wild-type cases. Notably, CDK12-LOF was not consistently associated with a homologous recombination deficiency genomic signature. Quantitative assessment of CDK12-associated FTDs by measurement of single copy number gains identified novel likely deleterious CDK12 kinase-domain mutations in prostate and ovarian cancers. CONCLUSION Detection of CDK12-LOF genomic alterations and their association with FTDs in a diverse spectrum of malignancies suggests that immunotherapy approaches targeting FINAs derived from CDK12-associated FTDs may be a broadly applicable strategy that could be explored across cancer types in a tumor-agnostic manner. IMPLICATIONS FOR PRACTICE CDK12 inactivation in ovarian and prostate cancer results in the generation of focal tandem duplications, which can cause fusion-induced neoantigens. In prostate cancer, CDK12 alterations have demonstrated promise as a potential predictive biomarker for response to immune checkpoint blockade. This study evaluated genomic profiling data from >142,000 tumors to determine the prevalence of CDK12 loss-of-function genomic alterations across tumor types and demonstrated that CDK12 alterations are associated with the tandem-duplicator phenotype in cancer types other than ovarian and prostate cancer. The association of CDK12 alterations with focal tandem duplications across broad cancer types suggests that CDK12 inactivation warrants further investigation as a pan-cancer biomarker for immunotherapy benefit.
Genetic diversity of Hepatozoon (Apicomplexa) from domestic cats in South Africa, with a global reassessment of Hepatozoon felis diversity

Genetic diversity within partial 18S rRNA sequences from Hepatozoon protozoan parasites from domestic cats in South Africa was assessed and compared against published data to assess global biogeographic patterns. Multiple distinct haplotypes of Hepatozoon felis were identified, as well as an unrelated Hepatozoon lineage. Hepatozoon felis genetic diversity globally is very high, indicating a likely complex of species. The recently described Hepatozoon apri from wild boars is closely related to some lineages of H. felis. Sarcocystis and Babesia parasites were also detected. Since Hepatozoon felis is apparently a species complex, potential differences between genetically distinct forms need to be assessed. The finding of an unrelated Hepatozoon indicates that felids can be infected by more species of Hepatozoon than currently known, and that trophic interactions may increase the number of Hepatozoon species found in carnivores. Genetic screening again is demonstrated to identify previously unrecognised parasites from vertebrate hosts.
MOMSonLINE: Lessons Learned From a Feasibility RCT of Online Support for Mothers Bereaved by Perinatal Loss

Online support groups are popular for peer support, particularly for uncommon or stigmatized topics including pregnancy and infant loss. We conducted a randomized, controlled, 6-week feasibility study of three groups: an anonymous BabyCenter.com loss support group, a closed Facebook loss group, or a control group. Intervention arm mothers were asked to sign on to their support sites for 6 weeks. Participants completed regular surveys, text message surveys after each log-in, and a final semistructured phone interview. Thirty women were randomized to each arm of the study. Women reported preference for anonymous groups and found it empowering to support others, although many noted an emotional cost to reading postings. Tracking usage online was a major issue despite multiple strategies to collect these data. This pilot demonstrated feasibility of a randomized trial for online perinatal support but noted a critical need for more reliable methods to track usage.
Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy

Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox‐treated H9c2 cardiac myoblast cells expressing either the mitochondria‐targeted fluorescent protein MitoDsRed or the novel dual‐fluorescent mitophagy reporter mt‐Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA–mediated knockdown of dynamin‐related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide‐positive cells and the cleavage of caspase‐3 and poly (ADP‐ribose) polymerase. Moreover, DRP1‐deficient mice were protected from Dox‐induced cardiac damage, strongly supporting a role for DRP1‐dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt‐Rosella, suggesting the necessity of mitochondrial fragmentation in Dox‐induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox‐induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity. —Catanzaro, M. P., Weiner, A. , Kaminaris, A. , Li, C. , Cai, F. , Zhao, F. , Kobayashi, S. , Kobayashi, T. , Huang, Y. , Sesaki, H. , Liang, Q. Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy. FASEB J. 33, 11096–11108 (2019). www.fasebj. org