bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective double-blind study on the value of musculoskeletal ultrasound by dermatologists as a screening instrument for psoriatic arthritis
Authors: Grobelski Jakub , Wilsmann-Theis Dagmar , Karakostas Pantelis , Behning Charlotte , Brossart Peter , Schäfer Valentin S
Published: December 2022

Objectives

This study evaluated musculoskeletal ultrasound (MSUS) use by dermatologists previously trained on a novel handheld, chip-based ultrasound device (HHUD) to screen for early PsA.

Methods

Twelve dermatologists were recruited to screen psoriasis patients for PsA using the novel HHUD in one major hospital in Bonn (Germany) and six private practices in surrounding regions. Patient screening was based on medical history, clinical examination, and the GEPARD questionnaire paired with an MSUS examination of up to three painful joints. All screened patients were then referred to rheumatologists, who determined the final diagnosis. The screening effect of MSUS was assessed according to its sensitivity and specificity before and after its application.

Results

Between 1 October 2020 and 26 May 2021, a total of 140 psoriasis patients with arthralgia participated in this study. PsA was diagnosed in 19 (13.6%) cases. Before applying MSUS, dermatologists’ screening sensitivity and specificity were recorded as 88.2% and 54.4%, respectively, while after applying MSUS the sensitivity and specificity changed to 70.6% and 90.4%, respectively. MSUS led to a change of PsA suspicion in 46 cases, with PsA no longer being suspected in 45 of them.

Conclusion

This study was able to demonstrate that PsA screening using MSUS by previously trained dermatologists can lead to more precise PsA detection and potentially decreased rheumatologist referral rates.
Survey of Late-Season Soilborne Pathogens Infecting Strawberry in Watsonville-Salinas, California
Authors: Steele Mary E. , Hewavitharana Shashika S. , Henry Peter , Goldman Polly , Holmes Gerald J.
Published: December 2022

There are four major soilborne pathogens of strawberries in California, but their distribution and prevalence in the Watsonville-Salinas production district are unknown. To fill this knowledge gap, 74 symptomatic strawberry plant samples were collected from 69 fields in the Watsonville-Salinas growing district between 11 August and 15 October 2021. Each sample consisted of eight plants exhibiting moderate to severe plant collapse. Crown tissue from each plant was excised and pooled for recombinase polymerase amplification (RPA) to detect Macrophomina phaseolina, Fusarium oxysporum f. sp. fragariae, Verticillium dahliae, and Phytophthora spp. Root, petiole, and crown tissue from plant samples in which no pathogens were detected by RPA was plated on semiselective media to verify the absence of the four pathogens and screen for other pathogenic fungi. At least one of the four pathogens was detected in 55 of the 74 samples (74.3%). All four of the major soilborne pathogens are prevalent in this growing district, as F. oxysporum f. sp. fragariae, M. phaseolina, Phytophthora spp., and V. dahliae were detected in 23 samples (31.1%), 22 samples (29.7%), 18 samples (24.3%), and 16 samples (22.0%), respectively. No strong associations were found between the pathogens and growing practices.
MiR-302c-5p affects the stemness and cisplatin resistance of nasopharyngeal carcinoma cells by regulating HSP90AA1
Authors: Zhou Xiangqi , Zheng Le , Zeng Chunya , Wu Yangjie , Tang Xiyang , Zhu Yuan , Tang Sanyuan
Published: December 2022

Nasopharyngeal carcinoma (NPC) is one of the most frequent malignant tumors diagnosed in China. Cisplatin is one of the most commonly used anticancer drugs containing platinum in combined chemotherapy. The molecular mechanism of NPC is still largely unknown, and we aim to spare no effort to elucidate it. Normal human nasopharyngeal epithelial cells and NPC cell lines were cultured. The expression levels of miR-302c-5p and HSP90AA1 were detected with quantitative real-time PCR. Western blotting was used to analyze levels of the HSP90AA1, protein kinase B (AKT), p-AKT, CD44 and SOX2 proteins. The interaction between miR-302c-5p and HSP90AA1 was detected using a luciferase reporter assay. The bicinchoninic acid assay was used to observe cisplatin resistance in NPC cells. Our records confirmed that the expression of miR-302c-5p was substantially reduced and HSP90AA1 was increased in NPC cells. Additionally, miR-302c-5p inhibited cisplatin resistance and the traits of stem cells in NPC. A luciferase assay confirmed that miR-302c-5p is bound to HSP90AA1. Overexpression of HSP90AA1 may reverse the effects of overexpressed miR-302c-5p and inhibit cisplatin resistance and stem cell traits of NPC. This study investigated whether miR-302c-5p inhibited the AKT pathway by regulating HSP90AA1 expression and altered the resistance of NPC cells to cisplatin and the traits of tumor stem cells, which has not yet been reported.
FEATURES OF VASCULATURE IN PATIENTS WITH RETINA ARTERIAL MACROANEURYSM USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Hu Liying , Zhang Luyuan , Li Zhiqing , Liu Juping , Yu Rongguo , Wang Linni , Xing Dongjun , Li Chang , Yang Yang , Li Xiaorong
Published: December 2022

Purpose:

To assess morphologic characteristics of retinal arterial macroaneurysm (RAM) and their vascular changes using optical coherence tomography angiography (OCTA).

Methods:

This observational study included 31 eyes of 29 participants diagnosed with RAM based on fundus fluorescein angiography in Tianjin Medical University Eye Hospital. Multimodal imaging modalities, including fundus photography, fluorescein angiography, and OCTA, were used to examine RAMs. The demographic and clinical characteristics of the RAMs were recorded.

Results:

Depending on the fundus fluorescein angiography examination, 40 cases of RAM were confirmed in 29 patients. Twenty-three patients were female (79%), and six patients were male (21%). Two patients had binocular RAM, and four eyes had more than one RAMs. Relying on the OCTA technology, RAMs have four different vascular morphology types (i.e., distended, meshed, malformed, and occult types). In the distended type, round or encircled thrombi caused asymmetrical or symmetrical distention of retinal arteriolar, leading to separate true lumen and false thrombus lumen in RAM. In the meshed type, the meshed or dendritic vascular network around the RAM was likely to be the neovascularization due to the ischemia and hypoxia of the arteriolar wall. Finally, in the malformed and occult type, the RAM usually regressed, and the retinal arterioles were remodeled to distorted or normal arterioles accompanied by capillary degradation.

Conclusion:

Relying on the OCTA technology, we found that the RAMs have four different types of vascular morphology. Each group of RAM has different vascular features. The application of OCTA in patients with RAM furthers our understanding of the vasculature of RAMs.
OUTER FOVEAL DEFECTS IN TYPE-2 MACULAR TELANGIECTASIA
Authors: Chandran Kiran , Giridhar Anantharaman , Gayathri M.S. , Antison Meghana , Gopalakrishnan Mahesh , Sivaprasad Sobha
Published: December 2022

Purpose:

To report characteristics of outer foveal defects (OFDs) in type-2 macular telangiectasia (MacTel) on spectral domain optical coherence tomography.

Methods:

This was a single-center observational study. From a registry of 745 patients with MacTel, patients with OFDs were characterized. All patients underwent multimodal imaging including color fundus photography, confocal blue reflectance, fundus autofluorescence, and spectral domain optical coherence tomography. Staging of eyes was done using the Gass and Blodi classification. Spectral domain optical coherence tomography characteristics in the central 1 mm of the macula in eyes with OFD are reported.

Results:

Outer foveal defect was observed in 21 eyes of 15/745 (2%) patients with MacTel. These defects were bilateral in 6/15 (40%) patients and seen in stage 2 MacTel eyes. In order of prevalence, foveal parameters seen in OFD included hyper-reflective dots in outer retina in 19/21 (90%), ellipsoid zone loss in 18/21 (86%) eyes, interdigitation zone loss in 17/21 (81%) eyes, outer retinal hyporeflective cavitation in 14 (67%) eyes, hyporeflective cavitation at foveal pit in 8 (38%) eyes, and loss of external limiting membrane in 1 (5%) eye. The mean baseline length of the foveal ellipsoid zone loss was 240.17 ± 117.249 µm. The mean baseline central subfield thickness was 155.43 ± 17.215 µm. A total of 8/11 eyes (73%) showed an increase in size of OFD on follow-up.

Conclusion:

Outer foveal defect in MacTel eyes is characterized predominantly by foveal loss of ellipsoid zone and interdigitation zone with relative preservation of external limiting membrane.
Descemet Membrane Endothelial Keratoplasty and Triple Descemet Membrane Endothelial Keratoplasty in Eyes With Macular Comorbidity
Authors: Steindor Friedrich A. , Büchau Till M. , Borgardts Klara Charlotte , Borrelli Maria , Guthoff Rainer , Geerling Gerd , Spaniol Kristina
Published: December 2022

Purpose:

The aim of this study was to evaluate results after Descemet membrane endothelial keratoplasty (DMEK) and DMEK with cataract surgery (triple DMEK) in eyes with endothelial dysfunction and concomitant macular pathology.

Methods:

A monocentric, prospective clinical observational study of patients who underwent DMEK or triple DMEK surgery at the Department of Ophthalmology, University Hospital Düsseldorf, Germany, from June 2013 to February 2016 was conducted. Sex, age, best-corrected visual acuity (BCVA), central corneal thickness, endothelial cell density, and central retinal thickness in the 1 millimeter zone were analyzed.

Results:

A total of 209 eyes were included in the study. Forty-two eyes (20.1%) had vision-limiting concomitant maculopathies. These were age-related macular degeneration (n = 17, 8.1%), epiretinal gliosis (n = 13, 6.2%), chronic macular edema (n = 7, 3.3%), macular holes (n = 3, 1.4%), and macular scarring (n = 2, 1.0%). BCVA significantly increased in patients without maculopathy from 0.6 ± 0.33 logMAR to 0.1 ± 0.15 logMAR (P < 0.001) and also in patients with maculopathy from 0.9 ± 0.38 logMAR to 0.27 ± 0.23 logMAR 12 months postoperatively (P < 0.001). There was a significant central retinal thickness increase of 34.1 μm 6 weeks after triple DMEK in the central 1-mm zone (P = 0.011). This increase was insignificant after DMEK. Postoperative macular edema occurred in 5.9% of cases after DMEK and 8.1% after triple DMEK, which was not significantly different.

Conclusions:

DMEK and triple DMEK significantly increase BCVA in eyes with concomitant maculopathy. Postoperative macular edema is a common disorder after lamellar keratoplasty; therefore, prophylactic treatment with nonsteroidal antiinflammatory drugs should be considered. Maculopathies did not predispose the development of postoperative macular edema.
Patient-Reported Quality of Vision in a Prospective Randomized Contralateral-Eye Trial Comparing LASIK and SMILE
Authors: Ma Kevin K. , Manche Edward E.
Published: December 2022

Purpose:

To compare patient-reported quality of vision and visual symptoms in participants undergoing laser in situ keratomileusis (LASIK) and small incision lenticule extraction (SMILE).

Setting:

Byers Eye Institute at Stanford University

Design:

Prospective randomized contralateral-eye clinical trial

Methods:

Subjects with myopia were randomized to receive wavefront-guided femtosecond LASIK in one eye and SMILE in the fellow eye. Participants reported the presence and severity of adverse visual symptoms via the Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) questionnaire and reported which eye had better vision at the preoperative and the postoperative 1-, 3-, 6-, and 12-month visits.

Results:

80 eyes of 40 participants were treated. There was no difference in the presence or severity of double vision, glare, halo, or starbursts between eyes that underwent LASIK or SMILE at each visit (P ≥ 0.85 for each comparison). Scaled scores for the presence of visual symptoms improved from the preoperative visit to the postoperative month 12 visit for double vision (88 vs 97, P=0.03), glare (77 vs 92, P=0.02), halos (68 vs 87, P<0.01), and starbursts (60 vs 86, P<0.01). At the postoperative month 12 visit, 17/37 (46%) of participants preferred the vision from the eye that underwent LASIK compared to 7/37 (19%) that underwent SMILE. The preferred eye was correlated with uncorrected visual acuity (r=0.52, P<0.01).

Conclusions:

Rates of visual symptoms were similar for LASIK and SMILE, and visual symptoms improved with time. More patients preferred vision from the eye that underwent LASIK compared to SMILE.
New features of parenteral nutrition in home care and acute care setting for the older population
Authors: Salonen Bradley , Martindale Robert G.
Published: December 2022

Purpose of review

The intent of this review is to highlight any recent changes in the delivery of parenteral nutrition to the geriatric population. The percentage of patients in the geriatric age group increases clinical awareness of the potential risks and benefits of appropriate parenteral nutrition delivery, which is crucial to well tolerated and optimum outcomes.

Recent findings

The major recent finding is the increased awareness of risk of parenteral nutrition in the elderly population.

The implications of this very brief review expose the need for further focused studies to better clarify the specifics of parenteral nutrition in this vulnerable ageing population. The importance of nutritional risk assessment cannot be overstated. With the rapidly expanding volume of geriatric population, the need for more data to better understand the delicate balance in parenteral nutrition therapy for both the acute care setting and home parenteral population is needed.
Utilizing type 2 diabetes medications outside glycemic parameters – where are we headed?
Authors: Malkani Natasha Prakash , Aroda Vanita R.
Published: December 2022

Purpose of review

Glucose-lowering medications have become strong choices for purposes beyond glucose control in both patients with and without type 2 diabetes. Recent studies have explored the use of specific glucose-lowering therapies in areas such as cardiovascular disease, renal disease, obesity, nonalcoholic fatty liver disease (NAFLD), and Alzheimer's disease, among others. This begs the question if glycemic parameters should be the sole criteria utilized for initiation of diabetes therapeutic agents.

Recent findings

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in particular have demonstrated significant benefits beyond glucose control, with each demonstrating improvement, to various extent, on cardiovascular and renal outcomes, disease-modifying weight loss, progression from prediabetes, and treatment of NAFLD by ameliorating inflammation.

Clinical practice guidelines have been updated to reflect the use of these medications to achieve cardiometabolic, renal, and weight goals in addition to glycemic control. The success of glucose-lowering medications in the aforementioned areas have informed the research pursuits in investigating these agents for their anti-inflammatory, neuroprotective, and lipotoxic reduction effects in other diseases entirely.
Prediction of significant coronary artery disease in acute chest pain without infarction in emergency department: MAPAC Cardio-PreTest model
Authors: Fernandez-Felix Borja M. , Corres Jesús , Estelles Lerga Pilar , Arana-Arri Eunate , Arenaza Choperena Gorka , Castillo Miguel , Pecharromán Inés , San José-Saras Diego , Piqueras Olmeda Rosa , García de Vicuña Aitor , Gómez Usabiaga Virginia , Vicente Agustina , Zamora Javier
Published: December 2022

Acute nontraumatic chest pain is a frequent reaso n for consultation in emergency departments and represents a diagnostic challenge. The objective is to estimate the risk of significant coronary artery disease (CAD) in patients with cardiogenic acute chest pain for whom the diagnosis of infarction was ruled out in the emergency department with a nondiagnostic ECG and negative high-sensitivity troponins. We prospectively recruited 1625 patients from emergency departments of seven Spanish hospitals. The outcome was presence of significant CAD determined by presence of ischaemia in functional tests or more than 70% stenosis in imaging tests. In this study, we developed a predictive model and evaluated its performance and clinical utility. The prevalence of significant CAD was 14% [227/1625; 95% confidence interval (CI), 12–16]. MAPAC Cardio-PreTest model included seven predictors: age, sex, smoking, history of hypertension, family history of CAD, history of hyperuricaemia, and type of chest pain. The optimism-adjusted model discrimination was C-statistic 0.654 (95% CI, 0.618–0.693). Calibration plot showed good agreement between the predicted and observed risks, and calibration slope was 0.880 (95% CI, 0.731–1.108) and calibration-in-the-large −0.001 (95% CI, −0.141 to 0.132). The model increased net benefit and improved risk classification over the recommended approach by the European Society of Cardiology [Net Reclassification Index (NRI) of events = 5.3%, NRI of nonevents = 7.0%]. MAPAC Cardio-PreTest model is an online prediction tool to estimate the individualised probability of significant CAD in patients with acute chest pain without a diagnosis of infarction in emergency department. The model was more useful than the current alternatives in helping patients and clinicians make individually tailored choices about the intensity of monitoring or additional coronary tests.
Academy of Clinical Essentials
Authors: Rowen Lisa , Howett Maeve , Embert Casey , Beeson Nicole , Bosah Barbara , Chen Lynn , Day Jennifer , Nichols DoRhonja , O'Malley Cassie
Published: December 2022

A revolutionary academic-practice partnership model was implemented at the University of Maryland Medical System (UMMS) with the University of Maryland School of Nursing, through which the preparation and transition to practice of new graduate nurses were reimagined, resulting in intentional support for staffing the nursing workforce. Groups of nursing students were paired with a UMMS-funded clinical instructor to take a full patient assignment for one 12-hour shift in a UMMS hospital each week. This instructor-led cohort is equivalent to one UMMS nurse and was included in the staffing numbers of participating units.
Successful treatment of switching from benzodiazepine to orexin receptor antagonists improves cognitive function in psychiatric disorders: four case reports
Authors: Hori Hikaru
Published: December 2022

Objective

Benzodiazepines are used in the treatmentof anxiety and insomnia. On the other hand, they not only have side effects such as drowsiness, poor concentration, and muscle relaxation but also persistent cognitive decline. Even if we try to reduce the dose of these drugs to improve drug-induced cognitive function, it is difficult to do so due to dependence and worsening insomnia.

Methods

I report four cases in which cognitive dysfunction was improved by switching from benzodiazepines to orexin receptor antagonists (suvorexant and lemborexant ).

Results

Orexin receptor antagonists were effective to improve cognitive impairment.

Conclusion

In cognitive dysfunction caused by benzodiazepines, switching to orexin receptor antagonists may be effective.
Naomi Datta. 17 September 1922—30 November 2008
Authors: Barth Peter Thomas
Published: December 2022

Naomi Datta was distinguished for her discovery of bacterial plasmids carrying genes giving resistance to antibiotics. She studied medicine and successfully combined a career with bringing up her family. Appointed to the Royal Postgraduate Medical School, she studied an outbreak of
Salmonella
at Hammersmith Hospital in 1959. She discovered genetic factors responsible for transfer of resistance between strains. Her publication on this was the first in Europe. Collaboration with Bill Hayes (FRS 1964) and others at the adjacent Medical Research Council Unit revealed that transfer was due to small replicating loops of DNA, later called plasmids. With Bob Hedges, Naomi classified plasmids into families; their work was recognized worldwide. Molecular analysis of plasmids revealed that drug resistance genes were carried on small vectors called transposons, which could transfer themselves between plasmids and bacterial chromosomes. This facilitated gene mapping and later gene cloning and genetic engineering, which became highly controversial.
SpyDisplay: A Versatile Phage Display Selection System using SpyTag/SpyCatcher Technology
Authors: Kellmann Sarah-Jane , Hentrich Christian , Putyrski Mateusz , Hanuschka Hanh , Cavada Manuel , Knappik Achim , Ylera Francisco
Published: December 2022

Phage display is an established method for thein vitroselection of recombinant antibodies and other proteins or peptides from gene libraries. Here we describe SpyDisplay, a phage display method in which the display is achieved via SpyTag/SpyCatcher protein ligation instead of genetically fusing the displayed protein to a phage coat protein. In our implementation, SpyTagged Fab antibody fragments are displayed via protein ligation on filamentous phages carrying SpyCatcher fused to the pIII coat protein. A library of genes encoding Fab antibodies was cloned in an expression vector containing f1 replication origin, and SpyCatcher-pIII was separately expressed from a genomic locus in engineeredE. coli. We demonstrate the functional, covalent display of Fab on phage, and rapidly isolate specific high-affinity clones via phage panning, confirming the robustness of this selection system. SpyTagged Fabs – the direct outcome of the panning campaign - are compatible with modular antibody assembly using prefabricated SpyCatcher modules and can be directly tested in diverse assays. Furthermore, SpyDisplay streamlines additional applications that have traditionally been challenging for phage display: we show that it can be applied to N-terminal display of the protein of interest and it also enables display of cytoplasmically folding proteins exported to periplasm via the TAT pathway.
Transcriptomic reprogramming in a susceptiblePhaseolus vulgarisL. variety duringPseudomonas syringaeattack: The key role of homogalacturonan methylation
Authors: De la Rubia Alfonso G. , Largo-Gosens Asier , Yusta Ricardo , Sepúlveda Pablo , Riveros Aníbal , Centeno Mª Luz , Sanhueza Dayan , Meneses Claudio , Saez-Aguayo Susana , García-Angulo Penélope
Published: December 2022

The susceptibility of common bean varieties toPseudomonas syringaepv.phaseolicola(Pph) has been well-documented. However, the molecular mechanism that drives this susceptibility has not been clarified yet. In an attempt to understand this process, 15-day-old common bean plants, varietyriñón,were infected with Pph to analyze the transcriptomic changes during the first steps of the infection (at 2 and 9 h). RNA-seq analysis showed an upregulation of defense-and signaling-related genes at 2h, most of them being downregulated at 9h, suggesting that Pph would inhibit the transcriptomic reprogramming of the plant. This trend was also observed in the modulation of 101 cell wall (CW) related genes, suggesting that Pph could produce/induce changes in the CW. However, the changes in CW composition at early stages of Pph infection were related to homogalacturonan (HG) methylation and the formation of HG egg boxes. From all HG-related genes modulated by the infection, a common bean pectin methylesterase inhibitor 3 (PvPMEI3) gene – closely related toAtPMEI3— was detected. In addition, PMEI3 protein was located in the apoplast and its PME inhibitory activity was demonstrated. Therefore, PvPMEI3 seems to be a good candidate to play a key role in Pph infection. This premise was supported by the analysis of Arabidopsispmei3mutant, which showed susceptibility to Pph, in contrast to resistant Col-0 control plants. All these changes could be an attempt to reinforce the CW structure and thus, hinder the attack of the bacterium. However, these transcriptional and CW-remodeling processes are neither maintained during the necessary time, nor are deep enough to block the action of the pathogen, facilitating the well-known susceptibility ofriñónvariety to Pph.
Stratification of hypertensive COVID-19 patients by quantitative NMR spectroscopy of serum metabolites, lipoproteins and inflammation markers
Authors: Kazenwadel Jasmin , Berezhnoy Georgy , Cannet Claire , Schäfer Hartmut , Geisler Tobias , Rohlfing Anne-Katrin , Gawaz Meinrad , Merle Uta , Trautwein Christoph
Published: December 2022

Background

The exact pathophysiology of humans suffering from the multifaceted SARS-CoV-2 infection is not yet conclusively understood and risk stratification is needed. Novel diagnostic approaches like the nuclear magnetic resonance spectroscopy (NMR) based quantification of metabolites, lipoproteins, and inflammation markers has helped to identify typical alterations in the blood serum of COVID-19 patients. However, important confounders such as age, sex, and comorbidities, which strongly influence the metabolome, were often not considered. Therefore, the aim of this NMR study was to consider gender, as well as arterial hypertension (AHT) which affects more than 1.2 billion people worldwide, when investigating COVID-19-positive serum samples in a large age-matched cohort. As AHT is a risk factor for severe COVID-19 disease, this study focuses on comparing metabolomic characteristics of COVID-19 patients with and without AHT.

Methods and Findings

NMR serum data from 329 COVID-19 patients were compared with 305 individuals from a healthy age and sex-matched control cohort. 134 of the 329 COVID-19 patients were affected by AHT. These were analyzed together with NMR data from 58 hypertensives without COVID-19. In addition to metabolite, lipoprotein, and glycoprotein data from NMR, common laboratory parameters were considered. Statistical comparison of the COVID-19 cohort with the control cohort reproduced results of previous studies. However, several differences emerged when AHT was considered. Especially, the previously described triglyceride-rich lipoprotein profile was no longer observed in COVID-19 patients, nor was an increase in ketone bodies. Typical metabolic changes that were apparent in COVID-19 patients in both sexes and with AHT were an increase in C-reactive protein (CRP) and the ratio of total glycoprotein (Glyc) to supramolecular phospholipids composite (SPC) which is an inflammatory NMR parameter. Further alterations were a decrease in glutamine, leucine, isoleucine, and lysine, citric acid, HDL-4 particles, and total cholesterol. Typical metabolic cardiovascular risk markers could be detected in hypertensive COVID-19 patients, as well as higher inflammatory NMR parameters than in normotensive COVID-19 patients.

Conclusion

We could show that a more precise picture of COVID-19 blood serum parameters emerge when AHT is considered which accordingly should be included in future studies and would help for a refined patient stratification.
Causal Analysis for Multivariate Integrated Clinical and Environmental Exposures Data
Authors: Sinha Meghamala , Haaland Perry , Krishnamurthy Ashok , Lan Bo , Ramsey Stephen A. , Schmitt Patrick L. , Sharma Priya , Xu Hao , Fecho Karamarie
Published: December 2022

Electronic health records (EHRs) provide a rich source of observational patient data that can be explored to infer underlying causal relationships. These causal relationships can be applied to augment medical decision-making or suggest hypotheses for healthcare research. In this study, we explored a large-scale EHR dataset on patients with asthma or related conditions (N = 14,937). The dataset included integrated data on features representing demographic factors, clinical measures, and environmental exposures. The data were accessed via a service named the Integrated Clinical and Environmental Service (ICEES). We estimated underlying causal relationships from the data to identify significant predictors of asthma attacks. We also performed simulated interventions on the inferred causal network to detect the causal effects, in terms of shifts in probability distribution for asthma attacks.
Response of circulating miRNAs to acute exercise: A systematic Review and Meta-Analysis
Authors: MacGregor Kirstin , Moran Colin N , Broome Sophie , Owen Patrick J , Lamon Séverine , Hiam Danielle
Published: December 2022

Objective

Cell-free microRNAs (cf-miRNAs) are secreted from cells and transported via the blood to exert their effect on target tissues. Numerous pathophysiological adaptations, including exercise, alter cf-miRNA levels. The aim of the systematic review was to investigate the cf-miRNA response to an acute bout of exercise and to interpret it using a robust correlated and hierarchical effects (CHE) meta-analysis.

Design

The systematic review was registered in PROSPERO (CRD42021256303). A CHE meta-analysis was used to compare the changes in cf-miRNA levels and the influence of exercise modality. An exploratory machine-learning-based approach was used to capture influential moderators.

Data sources

Primary studies were retrieved from PubMed and SPORTDiscus (09.03.2022). Relative changes in cf-miRNA expression in response to exercise were computed for each study. The ROBINS-I, GRADE and AMSTAR2 tools were used to assess evidence certainty and risk of bias.

Eligibility criteria

Thirty-six studies including an acute exercise intervention in N=880 healthy males and females aged 18-45yrs met the eligibility criteria.

Results

Muscle enriched cf-miR-1 (N=320), cf-miR-133a (N=195) and cf-miR-133b (N=132) levels increased 1-2hr (cf-miR1: FC = 2.72, 95% CI= 1.5-4.0; cf-miR133a: FC = 2.10, 95% CI = 1.6-2.6; cf-miR-133b: FC = 2.39, 95% CI = 1.2-3.6) and 24 hr post-exercise (cf-miR1: FC = 2.25, 95% CI= 1.3-3.2; cf-miR133a: FC = 1.81, 95% CI = 1.4-2.2; cf-miR-133b: FC = 1.99, 95% CI = 1.2-2.8).

Conclusion

Acute exercise triggers temporal and modality specific responses in cf-miRNAs. levels. Influential moderators included sample size, collection time point, exercise modality, age and the use of various technical quality controls.

What is already known?

Exercise acutely alters cell-free miRNA (cf-miRNA) levels in human serum and plasma, but research is poorly reproducible

What are the new findings?

Muscle-enriched cf-miRNA levels robustly increase following an acute bout of exercise, with temporal and modality specific responses

The implementation of a CHE model, a novel statistical approach within the miRNA field, allowed to identify key methodological factors moderating cf-miRNA levels.

Strict implementation of these factors is warranted to improve rigour and reproducibility in this field.
A morphological basis for path dependent evolution of visual systems
Authors: Varney Rebecca M. , Speiser Daniel I. , Cannon Johanna , Aguilar Morris , Eernissee Douglas J. , Oakley Todd H.
Published: December 2022

Path dependence influences macroevolutionary predictability by constraining potential outcomes after stochastic evolutionary events. Although demonstrated in laboratory experiments, the basis of path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here we show two types of complex distributed visual systems each recently evolved twice within chiton mollusks, demonstrating rapid and path dependent evolution. The type of visual system a chiton lineage evolves is constrained by the number of openings for optic nerves in its shell plates: lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable.

One-Sentence Summary

Multiple convergent origins of visual systems show macroevolution of complex traits can be rapid and contingent upon pre-existing structures
FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) accumulates in homo- and heterodimeric complexes in dynamic and inducible nuclear condensates associated with speckle components
Authors: Trofimov Ksenia , Gratz Regina , Ivanov Rumen , Stahl Yvonne , Bauer Petra , Brumbarova Tzvetina
Published: December 2022

Some nuclear proteins undergo condensation, but the functional importance remains often unclear. The basic helix-loop-helix (bHLH) FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) integrates internal and external signals to control iron acquisition and growth. The previously described C-terminal residues Ser271/272 allow FIT to form active complexes with subgroup Ib bHLH factors such as bHLH039. FIT has lower nuclear mobility than mutant FITmSS271AA. Here, we show that FIT undergoes a light-inducible subnuclear partitioning into nuclear condensates that we termed FIT nuclear bodies (NBs). FIT NB characteristics were examined using a standardized FIT NB analysis procedure coupled with different types of quantitative and qualitative microscopy-based approaches. FIT condensates were reversible and likely formed by liquid-liquid phase separation. FIT accumulated preferentially in FIT NBs versus nucleoplasm when engaged in protein complexes with itself and with bHLH039. FITmSS271AA, instead, localized to NBs with different dynamics. FIT colocalized with splicing and light signaling NB markers. The NB-inducing light conditions were linked with active FIT and elevated FIT target gene expression in roots. Hence, we conclude that inducible, highly dynamic FIT condensates form preferentially when transcription factor complexes are active. Inducible FIT nuclear condensates may affect nuclear mobility and integrate environmental and Fe nutrition signals.

Highlights

FIT undergoes light-induced, reversible condensation and localizes to nuclear bodies (NBs), likely via liquid-liquid phase separation

Functionally relevant Ser271/272 defines an intrinsically disordered region and influences NB formation dynamics

NBs are preferential sites for FIT dimerization with FIT and bHLH039, dependent on Ser271/272

FIT NBs colocalize with NB markers related to splicing and light signaling

Light conditions inducing NBs are linked with active FIT, in agreement with elevated FIT target gene expression in roots
The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes
Authors: Barreiro Rodrigo A. S. , Guardia Gabriela D. A. , Meliso Fabiana M. , Lei Xiufen , Li Wei-Qing , Savio Andre , Fellermeyer Martin , Conceição Helena B. , Mercuri Rafael L. V. , Landry Tesha , Qiao Mei , Blazquez Lorea , Ule Jernej , Penalva Luiz O. F. , Galante Pedro A. F.
Published: December 2022

The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumor development. High MAGOH/MAGOHB expression was observed in 14 tumor types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.
Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity
Authors: Safra Modi , Tamari Zvi , Polak Pazit , Shiber Shachaf , Matan Moshe , Karameh Hani , Helviz Yigal , Levy-Barda Adva , Yahalom Vered , Peretz Avi , Ben-Chetrit Eli , Brenner Baruch , Tuller Tamir , Gal-Tanamy Meital , Yaari Gur
Published: December 2022

The success of the human body in fighting SARS-CoV-2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance. We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV-2 compared with uninfected controls. In contrast to previous studies, our approach successfully stratifies non-infected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients. These features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges.
Nature and biological irrelevance of mixed-type enzyme inhibition
Authors: Pesaresi Alessandro
Published: December 2022

Mixed-type enzyme inhibitors were originally envisaged to decrease the enzyme affinity for the substrates and the maximum turnover rate by simultaneously targeting two distinct protein sites, i.e., the active site and an allosteric site. After a century from the first formulation of this hypothesis, the consensus on its validity is still unanimous, although several of its implications are in open conflict with the current knowledge on molecular recognition mechanisms. In particular, there is no plausible explanation for the experimental evidence that mixed-type inhibitors bind the enzyme active sites always more effectively than the allotopic sites. In an attempt to solve this controversy, it was found that the preference of mixed inhibitors for active sites emerges as an inevitable numerical artifact that is implicit in the equations used to model the apparent mixed inhibition caused under certain circumstances by active site-bound competitive inhibitors. Hence, proving that the consolidated model of mixed inhibition is incorrect and, more generally, strongly pointing to the biological irrelevance of mixed-type inhibition.
CEP signaling coordinates plant immunity with nitrogen status
Authors: Rzemieniewski Jakub , Leicher Henriette , Lee Hyun Kyung , Broyart Caroline , Nayem Shahran , Wiese Christian , Maroschek Julian , Camgöz Zeynep , Lalun Vilde Olsson , Djordjevic Michael Anthony , Corina Vlot A. , Hückelhoven Ralph , Santiago Julia , Stegmann Martin
Published: December 2022

Plant endogenous signaling peptides shape growth, development and adaptations to biotic and abiotic stress. Here, we identified C-TERMINALLY ENCODED PEPTIDEs (CEPs) as novel immune-modulatory peptides (phytocytokines) inArabidopsis thaliana. Our data reveals that CEPs induce immune outputs and are required to mount resistance against the leaf-infecting bacterial pathogenPseudomonas syringaepv. tomato. We show that effective immunity requires CEP perception by tissue-specific CEP RECEPTOR 1 (CEPR1) and CEPR2. Moreover, we identified the related RECEPTOR-LIKE KINASE 7 (RLK7) as a novel CEP4-specific CEP receptor contributing to CEP-mediated immunity, suggesting a complex interplay of multiple CEP ligands and receptors in different tissues during biotic stress. CEPs have a known role in the regulation of root growth and systemic nitrogen (N)-demand signaling. We now provide evidence that CEPs and their receptors promote immunity in an N status-dependent manner, suggesting a previously unknown molecular crosstalk between plant nutrition and cell surface immunity. We propose that CEPs and their receptors are central regulators for the adaptation of biotic stress responses to plant-available resources.
Effect of flavonoids hydroxygenkwanin on vascular smooth muscle cell proliferation, migration, and neointimal formation
Authors: Chen Chin-Chuan , Lin Mao-Shin , Chen Pin-Yu , Leu Yann-Lii , Wang Shu-Huei
Published: December 2022

Background

Restenosis and atherosclerosis are chronic inflammatory disease. Abnormal vascular smooth muscle cell (VSMC) proliferation and migration play crucial roles in neointimal hyperplasia and restenosis progression in response to stimulation with various inflammatory cytokines, such as platelet-derived growth factor-BB (PDGF-BB) and tumour necrosis factor-α (TNF-α). Hydroxygenkwanin (HGK) exerts remarkable anti-inflammatory, antitumour, antiproliferative and antimigratory effects. The aim of the study was to evaluate and elucidate the therapeutic effect and regulatory mechanism of HGK on neointimal hyperplasia.

Methods

To determine the therapeutic effects of HGK in PDGF-BB- or TNF-α-treated VSMCs, MTT assays, Western blotting analysis, cell cycle analysis, BrdU incorporation assay, wound healing assay and adhesion assay were performed in vitro. A docking assay was also used to elucidate the mechanism underlying the regulatory effect of HGK. Histological and immunohistochemical staining of denuded femoral arteries was conducted to elucidate the therapeutic effect of HGK in an in vivo assay.

Results

HGK inhibited the abnormal proliferation, migration, and inflammation of PDGF-BB- or TNF-α-treated VSMCs through regulation of the PDK1/AKT/mTOR pathway. In addition, HGK promoted circulating endothelial progenitor cell (EPC) chemotaxis. In an in vivo assay, HGK dramatically enhanced re-endothelization and reduced neointimal hyperplasia after femoral artery denudation with a guide wire in mice.

Conclusions

In the present study, HGK decreased the PDGF-BB- or TNF-α-induced abnormal proliferation, migration and inflammation in VSMCs and improved re-endothelialization and neointimal hyperplasia in denuded femoral arteries. These results provide a novel potential treatment for restenosis in the future.

Graphic abstract

HGK decreases VSMC abnormal proliferation, migration and inflammation through PDK1/AKT/mTOR/S6K inhibition and promotes EPC chemotaxis and reendothelialization. HGK is a potential therapeutic candidate for intimal hyperplasia and restenosis.
Host reverse transcriptase is required to maintain persistent dengue virus infections in C6/36 insect cells
Authors: Gangnonngiw Warachin , Flegel Timothy W. , Kanthong Nipaporn
Published: December 2022

It has been long known that C6/36 cells challenged with Dengue virus serotype 2 (DENV-2) show initial cytopathic effects (CPE) but overcome these within 3 split passages to resume normal growth and morphology. It is also known that establishment of persistent infections requires combined action of host reverse-transcriptase (RT) activity and RNA-mediated interference (RNAi). We hypothesized that RT inhibition in C6/36 cells would also prevent persistent infections with DENV-2 and that treatment of stable, grossly normal C6/36 cells persistently infected with DENV-2, even after long passaging, would revert to CPE and die under continuous exposure to the RT inhibitor tenofovir disoproxil fumarate (TDF). Toxicity tests using TDF with naive C6/36 cells revealed limited effects at 0.1 mM but challenge with DENV-2 in its presence resulted in death, as expected based on previous reports. However, TDF treatment of stable, grossly normal C6/36 cell cultures persistently infected with DENV-2 for up to 30 split passages also induced severe CPE and death. The results indicate a key role of host RT not only in the establishment of persistent infections but also in their long-term maintenance. Persistent infections in shrimp and insects are sometimes characterized with low to very low levels of viral infection that are not detectable by routine histological analysis,in situhybridization, immunohistochemistry or even by very sensitive PCR. Our results suggest that treatment of grossly normal insects or crustaceans with TDF may be a simple approach to induce higher replication by accommodated viruses. This could improve detection by histological or molecular methods and provide a way to invoke a disease state. It could also be used to increase viral quantities for purification purposes.
Genome editing of thevermilionlocus generates a visible eye color marker forOncopeltus fasciatus
Authors: Reding Katie , Lê Minh , Pick Leslie
Published: December 2022

Insects display a vast array of eye and body colors. Genes encoding products involved in biosynthesis and deposition of pigments are ideal genetic markers, contributing, for example, to the power ofDrosophilagenetics.Oncopeltus fasciatusis an emerging model for hemimetabolous insects, a member of the piercing-sucking feeding order Hemiptera, that includes pests and disease vectors. To identify candidate visible markers forO. fasciatus, we used parental and nymphal RNAi to identify genes that altered eye or body color while having no deleterious effects on viability. We selectedOf-vermilionfor CRISPR/Cas9 genome editing, generating three independent loss-of-function mutant lines. These studies mappedOf-vermilionto the X-chromosome, the first assignment of a gene to a chromosome in this species.Of-vermilionhomozygotes have bright red, rather than black, eyes and are fully viable and fertile. We used these mutants to verify a role forOf-xdh1, ortholog ofDrosophila rosy, in contributing to red pigmentation after RNAi. Rather than wild-type-like red bodies, bugs lacking bothvermilionandxdh1have bright yellow bodies, suggesting that ommochromes and pteridines contribute toO. fasciatusbody color. Our studies generated the first gene-based visible marker forO. fasciatusand expanded the genetic toolkit for this model system.
Post-secretory synthesis of a natural analog of iron-gall ink in the black nectar ofMelianthusspp.
Authors: Magner Evin T. , Roy Rahul , Saxhaug Katrina Freund , Zambre Amod , Bruns Kaitlyn , Snell-Rood Emilie C. , Hampton Marshall , Hegeman Adrian D. , Carter Clay J.
Published: December 2022

The black nectar ofMelianthusflowers is thought to serve as a visual attractant to pollinators, but the chemical identity and synthesis of the black pigment are unknown. Here we report that the black nectar contains a natural analog of iron-gall ink, which humans have used since medieval times. Specifically, dark black nectar at anthesis contains high levels of ellagic acid and iron; synthetic solutions of ellagic acid and iron(III) recapitulate the black color of the nectar. Conversely, lightly colored nectars before and after anthesis contain significantly lower levels of ellagic acid and iron, but higher levels of gallic acid. We then explored the possibility of post-secretory synthesis of ellagic acid from gallic acid. Indeed,Melianthusnectar contains a peroxidase that oxidizes gallic acid to form ellagic acid. Reactions containing the nectar peroxidase, gallic acid, hydrogen peroxide, and iron can fully recreate the black color of the nectar. Visual modeling indicates that the black color is both visible and conspicuous to birds within the context of the flower. In summary, the black nectar ofMelianthusis derived from an ellagic acid-Fe complex analogous to iron-gall ink and is likely involved in the attraction of passerine bird pollinators.