bluuebunny/crossref_metadata_2025 huggingface dataset:
Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide
Authors: Maione Angela S. , Faris Pawan , Iengo Lara , Catto Valentina , Bisonni Luca , Lodola Francesco , Negri Sharon , Casella Michela , Guarino Anna , Polvani Gianluca , Cerrone Marina , Tondo Claudio , Pompilio Giulio , Sommariva Elena , Moccia Francesco
Published: November 2022

Background

Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca2+) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown.

Thus, we aim to ascertain whether intracellular Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes.

Methods and results

ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE.

Conclusions

Altogether, our results extend the knowledge of Ca2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.
MICAL1 facilitates pancreatic cancer proliferation, migration, and invasion by activating WNT/β-catenin pathway
Authors: Cai Kun , Deng Lu , Zheng Dijie , Li Lin , He Zhiwei , Yu Chao
Published: November 2022

Background

MICAL1 is involved in the malignant processes of several types of cancer; however, the role of MICAL1 in pancreatic cancer (PC) has not been well-characterized. This study aimed to investigate the expression and function of MICAL1 in PC.

Methods

RT-qPCR and immunohistochemistry were used to detect MICAL1 expression in PC and adjacent nontumor tissues. Cell Counting Kit-8, EdU, clone formation, wound healing, and Transwell assays as well as animal models were used to investigate the effects of overexpression or inhibition of MICAL1 expression on the proliferation, invasion, and metastasis of PC cells. RNA-seq was used to explore the main pathway underlying the functions of MICAL1. Proteomics, mass spectrometry, and co-immunoprecipitation assays were used to investigate the interaction of proteins with MICAL1. Rescue experiments were conducted to validate these findings.

Results

Both MICAL1 mRNA and protein levels were upregulated in PC tissues compared with matched adjacent nontumor tissues. The expression level of MICAL1 was associated with the proliferative and metastatic status of PC. Repression of MICAL1 significantly inhibited PC cell growth, migration, and invasion in vitro and in vivo. RNA sequencing analysis indicated that MICAL1 was closely correlated with the WNT pathway. Overexpression of MICAL1 (1) promoted the phosphorylation of TBC1D1 at the Ser660 site, (2) facilitated the distribution of FZD7 on the cytomembrane, (3) inhibited the degradation of FZD7 in the lysosome, and (4) activated the WNT pathway.

Conclusions

MICAL1 was upregulated in PC and involved in stimulating the progression of PC cells by activating the WNT/β-catenin signaling pathway. Therefore, MICAL1 is a potential therapeutic target for PC.
Systemic lupus of pediatric onset in Afro-Caribbean children: a cohort study in the French West Indies and French Guiana
Authors: Felix Arthur , Delion Frederique , Suzon Benoit , Martin Elise , Ogrizek Anais , Mohamed Sahnoun M’hamed , Hospice Claudia , Armougon Aurelie , Cuadro Emma , Elenga Narcisse , Dramé Moustapha , Bader-Meunier Brigitte , Deligny Christophe , Hatchuel Yves
Published: November 2022

Background

Systemic diseases of pediatric onset are more frequent in the Afro-Caribbean population. We performed a study of patients followed in the French overseas departments of America (FOAD) for pediatric systemic lupus erythematosus (pSLE). The aims were to describe the clinical and biological specificities during childhood in this population.

Methods

A retrospective study was conducted between January 2000 and September 2021. Patients with pSLE were identified from multiple sources: computerized hospital archives, registry of referring pediatricians, adult specialists in internal medicine and the French National Registry for rare diseases. We studied SLE with pediatric onset defined by international criteria.

Results

Overall, 2148 patients were identified, of whom 54 were included. The average follow-up was 8.3 years (range: 0.3—25 years). We observed an increase in new diagnoses over time. At onset, pSLE patients had a median of 10 SLICC criteria (range: 4–12), and the median EULAR/ACR 2019 score was 38 (12—54). At onset, one third of patients had renal involvement, 15% had neurolupus and 41% cardiac involvement. During childhood, 54% had renal involvement, and 26% suffered from neurolupus. Patients suffered a median of 3 flares during childhood, and 26% had more than 5 flares. Patients with younger age at onset had worse outcomes than those who were older at diagnosis, i.e., more flares (median 5, p = 0.02) and requiring an average of 4 background therapies (p = 0.04).

Conclusion

The outcomes of Afro-Caribbean patients were similar to those in Western population, but with worse disease activity at onset. Further studies should be performed to identify the genetic and environmental factors in this population.
Patenting and patent challenges in South Korea after introducing a patent linkage system
Authors: Son Kyung-Bok
Published: November 2022

Background

South Korea introduced the patent linkage system in 2015 as part of the implementation of free trade agreements with the United States. This study assessed trends in brand-name drug patenting and generic patent challenges in South Korea after the introduction of the system.

Methods

From 2012–19, we constructed a novel dataset that combines information about listed patents with their corresponding brand-name drugs and patent challenges against these brand-name drugs. We analyzed brand-name drug patenting and generic patent challenges and elucidated factors in timely patent challenges using event history analysis.

Results

During the study period, 659 brand-name drugs listed their patents in the K-Orange Book and patent challenges against 95 brand-name drugs were initiated. The number of listed patents and their nominal patent term varied by the characteristics of the brand-name drugs. Patent challenges of generic drugs were marginal in South Korea even though the surge of patent challenges of generics were noticed right after the introduction of the patent linkage system.

Conclusions

Patenting and patent challenges are critical factors when introducing generic drugs into the market under the patent linkage system. However, the impact of the patent linkage system on patenting and patent challenges could be varied by the specific form of the patent linkage system and the contexts of pharmaceutical markets.
Growth pattern in children with X-linked hypophosphatemia treated with burosumab and growth hormone
Authors: Ertl Diana-Alexandra , Le Lorier Justin , Gleiss Andreas , Trabado Séverine , Bensignor Candace , Audrain Christelle , Zhukouskaya Volha , Coutant Régis , Berkenou Jugurtha , Rothenbuhler Anya , Haeusler Gabriele , Linglart Agnès
Published: November 2022

Background

X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.

Results

Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy.

Conclusion

To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.
Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial
Authors: van Schaik Mieke , Arends Eline J. , Soonawala Darius , van Ommen Ellen , de Leeuw Karina , Limper Maarten , van Paassen Pieter , Huizinga Tom W. J. , Toes René E. M. , van Kooten Cees , Rotmans Joris I. , Rabelink Ton J. , Teng Y. K. Onno
Published: November 2022

Background

Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.

Methods

Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.

Discussion

The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.

Trial registration

ClinicalTrials.govNCT03747159. Registered on 20 November 2018.
Kinetics study of anodic electrophoretic deposition for polytetrafluoroethylene (PTFE) coatings on AZ31 magnesium alloy
Authors: Xiang Qing , Qin Jiyao , Qin Taihong , Chen Lu , Zhang Daixiong
Published: November 2022

Electrophoretic deposition (EPD) coating has become a hot topic due to its simple experiment, wide application, and wide material range. In this study, the PTFE coating was successfully prepared by electrophoretic deposition through the systematic study of electrophoretic deposition kinetics. In particular, in the dispersion system with ethanol as solvent, Nafion and NaOH were simultaneously added as additives to obtain a beneficial synergistic effect on PTFE electrophoretic deposition. And the best additive scheme is: when the concentration of PTFE was 6 g·L− 1 and the deposition time was increased to 20 min, adding 0.10 g·L− 1 Nafion and 0.10 mM NaOH simultaneously. Compared with the scheme with Nafion being only additive, the addition of NaOH can improve the deposition rate from 0.16 mg·cm− 2 to 0.98 mg·cm− 2, and the deposition rate increases by about 6 times. According to electrophoretic deposition kinetics, there is an obvious critical transition time between linear and parabolic regions in the preparation of the coating. Prolonging the arrival of critical transition time is beneficial to effectively achieve stable growth of the coating in a longer time. It is found that a more ideal additive can not only increase the deposition rate of coating, but also significantly accelerate the arrival of critical transition time. Meanwhile, the deposition voltage also has an important influence on the critical transition time. Increasing the voltage can improve the deposition speed but shorten the critical transition time. Therefore, the application of deposition voltage needs to strike a balance between deposition rate and critical time point. The optimal deposition conditions proposed in this work are: deposition voltage 60 V, deposition time 20 min, additive 0.10 g·L− 1 Nafion and 0.10 mM NaOH.
The oviposition cue indole inhibits animal host attraction in Aedes aegypti (Diptera: Culicidae) mosquitoes
Authors: Dekel Amir , Sar-Shalom Evyatar , Vainer Yuri , Yakir Esther , Bohbot Jonathan D.
Published: November 2022

Background

Mosquitoes are responsible for disease transmission worldwide. They possess the ability to discriminate between different ecological resources, including nectar sources, animal hosts and oviposition sites, a feature mediated by their olfactory system. Insect repellents, such asN,N-diethyl-meta-toluamide (also called DEET), have been shown to activate and inhibit mosquito odorant receptors, resulting in behavioral modulation. This and other repellents currently available for personal protection against mosquitoes are topically applied to the skin and operate at a short range. In our search for potential long-range inhibitors of attractants to human hosts, we have hypothesized that the shared chemical similarities between indole and DEET may confer the former with the ability to block odorant receptor function and inhibit human host attraction in a similar way as DEET.

Methods

We used the two-electrode voltage clamp system to assayXenopus laevisoocytes as a platform to compare the pharmacological effect of commercially available insect repellents and indole on theAedes aegypti(R)-1-octen-3-ol receptor, OR8, a receptor involved in the decision-making of female mosquitoes to identify human hosts. We also conducted arm-in-a-cage and wind-tunnel bioassays to explore the effect of indole on human host-seeking femaleAedes aegyptimosquitoes.

Results

Our results demonstrate that indole inhibited theAedes aegypti(R)-1-octen-3-ol receptor OR8. In our arm-in-a-cage assay, 1 M of DEET reduced mosquito visits on average by 69.3% while the same indole concentration achieved 97.8% inhibition. This effect of indole on flight visits was dose-dependent and disappeared at 1 μM. In the flight tunnel, indole elicited on average 27.5% lower speed, 42.3% lower upwind velocity and 30.4% higher tortuosity compared to the control.

Conclusions

Indole significantly inhibits OR8 activation by (R)-1-octen-3-ol, mosquito visits to a human hand and long-range human host-seeking. The volatility of indole may be leveraged to develop a novel insect repellent in the context of personal mosquito protection.

Graphical abstract
Investigating pathological epigenetic aberrations by epi-proteomics
Authors: Robusti Giulia , Vai Alessandro , Bonaldi Tiziana , Noberini Roberta
Published: November 2022

Epigenetics includes a complex set of processes that alter gene activity without modifying the DNA sequence, which ultimately determines how the genetic information common to all the cells of an organism is used to generate different cell types. Dysregulation in the deposition and maintenance of epigenetic features, which include histone posttranslational modifications (PTMs) and histone variants, can result in the inappropriate expression or silencing of genes, often leading to diseased states, including cancer. The investigation of histone PTMs and variants in the context of clinical samples has highlighted their importance as biomarkers for patient stratification and as key players in aberrant epigenetic mechanisms potentially targetable for therapy. Mass spectrometry (MS) has emerged as the most powerful and versatile tool for the comprehensive, unbiased and quantitative analysis of histone proteoforms. In recent years, these approaches—which we refer to as “epi-proteomics”—have demonstrated their usefulness for the investigation of epigenetic mechanisms in pathological conditions, offering a number of advantages compared with the antibody-based methods traditionally used to profile clinical samples. In this review article, we will provide a critical overview of the MS-based approaches that can be employed to study histone PTMs and variants in clinical samples, with a strong focus on the latest advances in this area, such as the analysis of uncommon modifications and the integration of epi-proteomics data into multi-OMICs approaches, as well as the challenges to be addressed to fully exploit the potential of this novel field of research.
Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer’s disease
Authors: Wilson Edward N. , Young Christina B. , Ramos Benitez Javier , Swarovski Michelle S. , Feinstein Igor , Vandijck Manu , Le Guen Yann , Kasireddy Nandita M. , Shahid Marian , Corso Nicole K. , Wang Qian , Kennedy Gabriel , Trelle Alexandra N. , Lind Betty , Channappa Divya , Belnap Malia , Ramirez Veronica , Skylar-Scott Irina , Younes Kyan , Yutsis Maya V. , Le Bastard Nathalie , Quinn Joseph F. , van Dyck Christopher H. , Nairn Angus , Fredericks Carolyn A. , Tian Lu , Kerchner Geoffrey A. , Montine Thomas J. , Sha Sharon J. , Davidzon Guido , Henderson Victor W. , Longo Frank M. , Greicius Michael D. , Wagner Anthony D. , Wyss-Coray Tony , Poston Kathleen L. , Mormino Elizabeth C. , Andreasson Katrin I.
Published: November 2022

Background

The recent promise of disease-modifying therapies for Alzheimer’s disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.

Methods

We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer’s Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid β peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.

Results

The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aβ42/Aβ40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aβ+ and Aβ− groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.

Conclusions

This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.
Fibrosing mediastinitis in a child with Mendelian susceptibility to mycobacterial disease possibly due to Bacillus Calmette-Guérin
Authors: Sharifinejad Niusha , Mahdaviani Seyed Alireza , Fallah Shahrzad , Fard Nasrin Khakbazan , Norouzi Alireza , Jamee Mahnaz , Sadeghi-Shabestari Mahnaz , Marjani Majid , Malekshoar Mehran , Farnia Parisa , Velayati Ali Akbar
Published: November 2022

Background

Mendelian susceptibility to mycobacterial disease (MSMD) is an uncommon disorder with increased susceptibility to less virulent mycobacteria including bacillus Calmette-Guérin (BCG). Fibrosing mediastinitis (FM) is also a rare condition defined by excessive fibrotic reactions in the mediastinum. So far, some infectious organisms and autoimmune diseases have been introduced as possible etiologies of FM. However, no study has ever discussed the possible association of BCG infection and FM.

Case presentation

In this study, we report a 3-year-old female presenting with persistent fever, weakness, and bloody diarrhea in addition to mediastinal lymphadenopathy, hepatosplenomegaly, and pleural and pericardial effusion. Further examinations established a diagnosis of MSMD based on her clinical condition, immunologic data, positive tests for mycobacterial species, positive family history, and genetic study (IL12RB1 gene, c.G1193C, p.W398S). A year and a half later, she was referred with submandibular lymphadenitis and underwent immunologic work-up which revealed high inflammatory indices, a slight reduction in numbers of CD3 + and CD4 + cells as well as elevated CD16/56 + cell count and hyperimmunoglobulinemia. Purified protein derivative (PPD), QuantiFERON, and gastric washing test were all negative. Her chest computed tomography (CT) scan revealed suspicious para-aortic soft tissue and her echocardiography was indicative of strictures in superior vena cava and pulmonary veins. She further underwent chest CT angiography which confirmed FM development. Meanwhile, she has been treated with anti-mycobacterial agents and subcutaneous IFN-γ.

Conclusion

In summary, we described a novel case of MSMD in a child presenting with granulomatous FM possibly following BCG infection. This is the first report introducing aberrant BCG infection as the underlying cause of FM. This result could assist physicians in identifying early-onset FM in suspicious cases with MSMD. However, more studies are required to support this matter.
Impact of Moringa oleifera on rumen fermentation and methane emission under in vitro condition
Authors: Leitanthem Vandana Kumari , Chaudhary Parul , Bhakat Mukesh , Mohini Madhu , Mondal Goutam
Published: November 2022

Exploring innovative methods to provide essential nutrients and reducing ruminant greenhouse gas emission is crucial for animal production and diminishing global warming. This study was conducted to examine the efficacy ofMoringa oleiferaleaves (ML) in ruminants at 0%, 5%, 10%, 15%, 20%, 30% and 40% level in different roughage (R) and concentrate (C) (80R:20C, 70R:30C and 60R:40C) under in vitro conditions. Chemical composition of ML, concentrate mixture and berseem were estimated. Rumen fermentation parameters of male goat kids viz., total gas production, CH4, true dry matter digestibility (TDMD), organic matter digestibility (TOMD), partial fraction (PF), microbial biomass (MBP), ammonia (N), acetate, propionate, butyrate and acetate propionate ratio were observed under in vitro conditions. Results revealed that crude protein, organic matter and ethyl ether content were higher in ML as compared to concentrate mixture and berseem. Magnesium and iron content were also higher in ML as compared to concentrate and berseem. Total gas production, digestibility of DM and OM, MBP, acetate and propionate level were improved (P < 0.05) upto 10–20% replacement. In contrast, decreased in CH4(%) and CH4(mL/100 mg dDM) was noted with increased levels of ML incorporation. There was no change observed in ammonia, acetate: propionate ratios at all the three planes of nutrition. In this study, it is concluded that mixingMoringa oleiferaleaves in feed can be used as protein supplement and reduce the methane emission without causing any effect on digestibility and rumen fermentation parameters. However, ML can be suggested for widespread practice to attain the sustainable animal production (10–20%) and to alleviate the global warming.
Insights into glycosidic bond specificity of an engineered selective α-L-rhamnosidase N12-Rha via activity assays and molecular modelling
Authors: Yu Bo , Luo Shiyu , Ding Yuhan , Gong Zijie , Nie Ting
Published: November 2022

αL-rhamnosidase (EC 3.2.1.40) has been widely used in food processing and pharmaceutical preparation. The recombinant α-L-rhamnosidase N12-Rha from Aspergillus niger JMU-TS528 had significantly higher catalytic activity on α-1,6 glycosidic bond than α-1,2 glycosidic bond, and had no activity on α-1,3 glycosidic bond. The activities of hydrolyzed hesperidin and naringin were 7240 U/mL and 945 U/mL, respectively, which are 10.63 times that of native α-L-rhamnosidase. The activity could maintain more than 80% at pH 3–6 and 40–60℃. Quantum chemistry calculations showed that charge difference of the C-O atoms of the α-1,2, α-1,3 and α-1,6 bonds indicated that α-1,6 bond is most easily broken and α-1,3 bond is the most stable. Molecular dynamics simulations revealed that the key residue Trp359 that may affect substrate specificity and the main catalytic sites of N12-Rha are located in the (α/α)6-barrel domain.
A novel DOA estimation method for an antenna array under strong interference
Authors: Zuo Ming , Xie Shuguo
Published: November 2022

Strong interference will affect direction of arrival (DOA) estimation of weak desired signal and even cause DOA estimation failure. This paper investigates the weak signal DOA estimation for an antenna array under strong interference signals, and proposed a novel DOA estimation method for strong interference source suppression and weighted l1-norm sparse representation. A parallel adaptive beamforming algorithm based on power inversion is used to suppress strong interference and form new array data. To reduce spurious peaks in the spectrum under strong interference, a weighted matrix is determined by the optimized subspace algorithm for the subspace projection. Then, the DOA estimation, which is calculated by weighted l1-norm sparse representation, is formed by the weighted matrix and new array data. In this paper, the superiority of the proposed algorithm is illustrated by an example of unmanned aerial vehicle (UAV) video signal DOA estimation under strong interference signals. The simulated results of an orthogonal frequency division multiplexing signal indicate that the proposed algorithm shows merits of fewer snapshots, a sharper main lobe, a lower average noise spectrum value, higher DOA estimation accuracy and success rate. For validation, an outdoor experiment was conducted which demonstrated that the proposed algorithm is superior to other algorithms and can be used for DOA estimation of UAV video signals under strong WiFi interference. Both the simulations and experiments verify that the proposed algorithm can effectively suppress strong interference and achieve better DOA estimation performance for weak signals.
Study of weak solutions for degenerate parabolic inequalities with nonstandard conditions
Authors: Sun Yudong , Wu Tao
Published: November 2022

In this paper, we study the degenerate parabolic variational inequalities in a bounded domain. By solving a series of penalty problems, the existence and uniqueness of the solutions in the weak sense are proved by the energy method and a limit process.
Obesity and the risk of catheter-related bloodstream infection: a systematic review and meta-analysis
Authors: Wang Yong , Xiang Qian , Wu Jiayu , Xiao Na , Chen Jing
Published: November 2022

Background

The role of obesity in catheter-related bloodstream infection has been reported in several studies, but it is still controversial. We conducted this meta-analysis to summarize existing evidence to assess the relationship between obesity and the risk of catheter-related bloodstream infection.

Methods

We searched MEDLINE, EMBASE, PubMed and Web of Science for the related studies published before January 2022. Meta-analysis was performed by use of a random-effects model.

Results

A total of 5 articles were included in this meta-analysis. Patients with body mass index  ≥ 25 kg/m2 had an increased risk of catheter-related bloodstream infection (OR 1.75, 95% CI 1.38–2.22) in overall analysis. Further analysis indicated that patients with overweight, obesity and severely obesity were all significantly associated with a higher risk of for catheter-related bloodstream infection (OR 1.51 [1.10–2.08], OR 1.43 [1.12–1.82] and OR 2.74 [1.85–4.05], respectively).

Conclusion

This meta-analysis provided evidence that obesity was significantly associated with a higher risk of catheter-related bloodstream infection. Close attention should be paid to the complications and prognosis of obese patients with vascular catheterization in clinical work.
Fluid bolus therapy in pediatric sepsis: a narrative review
Authors: San Geroteo Julian , Levy Michaël , Gotchac Julien , Brissaud Olivier , Dauger Stéphane
Published: November 2022

Leading cause of death in children under five, pediatric sepsis remains a significant global health threat. The 2020 Surviving Sepsis Campaign guidelines revised the management of septic shock and sepsis-associated organ dysfunction in children. In addition to empiric broad-spectrum antibiotics, fluid bolus therapy is one of the cornerstones of management, due to theoretical improvement of cardiac output, oxygen delivery and organ perfusion. Despite a very low level of evidence, the possible benefit of balanced crystalloids in sepsis resuscitation has led to discussion on their position as the ideal fluid. However, the latest adult data are not consistent with this, and the debate is still ongoing in pediatrics. We provide here the current state of knowledge on fluid bolus therapy in pediatric sepsis with emphasis on balanced crystalloids.
Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis
Authors: Hussain Hafiz Muhammad Jafar , Cai Yikai , Weng Qinjie , Tong Jun , Aftab Ayesha , Jin Yuanmeng , Liu Jian , Yu Shuwen , Fang Zhengying , Du Wen , Pan Xiaoxia , Ren Hong , Xie Jingyuan
Published: November 2022

Background

Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS.

Methods

This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases.

Results

Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic.

Conclusions

Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.
Development of a novel BRCAness score that predicts response to PARP inhibitors
Authors: Oshi Masanori , Gandhi Shipra , Wu Rongrong , Asaoka Mariko , Yan Li , Yamada Akimitsu , Yamamoto Shinya , Narui Kazutaka , Chishima Takashi , Ishikawa Takashi , Endo Itaru , Takabe Kazuaki
Published: November 2022

Background

BRCAness is a characteristic feature of homologous recombination deficiency (HRD) mimicking BRCA gene mutation in breast cancer. We hypothesized that a measure to quantify BRCAness that causes synthetic lethality in BRCA mutated tumors will identify responders to PARP inhibitors.

Methods

A total of 6753 breast cancer patients from 3 large independent cohorts were analyzed. A score was generated by transcriptomic profiling using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer.

Results

The score was significantly associated with BRCA1 mutation, high mutation load and intratumoral heterogeneity as expected, as well as with high HRD, DNA repair and MKi67 expression regardless of BRCA mutations. High BRCAness tumors enriched not only DNA repair, but also all five Hallmark cell proliferation-related gene sets. High BRCAness tumors were significantly associated with higher cytolytic activity and with higher anti-cancerous immune cell infiltration. Not only did the breast cancer cell lines with BRCA-mutation show high score, but even the other cells in human breast cancer tumor microenvironment were contributing to the score. The BRCAness score was the highest in triple-negative breast cancer consistently in all 3 cohorts. BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative and ER-positive/HER2-negative breast cancer.

Conclusions

We established a novel BRCAness score using BRCA-mutation-related gene expressions and found that it associates with DNA repair and predicts response to PARP inhibitors regardless of BRCA mutation.
Readiness and willingness of Malaysian community pharmacists in providing vaccination services
Authors: Ang Wei Chern , Fadzil Mohamad Syafuan , Ishak Fatin Najihah , Adenan Nassrah Norissya , Nik Mohamed Mohamad Haniki
Published: November 2022

Background

Vaccination is an effective public health intervention in reducing morbidity and mortality of infectious diseases. Compared to other countries where community pharmacists (CPs) administer vaccines, CPs in Malaysia are not authorised. This study aimed to assess CPs' readiness and willingness to provide vaccination in Malaysia, identify potential barriers to and factors supporting the provision of this service.

Methods

A cross-sectional study was conducted among Malaysian CPs from April to June 2021. A validated online questionnaire was distributed through social media, instant messaging, email, and pharmacy societies.

Results

Of 492 CPs recruited throughout Malaysia, 439 (89.2%) expressed willingness to provide vaccination services to the public, 403 (81.9%) agreed with the accessibility of community pharmacies to the public, and 73.4% agreed that their role in vaccination could help to improve the overall vaccination coverage rate. The lack of pharmacist training in vaccination and concerns on maintaining patient safety were identified as barriers to CPs' implementation of vaccination services, with 52.8% and 47.8% of them agreeing, respectively. Training sessions and operational guidelines on providing vaccination services are required to overcome the barriers.

Conclusion

CPs in Malaysia were ready and willing to provide vaccination services to the public. However, the implementation demands training workshops and re-evaluation of CPs in public vaccination programmes by Malaysian healthcare policymakers.
A novel rotation method with variable-angle anterior probe for correcting the depth of the kidney to optimize renal dynamic imaging
Authors: Wei Hua , Han Ke , Wu Jiaojiao , Hu Guang , Wu Zhifang , Wang Hongliang , Guo Xiaoshan , Hou Yansong , Wang Rui , Li Sijin
Published: November 2022

Purpose

We aimed to investigate the effect and significance of the rotation method with variable-angle anterior probe corrected for the depth of two kidneys on the determination of glomerular filtration rate (GFR) in total and single kidneys by the renal dynamic imaging Gates method.

Methods

Seventy-two patients who underwent dynamic renal imaging by the rotation method and abdominal CT in our hospital were collected in the present study. CT scanning, rotation method, Tonnesen's formula, and Li-Qian's formula were compared in terms of the depth of two kidneys, the depth difference between the two kidneys, and the total renal and single GFR obtained by substituting the renal depth values into Gates' formula.

Results

①The depth of kidneys and GFR: Compared to CT, Tonnesen's formula significantly underestimated the depth of both kidneys and the total and single renal GFR (P < 0.05). No significant differences were found in the depth of both kidneys and the total and single renal GFR between Li-Qian's formula and the rotation method (P > 0.05), with a strong agreement and with the least bias in the values measured by the rotation method. ②Renal depth difference: Compared to CT, Tonnesen's formula and Li-Qian's formula underestimated the difference in depth between the two kidneys (P < 0.05). None of the differences were statistically significant based on the rotation method (P > 0.05). The depth difference was positively correlated with the resulting changes in single renal function (|R(CT)-R(Li-Qian)|) and (|R(Rotation)-R(Li-Qian)|) (r = 0.881, 0.641, P < 0.001). As the depth difference increased, Li-Qian's formula could not visualize changes in single renal function accurately. In contrast, the accuracy of the rotation method in assessing single renal function remains unaffected.

Conclusion

The rotation method obtains an accurate depth and depth difference between the two kidneys without additional CT radiation, enhancing the accuracy of the Gates method for determining total and single renal GFR.

Trial registration Medical Ethics Committee of First Hospital of Shanxi Medical University, 2021BAL0146. Registered 12 January 2021.
Oocyte quality assessment in marine invertebrates: a novel approach by fluorescence spectroscopy
Authors: Gallo Alessandra , Esposito Maria Consiglia , Boni Raffaele , Tosti Elisabetta
Published: November 2022

Background

The assessment of oocyte quality is, nowadays, a major challenge in aquaculture, oocyte cryopreservation, and environmental science. Oocyte quality is a determining factor in fertilization and embryo development; however, there is still a lack of rapid and sensitive cellular markers for its assessment. Currently, its estimation is predominantly based on morphological analysis, which is subjective and does not consistently reflect the developmental competence of the oocytes. Despite several recent studies investigating molecular markers related to oocyte quality, methods currently available for their determination pose various technical challenges and limitations. In this study, we developed a novel approach based on fluorescence spectroscopy to assess different intrinsic physiological parameters that can be employed to evaluate egg quality in marine invertebrates that are widely used as animal models such as sea urchins and mussels.

Results

Different physiological parameters, such as viability, mitochondrial activity, intracellular ROS levels, plasma membrane lipid peroxidation, and intracellular pH, for egg quality evaluation have been successfully assessed in sea urchins and mussels by using specific fluorescent dyes and detecting the fluorescent signals in eggs through fluorescence spectroscopy.

Conclusions

Based on our findings, we propose these physiological markers as useful predictors of egg quality in marine invertebrates; they can be estimated rapidly, selectively, and sensitively by employing this novel approach, which, due to the speed of analysis, the low cost, and easy use can be considered a powerful analytical tool for the egg quality assessment.
Association between cumulative cisplatin dose and reproductive and sexual functions in patients with malignant ovarian germ cell tumors treated with bleomycin, etoposide, and cisplatin therapy: a case series study
Authors: Akasaka Miki , Hirai Toshinori , Yoshida Kenta , Kondo Eiji , Ikeda Tomoaki , Iwamoto Takuya
Published: November 2022

Background

The impact of cumulative dose of cisplatin on gonadal function has not been clarified. We evaluated whether the cumulative cisplatin dose affects the resumption of menses in patients treated with bleomycin, etoposide, and cisplatin (BEP).

Main body

A case series study of women < 40 years with malignant ovarian germ cell tumors receiving BEP was conducted at Mie University Hospital. Using linear regression analysis, the correlation between the cumulative dose and resumption of menses was determined. Additionally, we compared the resumption of menses stratified by age (age < 20 years or ≥ 20 years). Ten women (median age: 20 [interquartile range: 15–26] years) have received a median of 4 cycles of BEP. The median period of resumption of menses was 5 months, which had no correlation with cumulative doses of bleomycin (143 mg/m2 [71–220], y = -0.0069 x + 6.15, r = 0.19, P = 0.60), etoposide (1,533 mg/m2 [900–2,000], y = 0.0004 x + 4.56, r = 0.08, P = 0.82), and cisplatin (363 mg/m2 [225–400], y = 0.01 x + 1.67, r = 0.35, P = 0.32). Although the resumption of menses was comparable across ages, the cumulative doses of cisplatin were higher in patients aged < 20 years than in those aged ≥ 20 years (400 mg/m2 [363–450] vs. 225 mg/m2 [225–350], P = 0.02). Similarly, patients aged < 20 years had a higher cumulative etoposide dose than those aged ≥ 20 years (2,000 mg/m2 [1,533–2,250] vs. 900 mg/m2[900–1,600], P = 0.03). Moreover, patients aged < 20 years received more cycles of BEP than those aged ≥ 20 years (4 cycles vs. 3 cycles, P = 0.03).

Short conclusion

All patients can recover menses after BEP, and the resumption of menses appeared at the median period of 5 months after BEP. The timing of menses resumption did not correlate with the cumulative doses of cisplatin.
Auditory rhythmical cueing to improve gait in community-dwelling stroke survivors (ACTIVATE): a pilot randomised controlled trial
Authors: Shaw Lisa , McCue Patricia , Brown Philip , Buckley Christopher , Del Din Silvia , Francis Richard , Hunter Heather , Lambert Allen , Lord Sue , Price Christopher I. M. , Rodgers Helen , Rochester Lynn , Moore Sarah A.
Published: November 2022

Background

Gait impairment limiting mobility and restricting activities is common after stroke. Auditory rhythmical cueing (ARC) uses a metronome beat delivered during exercise to train stepping and early work reports gait improvements. This study aimed to establish the feasibility of a full scale multicentre randomised controlled trial to evaluate an ARC gait and balance training programme for use by stroke survivors in the home and outdoors.

Methods

A parallel-group observer-blind pilot randomised controlled trial was conducted. Adults within 2 years of stroke with a gait-related mobility impairment were recruited from four NHS stroke services and randomised to an ARC gait and balance training programme (intervention) or the training programme without ARC (control). Both programmes consisted of 3x30 min sessions per week for 6 weeks undertaken at home/nearby outdoor community. One session per week was supervised and the remainder self-managed. Gait and balance performance assessments were undertaken at baseline, 6 and 10 weeks. Key trial outcomes included recruitment and retention rates, programme adherence, assessment data completeness and safety.

Results

Between November 2018 and February 2020, 59 participants were randomised (intervention n=30, control n=29), mean recruitment rate 4/month. At baseline, 6 weeks and 10 weeks, research assessments were conducted for 59/59 (100%), 47/59 (80%) and 42/59 (71%) participants, respectively. Missing assessments were largely due to discontinuation of data collection from mid-March 2020 because of the UK COVID-19 pandemic lockdown. The proportion of participants with complete data for each individual performance assessment ranged from 100% at baseline to 68% at 10 weeks. In the intervention group, 433/540 (80%) total programme exercise sessions were undertaken, in the control group, 390/522 (75%). Falls were reported by five participants in the intervention group, six in the control group. Three serious adverse events occurred, all unrelated to the study.

Conclusion

We believe that a definitive multicentre RCT to evaluate the ARC gait and balance training programme is feasible. Recruitment, programme adherence and safety were all acceptable. Although we consider that the retention rate and assessment data completeness were not sufficient for a future trial, this was largely due to the UK COVID-19 pandemic lockdown.

Trial registration

ISRCTN, ISRCTN10874601, Registered on 05/03/2018,