bluuebunny/crossref_metadata_2025 huggingface dataset:
Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury
Authors: Pedriali Gaia , Ramaccini Daniela , Bouhamida Esmaa , Wieckowski Mariusz R. , Giorgi Carlotta , Tremoli Elena , Pinton Paolo
Published: December 2022

Cardiovascular disease is the most common cause of death worldwide and in particular, ischemic heart disease holds the most considerable position. Even if it has been deeply studied, myocardial ischemia-reperfusion injury (IRI) is still a side-effect of the clinical treatment for several heart diseases: ischemia process itself leads to temporary damage to heart tissue and obviously the recovery of blood flow is promptly required even if it worsens the ischemic injury. There is no doubt that mitochondria play a key role in pathogenesis of IRI: dysfunctions of these important organelles alter cell homeostasis and survival. It has been demonstrated that during IRI the system of mitochondrial quality control undergoes alterations with the disruption of the complex balance between the processes of mitochondrial fusion, fission, biogenesis and mitophagy. The fundamental role of mitochondria is carried out thanks to the finely regulated connection to other organelles such as plasma membrane, endoplasmic reticulum and nucleus, therefore impairments of these inter-organelle communications exacerbate IRI. This review pointed to enhance the importance of the mitochondrial network in the pathogenesis of IRI with the aim to focus on potential mitochondria-targeting therapies as new approach to control heart tissue damage after ischemia and reperfusion process.
Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase
Authors: Hagemann Anna , Altrogge Philipp Klemens , Kehrenberg Miriam Caroline Alice , Diehl Daniel , Jung Dominik , Weber Lea , Bachmann Hagen Sjard
Published: December 2022

Manumycin A is postulated to be a specific inhibitor against the farnesyltransferase (FTase) since this effect has been shown in 1993 for yeast FTase. Since then, plenty of studies investigated Manumycin A in human cells as well as in model organisms like Caenorhabditis elegans. Some studies pointed to additional targets and pathways involved in Manumycin A effects like apoptosis. Therefore, these studies created doubt whether the main mechanism of action of Manumycin A is FTase inhibition. For some of these alternative targets half maximal inhibitory concentrations (IC50) of Manumycin A are available, but not for human and C. elegans FTase. So, we aimed to 1) characterize missing C. elegans FTase kinetics, 2) elucidate the IC50 and Ki values of Manumycin A on purified human and C. elegans FTase 3) investigate Manumycin A dependent expression of FTase and apoptosis genes in C. elegans. C. elegans FTase has its temperature optimum at 40°C with KM of 1.3 µM (farnesylpyrophosphate) and 1.7 µM (protein derivate). Whilst other targets are inhibitable by Manumycin A at the nanomolar level, we found that Manumycin A inhibits cell-free FTase in micromolar concentrations (Ki human 4.15 μM; KiC. elegans 3.16 μM). Furthermore, our gene expression results correlate with other studies indicating that thioredoxin reductase 1 is the main target of Manumycin A. According to our results, the ability of Manumycin A to inhibit the FTase at the micromolar level is rather neglectable for its cellular effects, so we postulate that the classification as a specific FTase inhibitor is no longer valid.
Measuring adherence, acceptability and likability of an artificial-intelligence-based, gamified phone application to improve the quality of dietary choices of adolescents in Ghana and Vietnam: Protocol of a randomized controlled pilot test
Authors: Braga Bianca C. , Arrieta Alejandra , Bannerman Boateng , Doyle Frank , Folson Gloria , Gangupantulu Rohit , Hoang Nga Thu , Huynh Phuong Nam , Koch Bastien , McCloskey Peter , Tran Lan Mai , Tran Trang Huyen T. , Truong Duong Thuy T. , Nguyen Phuong H. , Hughes David , Gelli Aulo
Published: December 2022

Unhealthy diets are a critical global concern while dietary measure methods are time consuming and expensive. There is limited evidence that phone-based interventions can improve nutrition data collection and dietary quality, especially for adolescents in developing countries. We developed an artificial-intelligence-based phone application called Food Recognition Assistance and Nudging Insights (FRANI) to address these problems. FRANI can recognize foods in images, track food consumption, display statistics and use gamified nudges to give positive feedback on healthy food choice. This study protocol describes the design of new pilot studies aimed at measuring the feasibility (acceptability, adherence, and usability) of FRANI and its effects on the quality of food choice of adolescents in Ghana and Vietnam. In each country, 36 adolescents (12–18 years) will be randomly allocated into two groups: The intervention group with the full version of FRANI and the control group with the functionality limited to image recognition and dietary assessment. Participants in both groups will have their food choices tracked for four weeks. The control groups will then switch to the full version of FRANI and both groups will be tracked for a further 2 weeks to assess acceptability, adherence, and usability. Analysis of outcomes will be by intent to treat and differences in outcomes between intervention and control group will use Poisson and odds ratio regression models, accounting for repeated measures at individual levels. If deemed feasible, acceptable and usable, FRANI will address gaps in the literature and advance the nutrition field by potentially improving the quality of food choices of adolescent girls in developing countries. This pilot study will also provide insights on the design of a large randomized controlled trial. The functioning and dissemination of FRANI can be an important step towards highly scalable nutrition data collection and healthier food choices for a population at risk of malnutrition.

The study protocol and the methods and materials were approved by the Institutional Review Board (IRB) of the IFPRI on April 29th, 2020 (registration number #00007490), the Thai Nguyen National Hospital on April 14th, 2020 (protocol code 274/ĐĐĐ-BVTWTN) and the University of Ghana on August 10th, 2020 (Federalwide Assurance FWA 00001824; NMIMR-IRB CPN 078–19/20). The study protocol was registered in the International Standard Randomized Controlled Trial Number (ISRCTN 10681553; https://doi.org/10.1186/ISRCTN10681553) on November 12, 2021.
Face-to-face versus online-based lectures: A COVID-19 induced study on assessments
Authors: Fisher David , Solomons Deon , Makhathini Khayelihle Brian
Published: December 2022

Introduction

There is much debate regarding the impact of COVID-induced lockdown on the standard of assessments, mainly since students were assessed at home via an online assessment platform. Regular orthodox lectures and assessments were carried out during the first term, while the strictly enforced South African COVID lockdown warranted that 2nd term lectures and assessments were based online. This created the fortunate control conditions to statistically compare orthodox face-to-face with online-home-based assessments.

Methods

We compared the assessments of a cohort of second-year students studying physiology and anatomy during 2019 and 2020: Orthodox face-to-face teaching and assessments (2019) were compared to online teaching and their analogous online assessments (2020) during the COVID-19-induced lockdown.

Results

Although class pass rates and marks for online assessments (2020) were significantly higher than for traditional assessments (2019), an essential finding of the study was that the Gaussian distribution of the marks across the class for both modes of assessment was statistically identical. This indicated that although students performed better with home-based online assessments, poor-performing students populated the lower spread of marks, modal students occupied the central distribution, while good students occupied the higher mark distribution of the curve.

Discussion

The students were found to be resilient in adapting to things and learning, online presentations, and computer-based assessments. No gender-based difference or advantage to adjusting to newly introduced blended learning and concomitant changes in learning assessment strategies was found. The online-home-based assessments proved to incentivize prior learning and preparation for assessments by implementing strict time limits or assessments and randomizing the selections of questions and respective (MCQ) answer choices. We conclude that although home-based online assessments significantly improve the overall mark distribution, there was no distinction in the spread of the distribution of marks, which was indicative that the home-based online assessment process was able to provide an identical measure of course proficiency as in the orthodox sit-down assessment. Therefore, our statistical analysis of the performance of students under student assessment performances indicates that there is no rationale for thinking that the home-based online mode of assessment is equivalent to or better than the orthodox modes of assessment.
Career success: Analysis and development of career opportunities in students
Authors: Pshembayeva Elmira , Pfeyfer Nellie , Uaikhanova Meruyert , Bubenchikova Anastasiia
Published: December 2022

Effective implementation and development of the career development programmes determine the economic growth of countries. The research aims to discuss and analyze the characteristics and elements of the students’ career opportunities. The results help the scholars select the proper type of analysis and appropriate tools to examine the elements of career opportunities. The sample consisted of 102 third and fourth year students from NJSC Toraighyrov University. The following methods and criteria were used to analyze the initial stage of the student career development: emotional intelligence (based on the methodology proposed by J. N. Hall), communication skills (Test of communication skills by L. Mikhelson), self-assessment (S. A. Budassi’s method of self-assessment), career value orientations (Edgar Schein’s Career Anchors), motivation for success (The Questionnaire by T. Ehlers). The surveys were conducted using Google Forms. The results helped to identify the characteristics and elements of the students’ career opportunities. The data collected at NJSC Toraighyrov University of the Republic of Kazakhstan show that 35% of students have a low level of emotional intelligence, 47% have addictive behaviors during communication, 31% of respondents have low self-esteem, lack of motivation for success was identified in 18% of students. Only a small number of students could clearly define their career orientations regarding Lifestyle Integration, Challenge and Management. The research suggests that it is important to introduce career development programmes that empower students and encourage them to build professional career paths in the future. Used as a learning framework, the Career coaching programme helps to design, develop, assess and implement each element of the career opportunities. The implementation advantages of the Career coaching programme for students as part of the educational process are discussed in the present research. The programme Career coaching will develop awareness and advance careers among graduate students. Moreover, it will provide a guideline for the first steps toward developing a successful career path.
Why are they not coming back? A single-center follow-up study on oncological women oocyte’s storing for fertility preservation
Authors: Immediata Valentina , Cirillo Federico , Baggiani Annamaria , Zanagnolo Maria Federica , Ronchetti Camilla , Morenghi Emanuela , Cesana Amalia , Specchia Cristina , Levi-Setti Paolo Emanuele
Published: December 2022

Introduction

Oocyte cryopreservation is a valid option for female cancer patients to preserve fertility. The number of patients undergoing fertility preservation (FP) cycles has increased over the past years. Nevertheless, the rates of patients returning to use their cryopreserved material have shown to be considerably low, ranging from 5-8%, but significant data regarding the reasons of such low return rates are scarce.

Methods

This study is a single-center follow-up retrospective study evaluating the return rate of oncological women who underwent FP at a tertiary care Fertility Center and assessing the reasons influencing the patients who did not return. Data about patients who returned to attempt pregnancy were retrieved from internal registries. Non-returned patients were assessed with a standardized phone survey investigating health condition, marital status and family projects, spontaneous conceptions, and the reasons why they had not returned to use their gametes. A univariate analysis between returned and non-returned patients was performed.

Results

Of the 397 patients who received counseling about FP, 171 (43.1%) underwent oocyte cryopreservation between 2001 and 2017. Nine (5%) died, and 17 (10%) were lost at follow-up. A total of 20 patients (11.7%) returned and 125 did not. In the non-returned group, 37 (29.6%) did not have a partner, 10 (8%) had a previous spontaneous conception, and 15 (12%) had recurrent malignancy at the time of follow-up. In the univariate analysis, younger age at freezing (31.8±6.2 vs. 35.2±4.7; p 0.018), lack of a partner (p 0.002), type of cancer (other than breast cancer; p 0.024) were the significant factors in the non-returned group. As for the personal reason for not coming back, patients mainly answered as follows: lack of a partner (29, 23.2%), the desire for spontaneous motherhood (24, 19.2%), previous spontaneous pregnancies after FP procedures (16, 12.8%), and still ongoing hormonal therapy for breast cancer (13, 10.4%). All patients confirmed their will to keep the storage of their oocytes.

Discussion

The impact of a cancer diagnosis on a woman’s maternal desire, sentimental status and life priorities should be studied more thoroughly. Studies investigating hormonal therapy suppression in breast cancer patients seeking pregnancy should be encouraged.

Clinical trial registration

https://clinicaltrials.gov, identifier NCT05223764.
Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral macronodular adrenocortical hyperplasia
Authors: Zhang Ru , Rubinstein German , Vetrivel Sharmilee , Kunz Sonja , Vogel Frederick , Bouys Lucas , Bertherat Jérôme , Kroiss Matthias , Deniz Sinan , Osswald Andrea , Knösel Thomas , Bidlingmaier Martin , Sbiera Silviu , Reincke Martin , Riester Anna
Published: December 2022

Introduction

Adrenal vein sampling (AVS) is not a routine procedure in patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but has been used to determine lateralization of cortisol secretion in order to guide decision of unilateral adrenalectomy. Our aim was to characterize the steroid fingerprints in AVS samples of patients with PBMAH and hypercortisolism and to identify a reference hormone for AVS interpretation.

Method

Retrospectively, we included 17 patients with PBMAH from the German Cushing’s registry who underwent AVS. 15 steroids were quantified in AVS and peripheral blood samples using LC-MS/MS. We calculated lateralization indices and conversion ratios indicative of steroidogenic enzyme activity to elucidate differences between individual adrenal steroidomes and in steroidogenic pathways.

Results

Adrenal volume was negatively correlated with peripheral cortisone (r=0.62, p<0.05). 24-hour urinary free cortisol correlated positively with peripheral androgens (rDHEA=0.57, rDHEAS=0.82, rA=0.73, rT=0.54, p<0.05). DHEA was found to be a powerful reference hormone with high selectivity index, which did not correlate with serume cortisol and has a short half-life. All investigated steroids showed lateralization in single patients indicating the heterogenous steroid secretion pattern in patients with PBMAH. The ratios of corticosterone/aldosterone (catalyzed by CYP11B2), androstenedione/dehydroepiandrosterone (catalyzed by HSD3B2) and cortisone/cortisol (catalyzed by HSD11B2) in adrenal vein samples were higher in smaller adrenals (p<0.05). ARMC5 mutation carriers (n=6) showed lower androstenedione/17-hydroxyprogesterone and higher testosterone/androstenedione (p<0.05) ratios in peripheral blood, in line with lower peripheral androstenedione concentrations (p<0.05).

Conclusion

Steroid profiling by LC-MS/MS led us to select DHEA as a candidate reference hormone for cortisol secretion. Lateralization and different steroid ratios showed that each steroid and all three steroidogenic pathways may be affected in PBMAH patients. In patients with germline ARMC5 mutations, the androgen pathway was particularly dysregulated.
Application of feedback control to stomatal optimisation in a global land surface model
Authors: Jones Simon , Eller Cleiton B. , Cox Peter M.
Published: December 2022

Accurate representations of stomatal conductance are required to predict the effects of climate change on terrestrial ecosystems. Stomatal optimisation theory, the idea that plants have evolved to maximise carbon gain under certain constraints, such as minimising water loss or preventing hydraulic damage, is a powerful approach to representing stomatal behaviour that bypasses the need to represent complex physiological processes. However, while their ability to replicate observed stomatal responses is promising, optimisation models often present practical problems for those trying to simulate the land surface. In particular, when realistic models of photosynthesis and more complex cost functions are used, closed-form solutions for the optimal stomatal conductance are often very difficult to find. As a result, implementing stomatal optimisation in land surface models currently relies either on simplifying approximations, that allow closed-form solutions to be found, or on numerical iteration which can be computationally expensive. Here we propose an alternative approach, using a method motivated by control theory that is computationally efficient and does not require simplifying approximations to be made to the underlying optimisation. Stomatal conductance is treated as the control variable in a simple closed-loop system and we use the Newton-Raphson method to track the time-varying maximum of the objective function. We compare the method to both numerical iteration and a semi-analytical approach by applying the methods to the SOX stomatal optimisation model at multiple sites across the Amazon rainforest. The feedback approach is able to more accurately replicate the results found by numerical iteration than the semi-analytical approach while maintaining improved computational efficiency.
Identification of key genes in late-onset major depressive disorder through a co-expression network module
Authors: Yao Ping-An , Sun Hai-Ju , Li Xiao-Yu
Published: December 2022

Late-onset major depressive disorder (LOD) increases the risk of disability and suicide in elderly patients. However, the complex pathological mechanism of LOD still remains unclear. We selected 10 LOD patients and 12 healthy control samples from the GSE76826 dataset for statistical analysis. Under the screening criteria, 811 differentially expressed genes (DEGs) were screened. We obtained a total of two most clinically significant modules through the weighted gene co-expression network analysis (WGCNA). Functional analysis of the genes in the most clinically significant modules was performed to explore the potential mechanism of LOD, followed by protein–protein interaction (PPI) analysis and hub gene identification in the core area of the PPI network. Furthermore, we identified immune infiltrating cells using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm between healthy subjects and LOD patients with the GSE98793 dataset. Next, six hub genes (CD27, IL7R, CXCL1, CCR7, IGLL5, and CD79A) were obtained by intersecting hub genes with DEGs, followed by verifying the diagnostic accuracy with the receiver operating characteristic curve (ROC). In addition, we constructed the least absolute shrinkage and selection operator (LASSO) regression model for hub gene cross-validation. Finally, we found that CD27 and IGLL5 were good diagnostic indicators of LOD, and CD27 may be the key gene of immune function change in LOD. In conclusion, our research shows that the changes in the immune function may be an important mechanism in the development of LOD, which can provide some guidance for the related research of LOD in the future.
Subsidies and allocation: A legacy of distortion and intergenerational loss
Authors: Sinan Hussain , Willis Ciara , Swartz Wilf , Sumaila U. Rashid , Forsdyke Ruth , Skerritt Daniel J. , Le Manach Frédéric , Colléter Mathieu , Bailey Megan
Published: December 2022

One of the greatest threats to the conservation of transboundary stocks is the failure of Regional Fisheries Management Organizations (RFMOs) to equitably allocate future fishing opportunities. Across RFMOs, catch history remains the principal criterion for catch allocations, despite being recognized as a critical barrier to governance stability. This paper examines if and how subsidies have driven catch histories, thereby perpetuating the legacy of unfair resource competition between distant water fishing nations (DWFNs) and coastal States, and how this affects ongoing allocation negotiations in the Indian Ocean Tuna Commission (IOTC). Using limited publicly available data on subsidies to Indian Ocean tuna fleets, we show that subsidies have inflated catch histories of many DWFN's. As long as historical catch remains the key allocation criterion, future fishing opportunities will continue to be skewed in favor of DWFNs, in turn marginalizing half of the IOTC member States, which collectively account for a paltry 4% of the current catch. Without better transparency in past subsidies data, accounting for this distortion will be difficult. We provide alternative allocation options for consideration, with our analysis showing that re-attributing DWFN catch to the coastal State in whose waters it was caught may begin to alleviate this historical injustice.
A scalable model for simulating multi-round antibody evolution and benchmarking of clonal tree reconstruction methods
Authors: Zhang Chao , Bzikadze Andrey V. , Safonova Yana , Mirarab Siavash
Published: December 2022

Affinity maturation (AM) of B cells through somatic hypermutations (SHMs) enables the immune system to evolve to recognize diverse pathogens. The accumulation of SHMs leads to the formation of clonal lineages of antibody-secreting b cells that have evolved from a common naïve B cell. Advances in high-throughput sequencing have enabled deep scans of B cell receptor repertoires, paving the way for reconstructing clonal trees. However, it is not clear if clonal trees, which capture microevolutionary time scales, can be reconstructed using traditional phylogenetic reconstruction methods with adequate accuracy. In fact, several clonal tree reconstruction methods have been developed to fix supposed shortcomings of phylogenetic methods. Nevertheless, no consensus has been reached regarding the relative accuracy of these methods, partially because evaluation is challenging. Benchmarking the performance of existing methods and developing better methods would both benefit from realistic models of clonal lineage evolution specifically designed for emulating B cell evolution. In this paper, we propose a model for modeling B cell clonal lineage evolution and use this model to benchmark several existing clonal tree reconstruction methods. Our model, designed to be extensible, has several features: by evolving the clonal tree and sequences simultaneously, it allows modeling selective pressure due to changes in affinity binding; it enables scalable simulations of large numbers of cells; it enables several rounds of infection by an evolving pathogen; and, it models building of memory. In addition, we also suggest a set of metrics for comparing clonal trees and measuring their properties. Our results show that while maximum likelihood phylogenetic reconstruction methods can fail to capture key features of clonal tree expansion if applied naively, a simple post-processing of their results, where short branches are contracted, leads to inferences that are better than alternative methods.
Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
Authors: Wang Zhonglei , Yang Liyan , Song Xian-qing
Published: December 2022

GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.
Genome-wide identification of antisense lncRNAs and their association with susceptibility to Flavobacterium psychrophilum in rainbow trout
Authors: Ali Ali , Salem Mohamed
Published: December 2022

Eukaryotic genomes encode long noncoding natural antisense transcripts (lncNATs) that have been increasingly recognized as regulatory members of gene expression. Recently, we identified a few antisense transcripts correlating in expression with immune-related genes. However, a systematic genome-wide analysis of lncNATs in rainbow trout is lacking. This study used 134 RNA-Seq datasets from five different projects to identify antisense transcripts. A total of 13,503 lncNATs were identified genome-wide. About 75% of lncNATs showed multiple exons compared to 36.5% of the intergenic lncRNAs. RNA-Seq datasets from resistant, control, and susceptible rainbow trout genetic lines with significant differences in survival rate following Flavobacterium psychrophilum (Fp) infection were analyzed to investigate the potential role of the lncNATs during infection. Twenty-four pairwise comparisons between the different genetic lines, infectious status, and time points revealed 581 differentially expressed (DE) lncNATs and 179 differentially used exons (DUEs). Most of the DE lncNATs strongly and positively correlated in expression with their corresponding sense transcripts across 24 RNA-Seq datasets. LncNATs complementary to genes related to immunity, muscle contraction, proteolysis, and iron/heme metabolism were DE following infection. LncNATs complementary to hemolysis-related genes were DE in the resistant fish compared to susceptible fish on day 5 post-infection, suggesting enhanced clearance of free hemoglobin (Hb) and heme and increased erythropoiesis. LncNATs complementary to hepcidin, a master negative regulator of the plasma iron concentration, were the most downregulated lncNATs on day 5 of bacterial infection in the resistant fish. Ninety-four DE lncNAT, including five complementary to hepcidin, are located within 26 QTL regions previously identified in association with bacterial cold water disease (BCWD) in rainbow trout. Collectively, lncNATs are involved in the molecular architecture of fish immunity and should be further investigated for potential applications in genomic selection and genetic manipulation in aquaculture.
B7 family protein glycosylation: Promising novel targets in tumor treatment
Authors: Xiao Linlin , Guan Xiaoyan , Xiang Mingli , Wang Qian , Long Qian , Yue Chaoyi , Chen Lulu , Liu Jianguo , Liao Chengcheng
Published: December 2022

Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More effective and alternative inhibitory targets are critical for successful immune checkpoint blockade therapy. The interaction of the immunomodulatory ligand B7 family with corresponding receptors induces or inhibits T cell responses by sending co-stimulatory and co-inhibitory signals respectively. Blocking the glycosylation of the B7 family members PD-L1, PD-L2, B7-H3, and B7-H4 inhibited the self-stability and receptor binding of these immune checkpoint proteins, leading to immunosuppression and rapid tumor progression. Therefore, regulation of glycosylation may be the “golden key” to relieve tumor immunosuppression. The exploration of a more precise glycosylation regulation mechanism and glycan structure of B7 family proteins is conducive to the discovery and clinical application of antibodies and small molecule inhibitors.
Space-time statistics of extreme ocean waves in crossing sea states
Authors: Davison Silvio , Benetazzo Alvise , Barbariol Francesco , Ducrozet Guillaume , Yoo Jeseon , Marani Marco
Published: December 2022

The study of extreme ocean waves has gained considerable interest in recent years, due to their importance for offshore design and navigation safety, and several theoretical approaches have been developed for their statistical description. However, in the case of crossing seas, where two or more wave systems of different characteristics are present, a full understanding of the main physical mechanisms responsible for the occurrence of very high individual waves is still lacking. As a consequence, the prediction of extremes in such conditions currently relies on integrated parameters of the total sea state, such as the spectral wave steepness. In this study, to gain further insight into the role of the crossing wind sea and swell wave systems in producing extreme individual waves, we investigate realistic sea states during typhoon Kong-rey (2018) using an ensemble of numerical simulations obtained from a phase-resolving wave model based on the High-Order Spectral (HOS) method. The reliability of the numerical fields is assessed for the first time with stereo wave measurements of the sea surface elevation field collected from an offshore platform in the area of interest. We show that, in specific conditions, space-time extreme crest heights in crossing seas can be larger than in unimodal seas due to second-order bound wave interactions between the wind sea and the swell. To improve existing prediction capabilities, we propose a novel formulation for the wave steepness in crossing seas, which includes nonlinear effects up to the second order and accounts for the spectral parameters of the interacting wave systems.
Safety and efficacy of electrical stimulation for lower-extremity muscle weakness in intensive care unit 2019 Novel Coronavirus patients: A phase I double-blinded randomized controlled trial
Authors: Zulbaran-Rojas Alejandro , Mishra Ramkinker , Rodriguez Naima , Bara Rasha O. , Lee Myeounggon , Bagheri Amir Behzad , Herlihy James P. , Siddique Muhammad , Najafi Bijan
Published: December 2022

Background

Intensive care unit (ICU) prolonged immobilization may lead to lower-extremity muscle deconditioning among critically ill patients, particularly more accentuated in those with 2019 Novel Coronavirus (COVID-19) infection. Electrical stimulation (E-Stim) is known to improve musculoskeletal outcomes. This phase I double-blinded randomized controlled trial examined the safety and efficacy of lower-extremity E-Stim to prevent muscle deconditioning.

Methods

Critically ill COVID-19 patients admitted to the ICU were randomly assigned to control (CG) or intervention (IG) groups. Both groups received daily E-Stim (1 h) for up to 14 days on both gastrocnemius muscles (GNMs). The device was functional in the IG and non-functional in the CG. Primary outcomes included ankle strength (Ankles) measured by an ankle-dynamometer, and GNM endurance (GNMe) in response to E-Stim assessed with surface electromyography (sEMG). Outcomes were measured at baseline, 3 and 9 days.

Results

Thirty-two (IG = 16, CG = 16) lower extremities in 16 patients were independently assessed. The mean time between ICU admission and E-Stim therapy delivery was 1.8 ± 1.9 days (p = 0.29). At 3 days, the IG showed an improvement compared to the CG with medium effect sizes for Ankles (p = 0.06, Cohen’s d = 0.77) and GNMe (p = 0.06, d = 0.69). At 9 days, the IG GNMe was significantly higher than the CG (p = 0.04, d = 0.97) with a 6.3% improvement from baseline (p = 0.029). E-Stim did not alter vital signs (i.e., heart/respiratory rate, blood saturation of oxygen), showed no adverse events (i.e., pain, skin damage, discomfort), nor interfere with ICU standard of care procedures (i.e., mechanical ventilation, prone rotation).

Conclusion

This study supports the safety and efficacy of early E-Stim therapy to potentially prevent deterioration of lower-extremity muscle conditions in critically ill COVID-19 patients recently admitted to the ICU. If confirmed in a larger sample, E-Stim may be used as a practical adjunctive therapy.

Clinical trial registration

[https://clinicaltrials.gov/], identifier [NCT04685213].
Acute thrombocytopenia induced by trastuzumab due to complement reaction: A case report
Authors: Chen Guoping , Ou Jianghua , Liu Jun , Liao Haoran , Ding Linwei , Fan Pingming , Du Guankui
Published: December 2022

Background

The usual treatment option for HER2 breast cancer is targeted therapy with trastuzumab. The common adverse effects of trastuzumab treatment are thrombocytopenia, however, acute thrombocytopenia is rare and its mechanism is still largely unknown.

Case presentation

We reported a patient who presented with acute thrombocytopenia on two consecutive occasions, and the predisposing factor was identified on the second occasion because of trastuzumab-only treatment. Routine blood results showed a dramatic increase in white blood cell count and neutrophil count after both trastuzumab treatments. Moreover, the complement reaction results suggested that the dramatic thrombocytopenia was probably due to platelet destruction after complement activation.

Conclusion

This case suggests that it would be useful to perform a platelet complement reaction test before trastuzumab treatment in patients with HER2 breast cancer.
Identification of antibodies cross-reactive with woodchuck immune cells and activation of virus-specific and global cytotoxic T cell responses by anti-PD-1 and anti-PD-L1 in experimental chronic hepatitis B and persistent occult hepadnaviral infection
Authors: Corkum Christopher P. , Wiede Louisa L. , Ruble Cara L.-A. , Qiu Jiabin , Mulrooney-Cousins Patricia M. , Steeves Meredith A. , Watson David E. , Michalak Tomasz I.
Published: December 2022

Woodchuck (Marmota monax) infected with woodchuck hepatitis virus (WHV) is the most pathogenically compatible naturally occurring model of human hepatitis B virus (HBV) infection, chronic hepatitis B, and HBV-induced hepatocellular carcinoma. This system plays a crucial role in discovery and preclinical evaluation of anti-HBV therapies. Its utilization remains tempered by the relatively narrow range of validated immunologic and molecular tools. We evaluated commercial antibodies against immune cell phenotypic markers and T cell molecules for cross-reactivity with woodchuck antigenic equivalents. The confirmed antibodies against programed cell death protein-1 (PD-1) and its ligand (PD-L1) were examined for ex vivo ability to activate WHV-specific, global and bystander cytotoxic T cells (CTLs) in chronic hepatitis and asymptomatic infection persisting after self-resolved acute hepatitis. Examination of 65 antibodies led to identification or confirmation of 23 recognizing woodchuck T, regulatory T, B and natural killer cells, T cell-associated PD-1, PD-L1, CTLA-4 and TIM-3 molecules, CD25 and CD69 markers of T cell activation, and interferon gamma (IFNγ). Antibodies against woodchuck PD-1 and PD-L1 triggered in vitro highly individualized WHV-specific and global activation of CTLs in both chronic hepatitis and persistent occult infection. WHV-specific CTLs were more robustly augmented by anti-PD-1 than by anti-PD-L1 in chronic hepatitis, while global IFNγ-positive CTL response was significantly suppressed in chronic hepatitis compared to persistent occult infection. Anti-PD-1 and anti-PD-L1 also occasionally activated CTLs to specificities other than those tested suggesting their potency to trigger side effects. This was particularly apparent when T cells from chronic hepatitis were treated with anti-PD-L1. The current findings indicate that inhibition of the PD-1/PD-L1 pathway could reactivate virus-specific and global T cell responses in both chronic hepatitis and asymptomatic persistent infection. They suggest a mechanism of potential reactivation of clinically silent infection during anti-PD-1/PD-L1 treatment and indicate that this therapy may also subdue occult HBV infection.
Comparison of Aspergillus-specific antibody cut-offs for the diagnosis of aspergillosis
Authors: Hsiao Chien-Wen , Yen Tsai-Hung , Wu Yen-Ching , Chen Jun-Peng , Chen Yun-Yu , Huang Wen-Nan , Chen Yi-Hsing , Chen Yi-Ming
Published: December 2022

Background

Aspergillus diseases are frequently encountered in patients who are immunocompromised. Without a prompt diagnosis, the clinical consequences may be lethal. Aspergillus-specific antibodies have been widely used to facilitate the diagnosis of Aspergillus diseases. To date, universally standardized cut-off values have not been established. This study aimed to investigate the cut-off values of Aspergillus-specific antibodies and perform a narrative review to depict the geographic differences in the Taiwanese population.

Methods

We analyzed enrolled 118 healthy controls, 29 patients with invasive aspergillosis (IA), chronic pulmonary aspergillosis (CPA), and allergic bronchopulmonary aspergillosis (ABPA) and 99 with disease control, who were tested for Aspergillus fumigatus and Aspergillus niger-specific IgG and IgE using ImmunoCAP. 99 participants not fulfilling the diagnosis of IA, CPA, and ABPA were enrolled in the disease control group. The duration of retrieval of medical records from June 2018 to September 2021. Optimal cut-offs and association were determined using receiver operating characteristic curve (ROC) analysis.

Results

We found that patients with CPA had the highest A. fumigatus-specific IgG levels while patients with ABPA had the highest A. fumigatus-specific IgE, and A. niger-specific IgG and IgE levels. In patients with CPA and ABPA, the optimal cut-offs of A. fumigatus-specific IgG and A. niger-specific IgG levels were 41.6, 40.8, 38.1, and 69.9 mgA/l, respectively. Geographic differences in the cut-off values of A. fumigatus-specific IgG were also noted. Specifically, the levels were different in eco-climatic zones.

Conclusion

We identified the optimal cut-offs of Aspergillus-specific antibodies to facilitate a precise diagnosis of aspergillosis. The observed geographic differences of the antibody levels suggest that an eco-climatic-specific reference is needed to facilitate a prompt and accurate diagnosis of aspergillosis.
Dietary assessment of ochratoxin A in Chinese dark tea and inhibitory effects of tea polyphenols on ochratoxigenic Aspergillus niger
Authors: Zhao Yi-qiao , Jia Wen-bao , Liao Si-yu , Xiang Lin , Chen Wei , Zou Yao , Zhu Ming-Zhi , Xu Wei
Published: December 2022

In recent years, there has been an increasingly heated debate on whether Chinese dark tea is contaminated with mycotoxins and whether it poses health risks to consumers. In this study, a rapid method based on high-performance liquid chromatography was used to detect ochratoxin A (OTA) in Chinese dark tea samples from different regions of China and different years. Of the 228 Chinese dark tea samples tested, 21 were detected for OTA contamination, with a concentration ranging from 2.51 ± 0.16 to 12.62 ± 0.72 μg/kg. Subsequently, a dark tea drinking risk assessment was conducted, and the hazard quotient for each group was far below the acceptable level of 1.0. Of the 12 Aspergillus spp. strains isolated, one strain of Aspergillus niger had the ability to produce OTA. We also found that tea polyphenols and epigallocatechin gallate inhibited the growth of ochratoxin-producing Aspergillus niger and the expression of non-ribosomal peptide synthetase (NRPS), a key gene for ochratoxin synthesis. Thus, OTA contamination of dark tea is at an acceptable risk level, and the inhibition of ochratoxigenic Aspergillus niger by polyphenols provides new insights into the safety of dark tea consumption.
Why vary what’s working? Phase variation and biofilm formation in Francisella tularensis
Authors: Mlynek Kevin D. , Bozue Joel A.
Published: December 2022

The notoriety of high-consequence human pathogens has increased in recent years and, rightfully, research efforts have focused on understanding host-pathogen interactions.Francisella tularensishas been detected in an impressively broad range of vertebrate hosts as well as numerous arthropod vectors and single-celled organisms. Two clinically important subspecies,F. tularensissubsp.tularensis(Type A) andF. tularensissubsp.holarctica(Type B), are responsible for the majority of tularemia cases in humans. The success of this bacterium in mammalian hosts can be at least partly attributed to a unique LPS molecule that allows the bacterium to avoid detection by the host immune system. Curiously, phase variation of the O-antigen incorporated into LPS has been documented in these subspecies ofF. tularensis,and these variants often display some level of attenuation in infection models. While the role of phase variation inF. tularensisbiology is unclear, it has been suggested that this phenomenon can aid in environmental survival and persistence. Biofilms have been established as the predominant lifestyle of many bacteria in the environment, though, it was previously thought that Type A and B isolates ofF. tularensistypically form poor biofilms. Recent studies question this ideology as it was shown that alteration of the O-antigen allows robust biofilm formation in both Type A and B isolates. This review aims to explore the link between phase variation of the O-antigen, biofilm formation, and environmental persistence with an emphasis on clinically relevant subspecies and how understanding these poorly studied mechanisms could lead to new medical countermeasures to combat tularemia.
Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics
Authors: Chrienova Zofia , Rysanek David , Oleksak Patrik , Stary Dorota , Bajda Marek , Reinis Milan , Mikyskova Romana , Novotny Ondrej , Andrys Rudolf , Skarka Adam , Vasicova Pavla , Novak Josef , Valis Martin , Kuca Kamil , Hodny Zdenek , Nepovimova Eugenie
Published: December 2022

To date, the most studied drug in anti-aging research is the mTOR inhibitor – rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation – inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.
Instability of non-REM sleep in older women evaluated by sleep-stage transition and envelope analyses
Authors: Park Insung , Kokudo Chihiro , Seol Jaehoon , Ishihara Asuka , Zhang Simeng , Uchizawa Akiko , Osumi Haruka , Miyamoto Ryusuke , Horie Kazumasa , Suzuki Chihiro , Suzuki Yoko , Okura Tomohiro , Diaz Javier , Vogt Kaspar E. , Tokuyama Kumpei
Published: December 2022

Study objective

Traditionally, age-related deterioration of sleep architecture in older individuals has been evaluated by visual scoring of polysomnographic (PSG) recordings with regard to total sleep time and latencies. In the present study, we additionally compared the non-REM sleep (NREM) stage and delta, theta, alpha, and sigma wave stability between young and older subjects to extract features that may explain age-related changes in sleep.

Methods

Polysomnographic recordings were performed in 11 healthy older (72.6 ± 2.4 years) and 9 healthy young (23.3 ± 1.1 years) females. In addition to total sleep time, the sleep stage, delta power amplitude, and delta, theta, alpha, and sigma wave stability were evaluated by sleep stage transition analysis and a novel computational method based on a coefficient of variation of the envelope (CVE) analysis, respectively.

Results

In older subjects, total sleep time and slow-wave sleep (SWS) time were shorter whereas wake after sleep onset was longer. The number of SWS episodes was similar between age groups, however, sleep stage transition analysis revealed that SWS was less stable in older individuals. NREM sleep stages in descending order of delta power were: SWS, N2, and N1, and delta power during NREM sleep in older subjects was lower than in young subjects. The CVE of the delta-band is an index of delta wave stability and showed significant differences between age groups. When separately analyzed for each NREM stage, different CVE clusters in NREM were clearly observed between young and older subjects. A lower delta CVE and amplitude were also observed in older subjects compared with young subjects in N2 and SWS. Additionally, lower CVE values in the theta, alpha and sigma bands were also characteristic of older participants.

Conclusion

The present study shows a decrease of SWS stability in older subjects together with a decrease in delta wave amplitude. Interestingly, the decrease in SWS stability coincided with an increase in short-term delta, theta, sigma, and alpha power stability revealed by lower CVE. Loss of electroencephalograms (EEG) variability might be a useful marker of brain age.
A mutation operator self-adaptive differential evolution particle swarm optimization algorithm for USV navigation
Authors: Gong Yuehong , Zhang Shaojun , Luo Min , Ma Sainan
Published: December 2022

To keep the global search capability and robustness for unmanned surface vessel (USV) path planning, an improved differential evolution particle swarm optimization algorithm (DePSO) is proposed in this paper. In the optimization process, approach to optimal value in particle swarm optimization algorithm (PSO) and mutation, hybridization, selection operation in differential evolution algorithm (DE) are combined, and the mutation factor is self-adjusted. First, the particle population is initialized and the optimization objective is determined, the individual and global optimal values are updated. Then differential variation is conducted to produces new variables and cross over with the current individual, the scaling factor is adjusted adaptively with the number of iterations in the mutation process, particle population is updated according to the hybridization results. Finally, the convergence of the algorithm is determined according to the decision standard. Numerical simulation results show that, compared with conventional PSO and DE, the proposed algorithm can effectively reduce the path intersection points, and thus greatly shorten the overall path length.