bluuebunny/crossref_metadata_2025 huggingface dataset:
Condensation transition in large deviations of self-similar Gaussian processes with stochastic resetting
Authors: Smith Naftali R , Majumdar Satya N
Published: June 2022

We study the fluctuations of the areaA(t)=∫0tx(τ)dτunder a self-similar Gaussian processx(τ) with Hurst exponentH> 0 (e.g., standard or fractional Brownian motion, or the random acceleration process) that stochastically resets to the origin at rater. Typical fluctuations ofA(t) scale as∼tfor largetand on this scale the distribution is Gaussian, as one would expect from the central limit theorem. Here our main focus is on atypically large fluctuations ofA(t). In the long-time limitt→ ∞, we find that the full distribution of the area takes the formPrA|t∼exp−tαΦA/tβwith anomalous exponentsα= 1/(2H+ 2) andβ= (2H+ 3)/(4H+ 4) in the regime of moderately large fluctuations, and a different anomalous scaling formPrA|t∼exp−tΨA/t2H+3/2in the regime of very large fluctuations. The associated rate functions Φ(y) and Ψ(w) depend onHand are found exactly. Remarkably, Φ(y) has a singularity that we interpret as a first-order dynamical condensation transition, while Ψ(w) exhibits a second-order dynamical phase transition above which the number of resetting events ceases to be extensive. The parabolic behavior of Φ(y) around the originy= 0 correctly describes the typical, Gaussian fluctuations ofA(t). Despite these anomalous scalings, we find that all of the cumulants of the distributionPrA|tgrow linearly in time,⟨An⟩c≈cnt, in the long-time limit. For the case of reset Brownian motion (corresponding toH= 1/2), we develop a recursive scheme to calculate the coefficientscnexactly and use it to calculate the first six nonvanishing cumulants.
Activation of water in the downstream of low-pressure ammonia plasma discharge
Authors: Rathore Vikas , Desai Vyom , Jamnapara Nirav I. , Nema Sudhir Kumar
Published: June 2022

In the present work, we study the physicochemical changes that arise in water named plasma processed water (PPW) when it is exposed to the downstream low-pressure discharge of ammonia (NH3) gas. Optical emission spectroscopy and voltage-current characteristics of NH3 plasma are studied to identify species formed in NH3 plasma along with plasma characterization. A three-way full factorial design of experiment is performed to study the effect of process parameters named applied voltage, post-discharge gas-water interaction time, and NH3 gas pressure on physicochemical properties of PPW. The obtained results are analyzed using analysis of variance, standardized effect estimation, regression analysis, and response surfaces. The optimum values of these properties and PPW process parameters are estimated using MATLAB fmincon solver with experimental constraints. The emission spectrum of NH3 plasma showed strong intensity N2
+ lines along with weak intensity N2, NH, and N+ lines. The obtained results showed the post-discharge gas-water interaction time and applied voltage had a significant impact on physicochemical properties and ammonium ions concentration in PPW. The obtained optimum value of voltage and time is 550 V and 15 min with given experimental constraints.
Development of a T cell-redirecting bispecific antibody targeting B-cell maturation antigen for the suppression of multiple myeloma cell growth
Authors: Huo Jianxin , Huang Yuhan , Zheng Ziying , Tay Xin Ni , Mahfut Farouq Bin , Zhang Wei , Lam Kong-Peng , Yang Yuansheng , Xu Shengli
Published: June 2022

Background

Multiple myeloma (MM) is the second most common hematological malignancy. It has emerged as one of the next possible hematological diseases amenable to immunotherapy. B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is highly expressed in MM cells and is one target with the most potential for developing MM-targeting immunotherapy. Other than the FDA-approved BCMA-targeting CAR T-cell therapy, such as Abecma and CARVYKTI, T cell-engaging multi-specific antibody is another promising therapeutic modality for BCMA-targeting MM treatment. We develop a T-cell redirecting BCMA-targeting bispecific antibody (bsAb) and evaluate its anti-MM activity.

Methods

We first generated several clones of mouse anti-human BCMA monoclonal antibodies using DNA immunization. One of the anti-BCMA antibodies was then used to design and produce a T cell-redirecting BCMA × CD3 bsAb in CHO cells. Finally, we examined the effect of the bsAb on MM cell growth both in vitro and in vivo.

Results

The BCMA × CD3 bsAb was designed in a FabscFv format and produced in CHO cells with good yield and purity. Moreover, the bsAb can trigger robust T cell proliferation and activation and induce efficient T cell-mediated MM cell killing in vitro. Using a MM xenograft mouse model, we demonstrate that the bsAb can effectively suppress MM cell growth in vivo.

Conclusions

Our results suggest that the BCMA × CD3 bsAb in the FabscFv format can efficiently inhibit MM cell growth and have promising potential to be developed into a therapeutic antibody drug for the treatment of MM.
idenMD-NRF: a ranking framework for miRNA-disease association identification
Authors: Zhang Wenxiang , Wei Hang , Liu Bin
Published: June 2022

Identifying miRNA-disease associations is an important task for revealing pathogenic mechanism of complicated diseases. Different computational methods have been proposed. Although these methods obtained encouraging performance for detecting missing associations between known miRNAs and diseases, how to accurately predict associated diseases for new miRNAs is still a difficult task. In this regard, a ranking framework named idenMD-NRF is proposed for miRNA-disease association identification. idenMD-NRF treats the miRNA-disease association identification as an information retrieval task. Given a novel query miRNA, idenMD-NRF employs Learning to Rank algorithm to rank associated diseases based on high-level association features and various predictors. The experimental results on two independent test datasets indicate that idenMD-NRF is superior to other compared predictors. A user-friendly web server of idenMD-NRF predictor is freely available at http://bliulab.net/idenMD-NRF/.
DSEATM: drug set enrichment analysis uncovering disease mechanisms by biomedical text mining
Authors: Luo Zhi-Hui , Zhu Li-Da , Wang Ya-Min , Hu Qian Sheng , Li Menglu , Zhang Wen , Chen Zhen-Xia
Published: June 2022

Disease pathogenesis is always a major topic in biomedical research. With the exponential growth of biomedical information, drug effect analysis for specific phenotypes has shown great promise in uncovering disease-associated pathways. However, this method has only been applied to a limited number of drugs. Here, we extracted the data of 4634 diseases, 3671 drugs, 112 809 disease–drug associations and 81 527 drug–gene associations by text mining of 29 168 919 publications. On this basis, we proposed a ‘Drug Set Enrichment Analysis by Text Mining (DSEATM)’ pipeline and applied it to 3250 diseases, which outperformed the state-of-the-art method. Furthermore, diseases pathways enriched by DSEATM were similar to those obtained using the TCGA cancer RNA-seq differentially expressed genes. In addition, the drug number, which showed a remarkable positive correlation of 0.73 with the AUC, plays a determining role in the performance of DSEATM. Taken together, DSEATM is an auspicious and accurate disease research tool that offers fresh insights.
Research progress and application prospects of stable porcine pluripotent stem cells
Authors: Zhang Jinying , Zhi Minglei , Gao Dengfeng , Zhu Qianqian , Gao Jie , Zhu Gaoxiang , Cao Suying , Han Jianyong
Published: June 2022

Pluripotent stem cells (PSCs) harbor the capacity of unlimited self-renewal and multilineage differentiation potential, which are crucial for basic research and biomedical science. Establishment of PSCs with defined features was previously reported from mice and humans, while generation of stable large animal PSCs has experienced a relatively long trial stage and only recently has made breakthroughs. Pigs are regarded as ideal animal models for their similarities in physiology and anatomy to humans. Generation of porcine PSCs would provide cell resources for basic research, genetic engineering, animal breeding, and cultured meat. In this review, we summarize the progress on the derivation of porcine PSCs and reprogramed cells and elucidate the mechanisms of pluripotency changes during pig embryo development. This will be beneficial for understanding the divergence and conservation between different species involved in embryo development and the pluripotent-regulated signaling pathways. Finally, we also discuss the promising future applications of stable porcine PSCs. Even though challenges remain in the field of porcine stem cells, these progress and viewpoints would provide guidance in future research direction.
Validating visual evoked potentials as a preclinical, quantitative biomarker for remyelination efficacy
Authors: Cordano Christian , Sin Jung H , Timmons Garrett , Yiu Hao H , Stebbins Karin , Guglielmetti Caroline , Cruz-Herranz Andres , Xin Wendy , Lorrain Daniel , Chan Jonah R , Green Ari J
Published: June 2022

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease—and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.
Protocol for multicentre comparison of interictal high-frequency oscillations as a predictor of seizure freedom
Authors: Dimakopoulos Vasileios , Gotman Jean , Stacey William , von Ellenrieder Nicolás , Jacobs Julia , Papadelis Christos , Cimbalnik Jan , Worrell Gregory , Sperling Michael R , Zijlmans Maike , Imbach Lucas , Frauscher Birgit , Sarnthein Johannes
Published: June 2022

In drug-resistant focal epilepsy, interictal high-frequency oscillations (HFOs) recorded from intracranial EEG (iEEG) may provide clinical information for delineating epileptogenic brain tissue. The iEEG electrode contacts that contain HFO are hypothesized to delineate the epileptogenic zone; their resection should then lead to postsurgical seizure freedom. We test whether our prospective definition of clinically relevant HFO is in agreement with postsurgical seizure outcome. The algorithm is fully automated and is equally applied to all data sets. The aim is to assess the reliability of the proposed detector and analysis approach.

We use an automated data-independent prospective definition of clinically relevant HFO that has been validated in data from two independent epilepsy centres. In this study, we combine retrospectively collected data sets from nine independent epilepsy centres. The analysis is blinded to clinical outcome. We use iEEG recordings during NREM sleep with a minimum of 12 epochs of 5 min of NREM sleep. We automatically detect HFO in the ripple (80–250 Hz) and in the fast ripple (250–500 Hz) band. There is no manual rejection of events in this fully automated algorithm. The type of HFO that we consider clinically relevant is defined as the simultaneous occurrence of a fast ripple and a ripple. We calculate the temporal consistency of each patient’s HFO rates over several data epochs within and between nights. Patients with temporal consistency <50% are excluded from further analysis. We determine whether all electrode contacts with high HFO rate are included in the resection volume and whether seizure freedom (ILAE 1) was achieved at ≥2 years follow-up. Applying a previously validated algorithm to a large cohort from several independent epilepsy centres may advance the clinical relevance and the generalizability of HFO analysis as essential next step for use of HFO in clinical practice.
Faecal Metabolomics in Paediatric Inflammatory Bowel Disease: A Systematic Review
Authors: Jagt Jasmijn Z , Verburgt Charlotte M , de Vries Ralph , de Boer Nanne K H , Benninga Marc A , de Jonge Wouter J , van Limbergen Johan E , de Meij Tim G J
Published: June 2022

Background and Aims

Paediatric inflammatory bowel disease [IBD] is characterized by altered immunological and metabolic pathways. Metabolomics may therefore increase pathophysiological understanding and could develop into characterization of biomarkers for diagnosis and IBD treatment response. However, no uniform metabolomic profiles have been identified to date. This systematic review aimed to identify faecal metabolomic signatures in paediatric IBD vs controls, and to describe metabolites associated with disease activity and treatment response.

Methods

A literature search was performed in Embase, Medline, Web of Science and Cochrane Library. Studies assessing faecal metabolomics in paediatric patients < 18 years with IBD [de novo, active, inactive] with comparative groups [IBD vs non-IBD; responders vs non-responders] were included. The quality of included studies was assessed according to the Newcastle–Ottawa Scale.

Results

Nineteen studies were included [540 patients with IBD, 386 controls], assessing faecal short-chain fatty acids [SCFA] [five studies], amino acids [AA] [ten studies], bile acids [BA] [eight studies] and other metabolites [nine studies] using various methodologies. Significantly increased levels of AA [particularly phenylalanine], primary BA and lower levels of secondary BA were described in paediatric IBD compared to controls. Faecal SCFA results varied across studies. Additionally, responders and non-responders to exclusive enteral nutrition and infliximab showed differences in baseline faecal metabolites [based on BA, AA].

Conclusions

This systematic review provides evidence for distinct faecal metabolomic profiles in paediatric IBD. However, results varied across studies, possibly due to differences in study design and applied analytical techniques. Faecal metabolomics could provide more insight into host–microbial interactions in IBD, but further studies with standardized methodologies and reporting are needed.
Radial artery versus saphenous vein versus right internal thoracic artery for coronary artery bypass grafting
Authors: Gaudino Mario , Audisio Katia , Di Franco Antonino , Alexander John H , Kurlansky Paul , Boening Andreas , Chikwe Joanna , Devereaux P J , Diegeler Anno , Dimagli Arnaldo , Flather Marcus , Lamy Andre , Lawton Jennifer S , Tam Derrick Y , Reents Wilko , Rahouma Mohamed , Girardi Leonard N , Hare David L , Fremes Stephen E , Benedetto Umberto
Published: June 2022

OBJECTIVES

We used individual patient data from 4 of the largest contemporary coronary bypass surgery trials to evaluate differences in long-term outcomes when radial artery (RA), right internal thoracic artery (RITA) or saphenous vein graft (SVG) are used to complement the left internal thoracic artery-to-left anterior descending graft.

METHODS

Primary outcome was all-cause mortality. Secondary outcome was a composite of major adverse cardiac and cerebrovascular events (all-cause mortality, myocardial infarction and stroke). Propensity score matching and Cox regression were used to reduce the effect of treatment selection bias and confounders.

RESULTS

A total of 10 256 patients (1510 RITA; 1385 RA; 7361 SVG) were included. The matched population consisted of 1776 propensity score-matched triplets. The mean follow-up was 7.9 ± 0.1, 7.8 ± 0.1 and 7.8 ± 0.1 years in the RITA, RA and SVG cohorts respectively. All-cause mortality was significantly lower in the RA versus the SVG [hazard ratio (HR) 0.62, 95% confidence interval (CI): 0.51–0.76, P = 0.003] and the RITA group (HR 0.59, 95% CI 0.48–0.71, P = 0.001). Major adverse cardiac and cerebrovascular event rate was also lower in the RA group versus the SVG (HR 0.78, 95% CI 0.67–0.90, P = 0.04) and the RITA group (HR 0.75, 95% CI 0.65–0.86, P = 0.02). Results were consistent in the Cox-adjusted analysis and solid to hidden confounders.

CONCLUSIONS

In this pooled analysis of 4 large coronary bypass surgery trials, the use of the RA was associated with better clinical outcomes when compared to SVG and RITA.
Simultaneously Developing Interventions for Low-/Middle-Income and High-Income Settings: Considerations and Opportunities
Authors: Baker Zachary G , Nkimbeng Manka , Cuevas Pearl Ed G , Quiñones Ana R , Kaur Kang Harmeet , Gaugler Joseph E , Hinton Ladson , Gitlin Laura N , Shippee Tetyana P
Published: June 2022

Most older adults reside in low- and middle-income countries (LMICs) but most research dollars spent on interventions to improve the lives of older adults are awarded to researchers in high-income countries (HICs). One approach to improve the implementation of evidence-based innovations for older adults in LMICs is designing interventions that are relevant to LMICs and HICs simultaneously. We propose that researchers in HICs could partner with stakeholders in an LMIC throughout the intervention design process to better position their intervention for the implementation in that LMIC. We provide an example study from an adaptation of the Resources for Enhancing Caregiver Health II in Vietnam, which did not use this strategy but may have benefited from this strategy. We then turn to several considerations that are important for researchers to contemplate when incorporating this strategy. Finally, we explore incentives for creating interventions that are relevant to both HICs and LMICs for funders, intervention designers, and intervention receivers. Although this is not the only strategy to bring interventions to LMICs, it may represent another tool in researchers’ toolboxes to help expedite the implementation of efficacious interventions in LMICs.
The reconstructability of persuasive message variables affects the variability of experimental effect sizes: evidence and implications
Authors: Hoeken Hans , O’Keefe Daniel J
Published: June 2022

Whereas the persuasive impact of message variables such as weaker versus stronger threat appeals, vivid versus pallid messages, and one-sided versus two-sided messages has received much research attention, more abstract properties of such message variables have gone largely unexamined. This article reports an analysis of one such property, reconstructability: the degree to which one of the two messages in an experimental pair can be deduced from the other. Evidence is offered from research on persuasive communication that as message variables become less reconstructable, the variability of the associated effect sizes increases—which creates distinctive challenges for theoretical progress and practical message design. Attention to message-variable properties such as reconstructability promises to shed light on how and why effects differ across message variables.
Mudskippers Modulate their Locomotor Kinematics when Moving on Deformable and Inclined Substrates
Authors: Naylor Emily R , Kawano Sandy M
Published: June 2022

Synopsis

Many ecological factors influence animal movement, including properties of the media that they move on or through. Animals moving in terrestrial environments encounter conditions that can be challenging for generating propulsion and maintaining stability, such as inclines and deformable substrates that can cause slipping and sinking. In response, tetrapods tend to adopt a more crouched posture and lower their center of mass on inclines and increase the surface area of contact on deformable substrates, such as sand. Many amphibious fishes encounter the same challenges when moving on land, but how these finned animals modulate their locomotion with respect to different environmental conditions and how these modifications compare with those seen within tetrapods is relatively understudied. Mudskippers (Gobiidae: Oxudercinae) are a particularly noteworthy group of amphibious fishes in this context given that they navigate a wide range of environmental conditions, from flat mud to inclined mangrove trees. They use a unique form of terrestrial locomotion called “crutching,” where their pectoral fins synchronously lift and vault the front half of the body forward before landing on their pelvic fins, while the lower half of the body and tail are kept straight. However, recent work has shown that mudskippers modify some aspects of their locomotion when crutching on deformable surfaces, particularly those at an incline. For example, on inclined dry sand, mudskippers bent their bodies laterally and curled and extended their tails to potentially act as a secondary propulsor and/or anti-slip device. In order to gain a more comprehensive understanding of the functional diversity and context-dependency of mudskipper crutching, we compared their kinematics on different combinations of substrate types (solid, mud, and dry sand) and inclines (0°, 10°, and 20°). In addition to increasing lateral bending on deformable and inclined substrates, we found that mudskippers increased the relative contact time and contact area of their paired fins, while becoming more crouched, which are responses comparable to those seen in tetrapods and other amphibious fish. Mudskippers on these substrates also exhibited previously undocumented behaviors, such as extending and adpressing the distal portions of their pectoral fins more anteriorly, dorsoventrally bending their trunk, “belly-flopping” on sand, and “gripping” the mud substrate with their pectoral fin rays. Our study highlights potential compensatory mechanisms shared among vertebrates in terrestrial environments while also illustrating that locomotor flexibility and even novelty can emerge when animals are challenged with environmental variation.
Sample size calculators for planning stepped-wedge cluster randomized trials: a review and comparison
Authors: Ouyang Yongdong , Li Fan , Preisser John S , Taljaard Monica
Published: June 2022

Recent years have seen a surge of interest in stepped-wedge cluster randomized trials (SW-CRTs). SW-CRTs include several design variations and methodology is rapidly developing. Accordingly, a variety of power and sample size calculation software for SW-CRTs has been developed. However, each calculator may support only a selected set of design features and may not be appropriate for all scenarios. Currently, there is no resource to assist researchers in selecting the most appropriate calculator for planning their trials. In this paper, we review and classify 18 existing calculators that can be implemented in major platforms, such as R, SAS, Stata, Microsoft Excel, PASS and nQuery. After reviewing the main sample size considerations for SW-CRTs, we summarize the features supported by the available calculators, including the types of designs, outcomes, correlation structures and treatment effects; whether incomplete designs, cluster-size variation or secular trends are accommodated; and the analytical approach used. We then discuss in more detail four main calculators and identify their strengths and limitations. We illustrate how to use these four calculators to compute power for two real SW-CRTs with a continuous and binary outcome and compare the results. We show that the choice of calculator can make a substantial difference in the calculated power and explain these differences. Finally, we make recommendations for implementing sample size or power calculations using the available calculators. An R Shiny app is available for users to select the calculator that meets their requirements (https://douyang.shinyapps.io/swcrtcalculator/).
Phosphorylation of GluA1-Ser831 by CaMKII Activation in the Caudate and Putamen Is Required for Behavioral Sensitization After Challenge Nicotine in Rats
Authors: Kim Sunghyun , Sohn Sumin , Choe Eun Sang
Published: June 2022

Background

Phosphorylation of the glutamate receptor (GluA1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plays a crucial role in behavioral sensitization after exposure to psychostimulants. The present study determined the potential role of serine 831 (Ser831) phosphorylation in the GluA1 subunit of the caudate and putamen (CPu) in behavioral sensitization after challenge nicotine.

Methods

Challenge nicotine (0.4 mg/kg) was administered subcutaneously (s.c.) after 7 days of repeated exposure to nicotine (0.4 mg/kg, s.c.) followed by 3 days of withdrawal in rats. Bilateral intra-CPu infusions of drugs were mainly performed to test this hypothesis.

Results

Challenge nicotine increased both phosphorylated (p)Ser831 immunoreactivity (IR) and pCa2+/calmodulin-dependentprotein kinases II (pCaMKII)-IR in the medium spiny neurons (MSNs) of the CPu. These increases were prevented by bilateral intra-CPu infusion of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (0.5 nmol/side) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (2 nmol/side). However, the dopamine D1 receptor (D1R) antagonist SCH23390 (7.5 nmol/side) prevented only pSer831-IR alone. Bilateral intra-CPu infusion of the Tat-GluA1D peptide (25 pmol/side), which interferes with the binding of pCaMKII to GluA1-Ser831, decreased the challenge nicotine–induced increase in locomotor activity.

Conclusions

These findings suggest that the GluA1-Ser831 phosphorylation in the MSNs of the CPu is required for the challenge nicotine–induced behavioral sensitization in rats. CaMKII activation linked to mGluR5 and NMDA receptors, but not to D1R, is essential for inducing the CaMKII-Ser831 interaction.
Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis
Authors: Gausi Kamunkhwala , Chirehwa Maxwell , Ignatius Elisa H , Court Richard , Sun Xin , Moran Laura , Hafner Richard , Wiesner Lubbe , Rosenkranz Susan L , de Jager Veronique , de Vries Nihal , Harding Joseph , Gumbo Tawanda , Swindells Susan , Diacon Andreas , Dooley Kelly E , McIlleron Helen , Denti Paolo
Published: June 2022

Background

The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described.

Objectives

To characterize isoniazid pharmacokinetics at 5–15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen.

Methods

We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid.

Results

A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC.

Conclusions

Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.
Civil-Resistance Videography as Human Rights Practice: The Non-Survivor Testimony and the Striving for Criminal Jurisdiction in Syria and Beyond
Authors: Meis Mareike
Published: June 2022

This paper brings together the legal discourse on user-generated evidence and a media-cultural study focus to explore videography in conflict contexts as human rights practice. Through examples of civilians and activists who have recorded, documented, and shared atrocities and human rights violations during the Syrian conflict with the help of mobile and social media, the conceptional challenges arising from this human rights practice are explored to further the understanding of witnessing and testimony in the presence of mobile and social media. While Syrians engage in the life-threatening endeavour of recording atrocities and human rights violations to bring justice to perpetrators and victims alike, their video clips contain often only little probative value in juridical terms. Still, current human rights initiatives exist that aim to introduce such user-generated evidence into international criminal proceedings with the support of witnessing apps. To understand the material-semiotic practices that underlie such initiatives, civil-resistance videography is introduced as connected to a broader debate on eye-witnessing, testifying, and providing legal evidence of atrocities and human rights violations that links back to the Eichmann trial and the advent of the survivor witness in criminal proceedings. Applying an analytical approach that combines the feminist understanding of diffraction, interference, figuration, and ethnography, the survivor witness is read as a testimonial figure that interferes with the emerging figure of the non-survivor witness in the context of civil-resistance videography. This interference brings forward the figuration of the non-survivor testimony that requires a conceptional rethinking in the legal and socio-political discourse on user-generated evidence.
Large bilateral corneal ulcers caused by debromoaplysiatoxin from the blue-green alga Lyngbya majuscula in a fisherman
Authors: Ducrot Yves-Marie , Nicolas Maël , Payri Claude , Bertolotti Antoine
Published: June 2022

Toxic seaweed dermatitis is caused by toxins of the marine cyanobacterium Lyngbya majuscula after sea bathing in some tropical area. This rarely described irritant dermatitis results in papular and bullous lesions, mainly in the genital area but severe ocular lesions can occur.
Elucidating the lactic acid tolerance mechanism in vaginal clinical isolates of Candida glabrata
Authors: Gupta Payal , Gupta Hrishikesh , Kairamkonda Manikyaprabhu , Kumar Navin , Poluri Krishna Mohan
Published: June 2022

Incidence of vulvovaginal candidiasis are strikingly high and treatment options are limited with nearly 50% Candida glabrata cases left untreated or experience treatment failures. The vaginal microenvironment is rich in lactic acid (LA), and the adaptation of C. glabrata to LA is the main reason for clinical treatment failure. In the present study, C. glabrata and its vaginal clinical isolates were comprehensively investigated for their growth response, metabolic adaptation and altered cellular pathway to LA using different biochemical techniques, metabolic profiling and transcriptional studies. Candida glabrata shown considerable variations in its topological and biochemical features without compromizing growth in LA media. Chemical profiling data highlighted involvement of cell wall/membrane, ergosterol and oxidative stress related pathways in mediating adaptative response of C. glabrata towards LA. Furthermore, one dimensional proton (1H) NMR spectroscopy based metabolic profiling revealed significant modulation in 19 metabolites of C. glabrata cells upon growth in LA. Interestingly myo-inositol, xylose, putrescine, and betaine which are key metabolites for cell growth and viability were found to be differentially expressed by clinical isolates. These observations were supported by the transcriptional expression study of selected genes evidencing cell wall/membrane re-organization, altered oxidative stress, and reprogramming of carbon metabolic pathways. Collectively, the study advances our understanding on adaptative response of C. glabrata in vaginal microenvironment to LA for survival and virulence.

Lay Summary

In vaginal tract, LA present as a natural carbon source is a potentiating factor for vulvovaginal candidiasis caused by C. glabrata is highest. The present article delineates the lactic acid adaptation in vaginal clinical isolates of C. glabrata using a comprehensive approach of biochemical, metabolic, and transcriptional studies.
The massive system V375 Cassiopeia is a semidetached mass-transfer binary with a massive stellar companion
Authors: Li F-X , Qian S-B , Zhang J , Zhu L-Y , Zhao E-G , Liao W-P
Published: June 2022

V375 Cassiopeia (V375 Cas) is an early B-type close binary with an orbital period of 1.4734273 d. Based on high-quality and continuous light curves from the Transiting Exoplanet Survey Satellite (TESS) and new low-resolution spectra, we have determined photometric solutions of the eclipsing binary using the Wilson–Devinney method. We have found that V375 Cas is a semidetached binary where the secondary component fills the critical Roche lobe. Meanwhile, its O − C diagram was constructed with the data spanning 122 yr. An upward parabolic variation is discovered to be superimposed on a cyclic modulation with a semi-amplitude of 0.0938 (±0.0143) d and a period of 118.74 (±12.87) yr. The parabolic change reveals a period increase at a rate of ${\rm d}p/{\rm d}t = +5.42 \times {10^{-7}}\, {\rm d} \,\mathrm{yr}^{-1}$. Both the semidetached configuration and the period increase suggest that V375 Cas is undergoing a late case A mass transfer from the less-massive component to the more-massive component. The cyclic change is attributed to be the effect of the light travel time via the presence of a third body. The minimum mass of the tertiary companion is estimated as M3 = 4.24 (±0.87) M⊙, which orbits around the central eclipsing binary with a nearly circular orbit (e = 0.184). It is detected that the light contribution of the third body is about 8.0 per cent, indicating that it is a massive main-sequence star. All the results reveal that V375 Cas is a hierarchical triple system where a massive main-sequence star accompanies a massive semidetached mass-transfer binary at an orbital separation of 60.3 au.
The Davis–Chandrasekhar–Fermi method revisited
Authors: Chen Che-Yu , Li Zhi-Yun , Mazzei Renato R , Park Jinsoo , Fissel Laura M , Chen Michael C-Y , Klein Richard I , Li Pak Shing
Published: June 2022

Despite the rich observational results on interstellar magnetic fields in star-forming regions, it is still unclear how dynamically significant the magnetic fields are at varying physical scales, because direct measurement of the field strength is observationally difficult. The Davis–Chandrasekhar–Fermi (DCF) method has been the most commonly used method to estimate the magnetic field strength from polarization data. It is based on the assumption that gas turbulent motion is the driving source of field distortion via linear Alfvén waves. In this work, using MHD simulations of star-forming clouds, we test the validity of the assumption underlying the DCF method by examining its accuracy in the real 3D space. Our results suggest that the DCF relation between turbulent kinetic energy and magnetic energy fluctuation should be treated as a statistical result instead of a local property. We then develop and investigate several modifications to the original DCF method using synthetic observations, and propose new recipes to improve the accuracy of DCF-derived magnetic field strength. We further note that the biggest uncertainty in the DCF analysis may come from the linewidth measurement instead of the polarization observation, especially since the line-of-sight gas velocity can be used to estimate the gas volume density, another critical parameter in the DCF method.
Unexpected solar-cycle variation of acoustic mode power in Sun-as-a-star observations
Authors: Howe Rachel , Chaplin W J , Elsworth Y P , Hale S J , Nielsen M B
Published: June 2022

We examine the solar-cycle variation of the power in the low-degree helioseismic modes by looking at binned power spectra from 45 yr of observations with the Birmingham Solar Oscillations Network, which provides a more robust estimate of the mode power than that obtained by peak fitting. The solar-cycle variation of acoustic mode power in the 5-min band is clearly seen. Unusually, even though Cycle 24 was substantially weaker in terms of surface magnetic activity than Cycle 23, the reduction in mode power at solar maximum is very similar for the two cycles, suggesting that the relationship between mode power and magnetic activity is more complex than has previously been thought. This is in contrast to the mode frequencies, which show a strong correlation with activity with only subtle differences in the response across different solar cycles.
Improving the line of sight for the anisotropic 3-point correlation function of galaxies: Centroid and Unit-Vector-Average methods scaling as 𝒪 (N2)
Authors: Garcia Karolina , Slepian Zachary
Published: June 2022

The 3-point correlation function (3PCF) is a powerful tool for the current era of high-data volume, high-precision cosmology. It goes beyond the Gaussian cosmological perturbations probed by the 2-point correlation function, including late-time non-Gaussianities, and encodes information about peculiar velocities, which distort observed positions of galaxies along the line of sight away from their true positions. To access this information, we must track the 3PCF’s dependence not only on each triangle’s shape, but also on its orientation with respect to the line of sight. Consequently, different choices for the line of sight will affect the measured 3PCF. Up to now, the line of sight has been taken as the direction to a single triplet member, but which triplet member is used impacts the 3PCF by ∼20 per cent of the statistical error for a BOSS-like survey. For DESI (5× more precise) this would translate to ∼100 per cent of the statistical error. We propose a new method that is fully symmetric between the triplet members, and uses either the average of the three galaxy position vectors, or the average of their unit vectors. We prove that these methods are equivalent to $\mathcal {O}(\theta ^2)$, where θ is the angle subtended at the observer by any triangle side. By harnessing the solid harmonic shift theorem, we show how these methods can be evaluated scaling as N2, with N the number of objects. We expect that they can be used to make a robust, systematics-free measurement of the anisotropic 3PCF of upcoming redshift surveys such as DESI.
Do radiative losses determine the characteristic emission of the blazar Mkn 421?
Authors: Baheeja C , Sahayanathan S , Rieger Frank M , Jagan Sitha K , Ravikumar C D
Published: June 2022

The radiative loss interpretation for the broken power-law spectra of blazars is often questioned since the difference between the indices does not support this inference. Using the blazar Mkn 421 as a case study, we performed a detailed analysis of its characteristic photon energy where the spectral index changes significantly. We used the observations of the source by Swift–XRT from 2008 to 2019 to identify the characteristic photon energy and the corresponding spectral indices. The spectra in the energy range 0.3–10.0 keV can be well fitted by a log parabola as well as a smooth broken power law. From the smooth broken power-law spectral fit, we show that the spectral indices before and after the characteristic photon energy are strongly anticorrelated. Further, the spectral curvature measured at the characteristic photon energy indicates an anticorrelation with the low-energy spectral index while the high-energy spectral index shows a positive correlation. These findings are at variance with a simple radiative loss interpretation for the characteristic photon energy, and alternative scenarios are thus discussed. Though these scenarios are, in principle, capable of reproducing the correlation results, they deviate significantly from the observed properties.
Hamiltonian formalism for dynamics of particles in MOG
Authors: Rahvar Sohrab
Published: June 2022

MOG as a modified gravity theory is designed to be replaced with dark matter. In this theory, in addition to the metric tensor, a massive vector is a gravity field where each particle has a charge proportional to the inertial mass and couples to the vector field through the four-velocity of a particle. In this work, we present the Hamiltonian formalism for the dynamics of particles in this theory. The advantage of Hamiltonian formalism is a better understanding and analysing the dynamics of massive and massless particles. The massive particles deviate from the geodesics of space–time and photons follow the geodesics. We also study the dynamics of particles in the Newtonian and post-Newtonian regimes for observational purposes. An important result of Hamiltonian formalism is that while lensing on large scales is compatible with the observations, however the deflection angle from stellar size lensing is larger than general relativity. This result can rule out this theory unless we introduce a screening mechanism to change the effective gravitational constant near compact objects like stars.
A deep learning approach to halo merger tree construction
Authors: Robles Sandra , Gómez Jonathan S , Ramírez Rivera Adín , Padilla Nelson D , Dujovne Diego
Published: June 2022

A key ingredient for semi-analytic models of galaxy formation is the mass assembly history of haloes, encoded in a tree structure. The most commonly used method to construct halo merger histories is based on the outcomes of high-resolution, computationally intensive N-body simulations. We show that machine learning (ML) techniques, in particular Generative Adversarial Networks (GANs), are a promising new tool to tackle this problem with a modest computational cost and retaining the best features of merger trees from simulations. We train our GAN model with a limited sample of merger trees from the Evolution and Assembly of GaLaxies and their Environments (EAGLE) simulation suite, constructed using two halo finders–tree builder algorithms: SUBFIND – D-TREES and ROCKSTAR – ConsistentTrees. Our GAN model successfully learns to generate well-constructed merger tree structures with high temporal resolution, and to reproduce the statistical features of the sample of merger trees used for training, when considering up to three variables in the training process. These inputs, whose representations are also learned by our GAN model, are mass of the halo progenitors and the final descendant, progenitor type (main halo or satellite), and distance of a progenitor to that in the main branch. The inclusion of the latter two inputs greatly improves the final learned representation of the halo mass growth history, especially for SUBFIND-like ML trees. When comparing equally sized samples of ML merger trees with those of the EAGLE simulation, we find better agreement for SUBFIND-like ML trees. Finally, our GAN-based framework can be utilized to construct merger histories of low- and intermediate-mass haloes, the most abundant in cosmological simulations.
A Transcriptomic Atlas Underlying Developmental Plasticity of Seasonal Forms of Bicyclus anynana Butterflies
Authors: Tian Shen , Monteiro Antónia
Published: June 2022

Organisms residing in regions with alternating seasons often develop different phenotypes, or forms, in each season. These forms are often adaptations to each season and result from an altered developmental response to specific environmental cues such as temperature. Although multiple studies have examined form-specific gene expression profiles in a diversity of species, little is known about how environments and developmental transitions, cued by hormone pulses, alter post-transcriptional patterns. In this study, we examine how gene expression, alternative splicing, and miRNA-mediated gene silencing in Bicyclus anynana butterfly hindwing tissue, varies across two rearing temperatures at four developmental timepoints. These timepoints flank two temperature-sensitive periods that coincide with two pulses of the insect hormone 20E. Our results suggest that developmental transitions, coincident with 20E pulses, elicit a greater impact on all these transcriptomic patterns than rearing temperatures per se. More similar transcriptomic patterns are observed pre-20E pulses than those observed post-20E pulses. We also found functionally distinct sets of differentially expressed genes (DEGs) and differentially spliced genes (DSGs) in the seasonal forms. Furthermore, around 10% of DEGs are predicted to be direct targets of, and regulated by, differentially expressed miRNAs (DEmiRs) between the seasonal forms. Many DEGs, DEmiRs, or DSGs potentially regulate eyespot size plasticity, and we validated the differential splicing pattern of one such gene, daughterless. We present a comprehensive and interactive transcriptomic atlas of the hindwing tissue of both seasonal forms of B. anynana throughout development, a model organism of seasonal plasticity.
Hierarchical palladium catalyst for highly active and stable water oxidation in acidic media
Authors: Peng Jing , Sun Haofeng , Ni Kun , Wu Jiajing , Sun Xinyu , Su Yueqi , Cheng Han , Liu Yuhua , Guo Yuqiao , Bi Wentuan , Zhu Yanwu , Wu Changzheng , Xie Yi
Published: June 2022

Acidic water electrolysis is of great importance for boosting the development of renewable energy. However, it severely suffers from the trade-off between high activity and long lifespan for oxygen evolution catalysts on the anode side. This is because the sluggish kinetics of oxygen evolution reaction necessitates the application of a high overpotential to achieve considerable current, which inevitably drives the catalysts far away from their thermodynamic equilibrium states. Here we demonstrate a new oxygen evolution model catalyst-hierarchical palladium (Pd) whose performance even surpasses the benchmark Ir- and Ru-based materials. The Pd catalyst displays an ultralow overpotential (196 mV), excellent durability and mitigated degradation (66 μV h−1) at 10 mA cm−2 in 1 M HClO4. Tensile strain on Pd (111) facets weakens the binding of oxygen species on electrochemical etching-derived hierarchical Pd and thereby leads to two orders of magnitudes of enhancement of mass activity in comparison to the parent Pd bulk materials. Furthermore, the Pd catalyst displays the bifunctional catalytic properties for both oxygen and hydrogen evolutions and can deliver a current density of 2 A cm–2 at a low cell voltage of 1.771 V when fabricated into polymer electrolyte membrane electrolyser.