bluuebunny/crossref_metadata_2025 huggingface dataset:
Printed layers height calibration curve and porosity in laser melting deposition of Ti6Al4V combining experiments, mathematical modelling and deep neural network
Authors: Mahmood Muhammad Arif , Diana Chioibasu , Sajjad Uzair , Mihai Sabin , Tiseanu Ion , Popescu Andrei C.
Published: December 2023

Purpose

Porosity is a commonly analyzed defect in the laser-based additive manufacturing processes owing to the enormous thermal gradient caused by repeated melting and solidification. Currently, the porosity estimation is limited to powder bed fusion. The porosity estimation needs to be explored in the laser melting deposition (LMD) process, particularly analytical models that provide cost- and time-effective solutions compared to finite element analysis. For this purpose, this study aims to formulate two mathematical models for deposited layer dimensions and corresponding porosity in the LMD process.

Design/methodology/approach

In this study, analytical models have been proposed. Initially, deposited layer dimensions, including layer height, width and depth, were calculated based on the operating parameters. These outputs were introduced in the second model to estimate the part porosity. The models were validated with experimental data for Ti6Al4V depositions on Ti6Al4V substrate. A calibration curve (CC) was also developed for Ti6Al4V material and characterized using X-ray computed tomography. The models were also validated with the experimental results adopted from literature. The validated models were linked with the deep neural network (DNN) for its training and testing using a total of 6,703 computations with 1,500 iterations. Here, laser power, laser scanning speed and powder feeding rate were selected inputs, whereas porosity was set as an output.

Findings

The computations indicate that owing to the simultaneous inclusion of powder particulates, the powder elements use a substantial percentage of the laser beam energy for their melting, resulting in laser beam energy attenuation and reducing thermal value at the substrate. The primary operating parameters are directly correlated with the number of layers and total height in CC. Through X-ray computed tomography analyses, the number of layers showed a straightforward correlation with mean sphericity, while a converse relation was identified with the number, mean volume and mean diameter of pores. DNN and analytical models showed 2%–3% and 7%–9% mean absolute deviations, respectively, compared to the experimental results.

Originality/value

This research provides a unique solution for LMD porosity estimation by linking the developed analytical computational models with artificial neural networking. The presented framework predicts the porosity in the LMD-ed parts efficiently.
Effect of fly ash on compressive strength, carbonation and corrosion resistance of reinforced concrete: a systematic review
Authors: Gaikwad Prathamesh , Sathe Sandeep
Published: December 2023

Purpose

The purpose of this paper is to study and analyze the effects of fly ash (FA) as a mineral admixture on compressive strength (CS), carbonation resistance and corrosion resistance of reinforced concrete (RC). In addition, the utilization of inexpensive and abundantly available FA as a cement replacement in concrete has several benefits including reduced OPC usage and elimination of the FA disposal problem.

Design/methodology/approach

Reinforcement corrosion and carbonation significantly affect the strength and durability of the RC structures. Also, the utilization of FA as green corrosion inhibitors, which are nontoxic and environmentally friendly alternatives. This review discusses the effects of FA on the mechanical characteristics of concrete. Also, this review analyzes the impact of FA as a partial replacement of cement in concrete and its effect on the depth of carbonation in concrete elements and the corrosion rate of embedded steel as well as the chemical composition and microstructure (X-ray diffraction analysis and scanning electron microscopy) of FA concrete were also reviewed.

Findings

This review provides a clear analysis of the available study, providing a thorough overview of the current state of knowledge on this topic. Regarding concrete CS, the findings indicate that the incorporation of FA often leads to a loss in early-age strength. However, as the curing period increased, the strength of fly ash concrete (FAC) increased with or even surpassed that of conventional concrete. Analysis of the accelerated carbonation test revealed that incorporating FA into the concrete mix led to a shallower carbonation depth and slower diffusion of carbon dioxide (CO2) into the concrete. Furthermore, the half-cell potential test shows that the inclusion of FA increases the durability of RC by slowing the rate of steel-reinforcement corrosion.

Originality/value

This systematic review analyzes a wide range of existing studies on the topic, providing a comprehensive overview of the research conducted so far. This review intends to critically assess the enhancements in mechanical and durability attributes (such as CS, carbonation and corrosion resistance) of FAC and FA-RC. This systematic review has practical implications for the construction and engineering industries. This can support engineers and designers in making informed decisions regarding the use of FA in concrete mixtures, considering both its benefits and potential drawbacks.
Alopecia areata: What's new in the diagnosis and treatment with JAK inhibitors?
Authors: Dainichi Teruki , Iwata Masashi , Kaku Yo
Published: December 2023

Alopecia areata (AA) affects individuals of all ages and is intractable in severe relapsing cases. Dermatologists and other healthcare providers should consider AA in the medical context and prioritize treatment. Several randomized controlled clinical studies on Janus kinase (JAK) inhibitors with different specificities for the treatment of AA are ongoing. These studies have encouraged us to appreciate the importance of a definitive diagnosis and accurate evaluation of AA before and during treatment. Following our previous review article in 2017, here we provide the second part of this two‐review series on the recent progress in the multidisciplinary approaches to AA from more than 1800 articles published between July 2016 and December 2022. This review focuses on the evaluation, diagnosis, and treatment of AA. We also provide the latest information on the safety and efficacy of JAK inhibitors for the treatment of AA and describe their mechanisms of action.
Effects of repetitive transcranial magnetic stimulation combined with music therapy in non‐fluent aphasia after stroke: A randomised controlled study
Authors: Liu Qingqing , Li Weibo , Chen Yuanwu , Zhang Shaohua , Sun Zengxin , Yang Yuhui , Lv Peiyuan , Yin Yu
Published: December 2023

Background

Although existing studies have shown that both repetitive transcranial magnetic stimulation (rTMS) and music therapy have advantages in the treatment of non‐fluent aphasia, the efficacy of the combination of these two methods remains to be investigated.

Aims

To investigate the clinical efficacy of low‐frequency rTMS combined with music therapy on language function and depression in patients with non‐fluent aphasia after stroke.

Methods & Procedures

A single‐blind parallel randomised controlled trial was conducted. Sixty patients (mean duration = 93.78 days) with non‐fluent aphasia after stroke were randomly divided into a traditional therapy group (n = 20), a music therapy group (n = 20) and a combined therapy group (n = 20, 1 Hz). The language function and depression were evaluated before and 3 weeks after treatment with the Chinese version of the Western Aphasia Battery scale, Boston Diagnostic Aphasia Examination scale and Stroke Aphasic Depression Questionnaire Hospital Version scale.

Outcomes & Results

The combined therapy group was significantly better in all outcomes than the traditional therapy group and was significantly better in depression than the music therapy group. The music therapy group was significantly better in repetition and depression than the traditional therapy group. Language improvement was positively correlated with depression improvement. For adverse events, only two patients in the combined therapy group showed slight dizziness during rTMS treatment and their symptoms improved after rest.

Conclusions & Implications

Our preliminary randomised controlled study indicates that low‐frequency rTMS combined with music therapy is feasible and safe in improving language function and depression in non‐fluent aphasia patients after stroke.

WHAT THIS PAPER ADDS

What is already known on this subject

Repetitive transcranial magnetic stimulation (rTMS) and music therapy respectively have advantages in the treatment of non‐fluent aphasia after stroke, but whether the combination of the two methods is more effective is still unknown.

What this paper adds to the existing knowledge

This is one of the first randomised control trials to investigate whether the clinical efficacy of low‐frequency rTMS combined music therapy for non‐fluent aphasia is better. The findings show that low‐frequency rTMS combined music therapy is superior to traditional therapy in spontaneous speech, auditory comprehension, repetition, naming, aphasia quotient, functional language level and depression, and superior to music therapy in depression, while music therapy is superior to traditional therapy in repetition and depression.

What are the potential or actual clinical implications of this work?

Low‐frequency rTMS combined music therapy may be a better method for treatment of non‐fluent aphasia.
Protistan community composition and metabolism in the North Pacific Subtropical Gyre: Influences of mesoscale eddies and depth
Authors: Gleich Samantha J. , Hu Sarah K. , Krinos Arianna I. , Caron David A.
Published: December 2023

Marine protists and their metabolic activities are intricately tied to the cycling of nutrients and the flow of energy through microbial food webs. Physiochemical changes in the environment, such as those that result from mesoscale eddies, may impact protistan communities, but the effects that such changes have on protists are poorly known. A metatranscriptomic study was conducted to investigate how eddies affected protists at adjacent cyclonic and anticyclonic eddy sites in the oligotrophic ocean at four depths from 25 to 250 m. Eddy polarity impacted protists at all depths sampled, although the effects of eddy polarity were secondary to the impact of depth across the depth range. Eddy‐induced vertical shifts in the water column yielded differences in the cyclonic and anticyclonic eddy protistan communities, and these differences were the most pronounced at and just below the deep chlorophyll maximum. An analysis of transcripts associated with protistan nutritional physiology at 150 m revealed that cyclonic eddies may support a more heterotrophic community, while anticyclonic eddies promote a more phototrophic community. The results of this study indicate that eddies alter the metabolism of protists particularly in the lower euphotic zone and may therefore impact carbon export from the euphotic zone.
Stock Price Crash Risk and the Market for Corporate Control
Authors: Carline Nicholas F. , Gao Yang , Kuo Jing‐Ming
Published: December 2023

Recent studies suggest that greater exposure to the market for corporate control matters for managers and shareholders since it affects firms’ ex‐post risk of experiencing a stock price crash. The findings though question the direction of the effect. In contrast, in this study, we are the first to examine the effects of firms’ ex‐ante risk of experiencing a stock price crash, a likely antecedent of which is managers’ concealment of news on aspects of the market for corporate control. We find that higher crash risk leads to greater takeover target likelihood. This relationship, which is robust to duly circumventing reverse causality, depends to a significant extent on inferior managerial quality and greater managerial discretion around financial accruals, affording richer insight into the notion that correction of managerial behaviour is a stimulus for the market for corporate control, but one that depends on the likely extent of managers’ concealment of news. We also concurrently find that actual takeover targets with higher crash risk generate a lower bid premium and receive more payment with stock. Overall, our findings strongly suggest that decision‐making in the market for corporate control is at least partially explained by incentives linked to opportunistic prices and takeovers of lemons.
The Orphan Drug Act at 40: Legislative Triumph and the Challenges of Success
Authors: SALTONSTALL PETER , ROSS HEIDI , KIM PAUL T.
Published: December 2023

Policy Points

The Orphan Drug Act (ODA) was the result of patient advocacy and by many measures has been strikingly successful. However, approximately 95% of the more than 7,000 known rare diseases still have no US Food and Drug Administration–approved treatment.

The ODA's success led to sustained criticism of high drug prices, often for products that have orphan drug indications. Critics misconstrue the ODA's intent and propose reducing its incentives instead of pursuing policies focused on addressing broader prescription drug price challenges that exist in both the orphan and nonorphan drug market.

Patients and their families will continue to defend the purpose and integrity of the ODA and to drive investments into rare disease research and clinical development.
Individuals' career perceptions in different institutionalized contexts: A comparative study of career actors in liberal, coordinated, hierarchical and mediterranean market economies
Authors: Andresen Maike , Apospori Eleni , Gunz Hugh , Cotton Richard , Hall Douglas T. , Shen Yan , Bosak Janine , Dickmann Michael , Parry Emma
Published: December 2023

Leveraging Weiner's attribution theory of intrapersonal motivation at the micro level and varieties of capitalism theory at the macro level, we conduct a multi‐country and cross‐level study examining whether individuals' career goals (i.e., perceived importance of learning and development), behaviors (i.e., proactive career behaviors), and outcomes (i.e., perceived employability) as well as the relationships between these variables, differ between different market economies. We challenge extant literature that focuses on the agentic role of individuals and understates the role of context (i.e., market economy influence) in an individual's career development. Using multilevel structural equation modeling, we draw on a survey of 15,201 individuals between 2014 and 2016 from 22 countries representing four different varieties of capitalism. The results showed that workers in hierarchical (HME) and Mediterranean (MME) market economies systematically differed from individuals in coordinated (CME) and liberal (LME) market economies in proactive career behaviors and perceived employability. Moreover, while the positive relationship between perceived importance of learning and development and proactive career behaviors was stronger in CMEs and LMEs compared to HMEs and MMEs, the positive association between proactive career behaviors and perceived employability was weaker. Our study bridges the micro‐macro gap in career studies, adding new insights into the ongoing conversation of contextual influence in individuals' career development.
Climate heterogeneity, season variation, and sexual dimorphism modulate the association between MHC II diversity and parasite variation in striped hamster
Authors: LIU Pengbo , LI Guichang , ZHAO Ning , LIU Qiyong , LIU Xiaobo , SONG Xiuping , SHI Xinfei , LUN Xinchang , ZHANG Lu , WANG Jun , LU Liang
Published: December 2023

Parasite‐mediated selection is widely believed to play a crucial role in maintaining the diversity of the major histocompatibility complex (MHC) genes, which is thought to be maintained through heterozygote advantage, rare‐allele advantage, and fluctuating selection. However, the relationship between parasite pressure and MHC diversity has yielded inconsistent findings. These inconsistencies may arise from the influence of environmental factors and individual variations in traits on host–parasite interactions. To address these issues, our study extensively investigated populations of striped hamsters inhabiting regions characterized by environmental heterogeneity. The primary objective was to examine the universality of parasite‐mediated selection mechanisms. Our observations revealed the presence of multiple parasite infections, accompanied by spatial and temporal variations in parasite communities and infection patterns among individual hamsters. Specifically, the temperature was found to influence all four parasite indices, while the presence of gamasid mites and parasite richness decreased with increasing precipitation. We also noted significant seasonal variation in parasite dynamics. Moreover, a significant sexual dimorphism was observed with males exhibiting a considerably higher parasite burden compared to their female counterparts. Lastly, we identified the maintenance of MHC polymorphism in striped hamsters as being driven by the heterozygote advantage and fluctuating selection mechanisms. This study underscores the significance of ecological processes in comprehending host–parasite systems and highlights the necessity of considering environmental factors and individual traits when elucidating the mechanisms underlying MHC diversity mediated by parasites.
Diagnostic method of mass spectrometry for detecting lymph node metastasis of non‐small cell lung cancer
Authors: Yoshimura Ryuichi , Shigeeda Wataru , Fujita Yuji , Kokaji Tetsuo , Deguchi Hiroyuki , Tomoyasu Makoto , Kudo Satoshi , Kaneko Yuka , Kanno Hironaga , Iwai Hidenobu , Mase Tomohiko , Saito Hajime
Published: December 2023

Background

Histopathology by pathologists is essential in the diagnosis of non‐small cell lung cancer (NSCLC). However, auxiliary diagnostic procedures for malignant tumor have continued to evolve. Despite the poor prognosis of patients with NSCLC, the application of the latest procedures and technologies to the field of lung cancer has lagged. Mass spectrometry was used to detect trace amounts of peptides in human tissue with high accuracy. The aim of this study was to establish a method for diagnostic mass spectrometry to identify lymph node metastasis by detecting cytokeratin (CK)19, a useful biomarker in lung cancer.

Methods

We collected 81 lymph nodes with positive expression of CK19 in patients who underwent radical surgical resection in the Department of Thoracic Surgery at Iwate Medical University between May 2020 and December 2022. An X500R instrument was used for sample analysis. A positive result for lymph node metastasis as the detection at least two product ions (FGPGVAFR and ILGATIENSR) from CK19 was defined.

Results

Our study indicated a high diagnostic efficiency for mass spectrometry, with 87.5% sensitivity and 91.2% specificity. The mutual concordance of mass spectrometry methods and histopathological diagnosis was 90.1%.

Conclusions

Mass spectrometry offers high diagnostic accuracy and can be clinically applied to auxiliary diagnostic procedures for lymph node metastasis from NSCLC.
Agricultural shocks, coping policies and deforestation: Evidence from the coffee leaf rust epidemic in Mexico
Authors: Chort Isabelle , Öktem Berk
Published: December 2023

Deforestation in the tropics is a critical issue that interacts with global environmental changes, and the mediating role of negative agricultural shocks is ambiguous. We investigate the impact of the massive epidemic of coffee leaf rust (CLR) that affected Mexico from 2012 on deforestation. CLR is a fungal disease that negatively affects coffee production. We exploit the gradual spread of the epidemic across coffee‐growing municipalities and estimate a difference‐in‐differences model. We find that deforestation increased by 32% in CLR‐affected municipalities, but we find no increase in agricultural land. We find evidence of deforestation in cropland area, and our effects are driven by states where rustic coffee systems were predominant. These results suggest that deforestation occurred within coffee cultivation areas and point out the concurrent role of government subsidies and incentives through the PROCAFE program, launched in 2014, that promoted the replacement of traditional coffee trees by CLR‐resistant hybrids. We study the dynamic effects of CLR and exploit the delayed launch of PROCAFE to try to disentangle the impact of the epidemic from that of the policy response. Our results emphasize the vulnerability of agroforestry systems to exogenous shocks and suggest that PROCAFE, as a short‐term response to CLR, contributed to increasing deforestation and accelerating the transition of Mexican traditional coffee landscapes to monoculture.
CRISPR/Cas9‐mediated genome editing reveals seven testis‐enriched transmembrane glycoproteins dispensable for male fertility in mice
Authors: Ogawa Yo , Lu Yonggang , Kiyozumi Daiji , Chang Hsin‐Yi , Ikawa Masahito
Published: December 2023

Background

Mammalian fertilization is mediated by multiple sperm acrosomal proteins, many of which are testis‐enriched transmembrane glycoproteins expressed during spermiogenesis (e.g., Izumo sperm‐egg fusion 1, Sperm acrosome associated 6, and Transmembrane protein 95).

Methods

We hypothesized that proteins with these features might have a role in sperm–egg interaction and thus carried out an in‐silico screen based on multiple public databases. We generated knockout mouse lines lacking seven candidate proteins by the CRISPR/Cas9 system and conducted detailed analyses on the fecundity of the knockout males, as well as their testis appearance and weight, testis and epididymis histology, and sperm motility and morphology.

Results

Through the in‐silico screen, we identified 4932438H23Rik, A disintegrin and metalloproteinase domain‐containing protein 29, SAYSvFN domain‐containing protein 1, Sel‐1 suppressor of lin‐12‐like 2 (C. elegans), Testis‐expressed protein 2, Transmembrane and immunoglobulin domain‐containing 3, and Zinc and ring finger 4. Phenotypic analyses unveiled that the knockout males showed normal testis gross appearance, normal testis and epididymis histology, and normal sperm morphology and motility. Fertility tests further indicated that the knockout male mice could sire pups with normal litter sizes when paired with wild‐type females.

Discussion and conclusion

These findings suggest that these seven proteins are individually dispensable for male reproduction and fertilization. Future studies are warranted to devise advanced in‐silico screening approaches that permit effective identification of gamete fusion‐required sperm proteins.
The impact of electric scooters in Melbourne: data from a major trauma service
Authors: Cevik Jevan , Read David , Putland Mark , Fazio Timothy , Gumm Kellie , Varma Amrita , Santos Roselyn , Ramakrishnan Anand
Published: December 2023

Background

The proliferation of electric scooters globally has been associated with an increase in related injuries and consequent economic burden. This study aims to assess the injury patterns and the economic impact associated with electric scooter use in Melbourne, Australia.

Methods

A retrospective cohort study was conducted using hospital and registry data from January 2022 to January 2023. Data collected included demographic details, alcohol and helmet use, injury type and severity, operative treatment provided, and direct medical costs. The economic impact (in AUD) of the patient's emergency presentation and hospital admission was calculated.

Results

During the study period, 256 electric scooter related injuries were recorded, comprising 247 riders and nine pedestrians. The majority of patients were males (69%) with a median age of 29.5 (15–78). Alcohol use was reported by 34% and helmet use by 33%. Injuries most commonly affected the upper limb (53%) and head (50%), with abrasions (75%) and fractures (48%) being the most common type of injury sustained. The total hospital cost was $1 911 062, and the median cost was $1321.66 per patient (IQR: $479.37–$5096.65).

Conclusion

Electric scooter usage, as observed through patient presentations to the Royal Melbourne Hospital, is associated with a considerable number of injuries, primarily among young males, and an ensuing substantial economic burden. The findings underscore the urgent need for improved safety measures to minimize electric scooter‐related injuries and their clinical and economic repercussions.
Why do funders support social welfare crowdfunding platforms? An elaboration likelihood perspective
Authors: Sajjad Aqsa , Zhang Qingyu , Alarifi Ghadah , Battisti Enrico , Arrigo Elisa
Published: December 2023

Crowdfunding entails small funds or contributions collected from the public to support and develop certain services or products. It has been widely adopted as an alternative method to fund social, cultural, and technological projects. Crowdfunding platforms can capitalize the social and digital networks, making them more efficient in targeting funders with minimum operational costs. The emergence of crowdfunding platforms as social information systems attracts researchers and academicians to study their increasing acceptance. In complement to qualitative and big‐data analyses, behavioral models can offer robust insights into why individuals like to participate in the activities generated on these platforms. Prior research focuses on the user's acceptance of these platforms, but less attention has been given to users' engagement in crowdfunding‐based social welfare projects. The study highlights people's crowdfunding intentions to fund social welfare projects based on the elaboration likelihood model. The study hypothesizes argument quality and technical advantage as central signals and shared value and reputation as peripheral signals, where outcome efficacy and social consciousness directly affect intentions to participate and moderate the relationship between signals and intentions. We collect data from 467 potential donors from China's 30 online crowdfunding platforms. The results indicate a more significant peripheral route effect on donation participation in social welfare crowdfunding. Social consciousness significantly predicts donation intentions where outcome efficacy and social consciousness strengthen the relationship between argument quality, shared values, and donation intentions to participate in socially responsible crowdfunding. The study provides implications for social collaboration for welfare projects through these platforms in light of these dynamic factors.
Advancing type 2 diabetes therapy with iGlarLixi in older people: Pooled analysis of four randomized controlled trials
Authors: Munshi Medha , Ritzel Robert , Jude Edward B , Dex Terry , Melas‐Melt Lydie , Rosenstock Julio
Published: December 2023

Aim

To assess the efficacy and safety of iGlarLixi in older people (≥65 years) with type 2 diabetes (T2D) advancing or switching from oral agents, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), or basal insulin.

Materials and Methods

The data of participants aged <65 years and ≥65 years from four LixiLan trials (LixiLan‐O, LixiLan‐G, LixiLan‐L, SoliMix) were evaluated over 26 or 30 weeks.

Results

Participants aged <65/≥65 years (n = 1039/n = 497) had a mean baseline body mass index of 31.4 and 30.7 kg/m2 and glycated haemoglobin (HbA1c) concentration of 66 mmol/mol (8.2%) and 65 mmol/mol (8.1%), respectively. Least squares mean HbA1c change from baseline to end of treatment (EOT) was −14.32 mmol/mol (−1.31%) (95% confidence interval [CI] −14.97, −13.77 [−1.37%, −1.26%]) for those aged <65 years and −13.66 mmol/mol (−1.25%) (95% CI −14.54, −12.79 [−1.33%, −1.17%]) for those aged ≥65 years. At EOT, achievement of HbA1c targets was similar between the group aged <65 years and the group aged ≥65 years: <53 mmol/mol (<7%) (59.0% and 56.5%, respectively), <59 mmol/mol (<7.5%) (75.5% and 73.0%, respectively) and <64 mmol/mol (<8%) (83.8% and 84.1%, respectively). The incidence and event rate of American Diabetes Association Level 1 hypoglycaemia during the studies were also comparable between the two groups: 26.7% and 28.2% and 1.7 and 2.1 events per patient‐year for the group aged <65 years and the group aged ≥65 years, respectively. A clinically relevant reduction in HbA1c (>1% from baseline for HbA1c ≥64 mmol/mol [≥8%] or ≥0.5% from baseline for HbA1c <64 mmol/mol [<8%]) without hypoglycaemia was attained by 50.0% and 47.6% of participants aged <65 years and ≥65 years, respectively. Adverse events were similar between the two age groups.

Conclusions

iGlarLixi is a simple, well‐tolerated, once‐daily alternative for treatment advancement in older people with T2D that provides significant improvements in glycaemic control without increasing hypoglycaemia risk, thus reducing the treatment burden.
Flow cytometry for comprehensive assessment of platelet functional activity in response to ADP stimulation
Authors: Ponomarenko Evgeniya A. , Ignatova Anastasia A. , Polokhov Dmitrii M. , Filkova Aleksandra A. , Suntsova Elena V. , Zharkov Pavel A. , Fedorova Daria V. , Pisaryuk Alexandra S. , Meray Imad , Kobalava Zhanna D. , Tukhsanboev Yokubjon S. , Maschan Alexey A. , Novichkova Galina A. , Sveshnikova Anastasia N. , Panteleev Mikhail A.
Published: December 2023

Objectives

Flow cytometry with adenosine diphosphate (ADP) allows to characterize molecular changes of platelet function caused by this physiologically important activation, but the methodology has not been thoroughly investigated, standardized and characterized yet. We analyzed the influence of several major variables and chose optimal conditions for platelet function assessment.

Methods

For activation, 2.5 μM CaCl2, 5 μM ADP and antibodies were added to diluted blood and incubated for 15 min. We analyzed kinetics of antibody binding and effects of their addition sequence, agonist concentration, blood dilution, exogenous calcium addition and platelet fixation.

Results

We tested our protocol on 11 healthy children, 22 healthy adult volunteers, 9 patients after a month on dual antiplatelet therapy after percutaneous coronary intervention (PCI), 7 adult patients and 14 children with immune thrombocytopenia (ITP). We found that our protocol is highly sensitive to ADP stimulation with low percentage of aggregates formation. The assay is also sensitive to platelet function inhibition in post‐PCI patients. Finally, platelet preactivation with ITP plasma was stronger and caused increase in activation response to ADP stimulation compared to preactivation with low dose of ADP.

Conclusions

Our assay is sensitive to antiplatelet therapy and platelet preactivation in ITP patients under physiological conditions with minimal percentage of aggregates formation.
Sobetirome rescues α‐synuclein‐mediated demyelination in an in vitro model of multiple system atrophy
Authors: Mészáros Lisa , Himmler Marcus , Schneider Yanni , Arnold Philipp , Dörje Frank , Schubert Dirk W. , Winkler Jürgen
Published: December 2023

Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α‐synuclein (α‐syn), demyelination, inflammation and neuronal loss. To date, no disease‐modifying therapy is available. Targeting α‐syn‐driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood–brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α‐syn specifically in oligodendrocytes (MBP29 mouse line), a well‐described MSA model, and non‐transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin‐specific proteins in control and α‐syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α‐syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.
Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing
Authors: Coppola Antonietta , Krithika S. , Iacomino Michele , Bobbili Dheeraj , Balestrini Simona , Bagnasco Irene , Bilo Leonilda , Buti Daniela , Casellato Susanna , Cuccurullo Claudia , Ferlazzo Edoardo , Leu Costin , Giordano Lucio , Gobbi Giuseppe , Hernandez‐Hernandez Laura , Lench Nick , Martins Helena , Meletti Stefano , Messana Tullio , Nigro Vincenzo , Pinelli Michele , Pippucci Tommaso , Bellampalli Ravishankara , Salis Barbara , Sofia Vito , Striano Pasquale , Striano Salvatore , Tassi Laura , Vignoli Aglaia , Vaudano Anna Elisabetta , Viri Maurizio , Scheffer Ingrid E. , May Patrick , Zara Federico , Sisodiya Sanjay M.
Published: December 2023

Objective

Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure‐induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM.

Methods

We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM− (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder).

Results

We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM− subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM− an established association. Burden analysis did not identify any single burdened gene or gene set.

Significance

Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene–disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM− and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM− remains to be elucidated.
Widespread, depth‐dependent cortical microstructure alterations in pediatric focal epilepsy
Authors: Casella Chiara , Vecchiato Katy , Cromb Daniel , Guo Yourong , Winkler Anderson M. , Hughes Emer , Dillon Louise , Green Elaine , Colford Kathleen , Egloff Alexia , Siddiqui Ata , Price Anthony , Grande Lucilio Cordero , Wood Tobias C. , Malik Shaihan , Teixeira Rui Pedro A. G. , Carmichael David W. , O'Muircheartaigh Jonathan
Published: December 2023

Objective

Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment‐related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug‐resistant focal epilepsy and, secondarily, whether changes were related to disease severity.

Methods

To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug‐resistant focal epilepsy (age range = 4–18 years) and 46 typically developing children (age range = 2–18 years). We assessed depth‐dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof‐of‐concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative).

Results

We uncovered depth‐dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI‐positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held‐out MRI‐negative patients.

Significance

These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.
Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids
Authors: Miller Michelle S. , Cowan Angus D. , Brouwer Jason M. , Smyth Sean T. , Peng Liuyu , Wardak Ahmad Z. , Uren Rachel T. , Luo Cindy , Roy Michael J. , Shah Sayali , Tan Ziwen , Reid Gavin E. , Colman Peter M. , Czabotar Peter E.
Published: December 2023

The B‐cell lymphoma 2 (BCL2) family members, BCL2‐associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane‐active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2–α5. These structures provide an atomic resolution description of the interactions that drive BAX homo‐dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid‐interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK.
Fire transforms effects of terrestrial subsidies on aquatic ecosystem structure and function
Authors: Wall Christopher B. , Spiegel Cody J. , Diaz Evelyn M. , Tran Cindy H. , Fabiani Alexia , Broe Taryn Y. , Perez‐Coronel Elisabet , Jackrel Sara L. , Mladenov Natalie , Symons Celia C. , Shurin Jonathan B.
Published: December 2023

Fire can lead to transitions between forest and grassland ecosystems and trigger positive feedbacks to climate warming by releasing CO2 into the atmosphere. Climate change is projected to increase the prevalence and severity of wildfires. However, fire effects on the fate and impact of terrestrial organic matter (i.e., terrestrial subsidies) in aquatic ecosystems are unclear. Here, we performed a gradient design experiment in freshwater pond mesocosms adding 15 different amounts of burned or unburned plant detritus and tracking the chronology of detritus effects at 10, 31, 59, and 89 days. We show terrestrial subsidies had time‐ and mass‐dependent, non‐linear impacts on ecosystem function that influenced dissolved organic carbon (DOC), ecosystem metabolism (net primary production and respiration), greenhouse gas concentrations (carbon dioxide [CO2], methane [CH4]), and trophic transfer. These impacts were shifted by fire treatment. Burning increased the elemental concentration of detritus (increasing %N, %P, %K), with cascading effects on ecosystem function. Mesocosms receiving burned detritus had lower [DOC] and [CO2] and higher dissolved oxygen (DO) through Day 59. Fire magnified the effects of plant detritus on aquatic ecosystem metabolism by stimulating photosynthesis and respiration at intermediate detritus‐loading through Day 89. The effect of loading on DO was similar for burned and unburned treatments (Day 10); however, burned‐detritus in the highest loading treatments led to sustained hypoxia (through Day 31), and long‐term destabilization of ecosystem metabolism through Day 89. In addition, fire affected trophic transfer by increasing autochthonous nitrogen source utilization and reducing the incorporation of 15N‐labeled detritus into plankton biomass, thereby reducing the flux of terrestrial subsidies to higher trophic levels. Our results indicate fire chemically transforms plant detritus and alters the role of aquatic ecosystems in processing and storing carbon. Wildfire may therefore induce shifts in ecosystem functions that cross the boundary between aquatic and terrestrial habitats.
Groundwater is a hidden global keystone ecosystem
Authors: Saccò Mattia , Mammola Stefano , Altermatt Florian , Alther Roman , Bolpagni Rossano , Brancelj Anton , Brankovits David , Fišer Cene , Gerovasileiou Vasilis , Griebler Christian , Guareschi Simone , Hose Grant C. , Korbel Kathryn , Lictevout Elisabeth , Malard Florian , Martínez Alejandro , Niemiller Matthew L. , Robertson Anne , Tanalgo Krizler C. , Bichuette Maria Elina , Borko Špela , Brad Traian , Campbell Matthew A. , Cardoso Pedro , Celico Fulvio , Cooper Steven J. B. , Culver David , Di Lorenzo Tiziana , Galassi Diana M. P. , Guzik Michelle T. , Hartland Adam , Humphreys William F. , Ferreira Rodrigo Lopes , Lunghi Enrico , Nizzoli Daniele , Perina Giulia , Raghavan Rajeev , Richards Zoe , Reboleira Ana Sofia P. S. , Rohde Melissa M. , Fernández David Sánchez , Schmidt Susanne I. , van der Heyde Mieke , Weaver Louise , White Nicole E. , Zagmajster Maja , Hogg Ian , Ruhi Albert , Gagnon Marthe M. , Allentoft Morten E. , Reinecke Robert
Published: December 2023

Groundwater is a vital ecosystem of the global water cycle, hosting unique biodiversity and providing essential services to societies. Despite being the largest unfrozen freshwater resource, in a period of depletion by extraction and pollution, groundwater environments have been repeatedly overlooked in global biodiversity conservation agendas. Disregarding the importance of groundwater as an ecosystem ignores its critical role in preserving surface biomes. To foster timely global conservation of groundwater, we propose elevating the concept of keystone species into the realm of ecosystems, claiming groundwater as a keystone ecosystem that influences the integrity of many dependent ecosystems. Our global analysis shows that over half of land surface areas (52.6%) has a medium‐to‐high interaction with groundwater, reaching up to 74.9% when deserts and high mountains are excluded. We postulate that the intrinsic transboundary features of groundwater are critical for shifting perspectives towards more holistic approaches in aquatic ecology and beyond. Furthermore, we propose eight key themes to develop a science‐policy integrated groundwater conservation agenda. Given ecosystems above and below the ground intersect at many levels, considering groundwater as an essential component of planetary health is pivotal to reduce biodiversity loss and buffer against climate change.
The effect of graphitization degree of carbon and Si─O─C network on the electrochemical performance of SiOC anodes
Authors: Han Qing , Zhang Junzhan , Chen Hongxia , Wang Linxiang , Yuan Hudie , Hu Guoxin , Zhang Qiantao , Zhang Ying , Shi Zongmo
Published: December 2023

Silicon oxycarbide (SiOC) is a promising anode material for lithium‐ion batteries, owing to the high capacity and superior structural stability. However, the application of SiOC anode is limited by its low conductivity and poor rate performance. Here, SiOC anodes were prepared by the pyrolysis of silicone resin (RSN‐217) at different temperatures (700, 850, 1000, and 1150° C), and the effect of graphitization degree and Si─O─C network on the electrochemical performance of SiOC anodes was investigated. The elemental and structural characteristics of the pyrolyzed SiOC ceramics at different temperatures were inspected using a broad spectrum of characterization techniques, and electrochemical performance testing methods, such as cyclic voltammetry and galvanostatic charge/discharge, were conducted on SiOC anode. SiOC‐1000 showed excellent electrochemical performance due to the highest graphitization degree of free carbon phase and the highest content of SiO2C2 and SiO3C units. Considerable research effort laid a foundation for exploring the lithium storage mechanism of SiOC anode.
Synthesize and crystallization behavior of SiOC/SiC nanocomposites derived from organosilane slurry residue
Authors: Guo Xiaolin , Wang Hong , Fu Ning , Xing Pengfei , Wang Shuai , Wu Bowen , Zhuang Yanxin
Published: December 2023

A route preparing SiOC/SiC nanocomposites directly by pyrolysis of organosilane slurry residue was investigated. Organosilane slurry residue's unique composition, containing both silicon and carbon, offers an intriguing platform for developing advanced ceramic materials. The pyrolysis process is examined comprehensively, revealing the chemical reactions and structural changes leading to SiC crystals formation. The phase evolution at various annealing temperatures was revealed. Crystallization behavior in the process were studied. The results reveal that SiOC matrix was generated at annealed temperature 800°C and SiC nanoparticles were formed at 1300°C. In comparison to phase separation of SiOC, carbothermal reduction of SiO2 was domain in SiC formation. This research advances the understanding of SiOC/SiC nanocomposites, highlighting the value of repurposing industrial byproducts for sustainable and innovative materials development.