bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ruthenium 360 and mitoxantrone inhibit mitochondrial calcium uniporter channel to prevent liver steatosis induced by high‐fat diet
Authors: Zhang Zhiwang , Luo Zupeng , Yu Lin , Xiao Yang , Liu Siqi , ALuo Zhier , Ma Zeqiang , Huang Liang , Xiao Lianggui , Jia Mengting , Song Ziyi , Zhang Haojie , Li Yixing , Zhou Lei 
Published: December 2021

Background and PurposeNon‐alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis.Experimental ApproachIn this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high‐fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum–mitochondrial linker was adopted to increase mitochondria‐associated membranes (MAMs) and MICU1‐EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel.Key ResultsHere, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD‐induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high‐calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD‐induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01‐μM·kg−1 bodyweight) can alleviate HFD‐induced hepatic steatosis.Conclusion and ImplicationsThese findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.
Amlodipine, an anti‐hypertensive drug, alleviates non‐alcoholic fatty liver disease by modulating gut microbiota
Authors: Li Yang , Zhao Danyang , Qian Minyi , Liu Jun , Pan Chuyue , Zhang Xinxin , Duan Xubin , Zhang Yufei , Jia Wenxin , Wang Lirui 
Published: December 2021

Background and PurposeNon‐alcoholic fatty liver disease (NAFLD) represents a severe public health problem. It often coexists with hypertension in the context of metabolic syndrome. We investigated the effects of amlodipine on NAFLD combined with hypertension and investigated the underlying mechanism/s.Experimental ApproachMice were fed with high‐fat diet (HFD) and 0.05% N‐nitro‐L‐arginine methylester sterile water to induce NAFLD with hypertension. Gut microbiota composition and function were assessed by 16S ribosomal DNA and metagenomic sequencing. Untargeted metabolome profiles were applied to identify differential metabolites in mice caecum.Key ResultsAmlodipine besylate and amlodipine aspartate significantly decreased liver injury and hepatic steatosis, and improved lipid metabolism with a concomitant reduction in the expression of lipogenic genes in mice with NAFLD and hypertension. Mechanistically, amlodipine besylate and amlodipine aspartate have potential to restore intestinal barrier integrity and improve antimicrobial defence, along with the elevated abundances of Akkermansia, Bacteroides and Lactobacillus. Noteworthily, the gut microbiota in amlodipine besylate‐ and amlodipine aspartate‐treated mice had higher abundance of functional genes involved in taurine and hypotaurine metabolism. Consistently, the strengthened taurine and hypotaurine metabolism was confirmed by untargeted metabolome analysis. Based on the correlation and causal analysis, the altered gut microbiota composition and the enhancement of taurine and hypotaurine metabolism may synergistically decreased alanine aminotransferase, liver triglycerides, lipogenic genes and plasma cholesterol in HFD‐fed hypertensive mice.Conclusion and ImplicationsAmlodipine besylate and amlodipine aspartate exert multifactorial improvements in NAFLD and hypertension by modulating gut microbiota. They may serve as promising therapeutic agents for treating these diseases.
Wildlife predation by dogs in Madagascar
Authors: Merz Leandra , Kshirsagar Akhil R. , Rafaliarison Radoniaina R. , Rajaonarivelo Tsiky , Farris Zach J. , Randriana Zoavina , Valenta Kim 
Published: December 2021

AbstractHuman–wildlife conflicts are increasing in number and intensity making conflict mitigation and coexistence a top priority for wildlife conservation. Domesticated dogs (Canis lupus familiaris) can mitigate or exacerbate human–wildlife conflict leading to positive and negative impacts on both humans and wildlife. However, the human–dog–wildlife interface is not well understood, particularly in biodiversity hot spots. Madagascar is a tropical biodiversity hot spot with many rare and threatened species of high conservation concern. Here we assess wildlife predation by free‐roaming dogs in communities surrounding Andasibe–Mantadia and Ranomafana National Parks in eastern Madagascar using surveys of dog owners living adjacent to protected areas. Nearly half of survey respondents reported that their dog(s) had killed wildlife. Dogs that spent more time away from home, that traveled to the forest more frequently, that had killed domestic livestock, and that were owned for hunting were more likely to have killed wildlife. Dogs that were fed were approximately 20% less likely to have killed wildlife than dogs that were not fed. Keeping dogs restrained more often and providing food are therefore likely to reduce wildlife predation by dogs provided these are socially acceptable options. Additionally, we found spatial variation in wildlife predation by dogs both between and within our two study regions. These results can help conservation organizations develop targeted, effective interventions appropriately tailored to the local context and prioritize specific areas with higher wildlife predation by dogs.Abstract in French is available with online material.
Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors
Authors: Chigan Jia‐Zhu , Li Jia‐Qi , Ding Huan‐Huan , Xu Yin‐Sui , Liu Lu , Chen Cheng , Yang Ke‐Wu 
Published: December 2021

AbstractBacterial resistance caused by metallo‐β‐lactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O‐aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase‐1 (IMP‐1) and New Delhi metallo‐β‐lactamase‐1, exhibiting an IC50 value in the range of 0.10–18.42 and 0.23–22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP‐MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP‐1, while the rapid dilution, thermal shift and MALDI‐TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF‐7 cells. This work provided a potent scaffold for the development of MβLs inhibitors.
How frequent is burnout among informal caregivers of disabled children? Findings from a cross‐sectional study in Karachi, Pakistan
Authors: Zeeshan Mehwish , Shaikh Shiraz , Ahmer Zaeema 
Published: December 2021

AbstractBackgroundInformal caregivers are those who care for children without getting paid. They are often more prone to stress due to their extra daily tasks which leads to burnout. This study aimed to determine the frequency and associated risk factors of burnout among informal caregivers of children with disabilities in Karachi.MethodologyA cross‐sectional study was done in 10 rehabilitation institutes of Karachi with 310 mothers of children with disabilities from infancy till 18 years of age in 2019. Pretested questionnaire was administered to collect data in which 31 mothers were interviewed through convenience sampling from each rehabilitation institute. To assess burnout, the Maslach Burnout Inventory (MBI) was used. Association of different variables of study participants with the scores of its three subdimensions, Emotional Exhaustion (EE), Depersonalization (DP) and Personal Accomplishment (PA), were analysed using linear regression modelling.ResultsMean EE score was high in 6.5% of the mothers while PA scores were low in 58.7% of the mothers. High EE with low PA (defined by our team as ‘burnout’) was found in 4.2% of the mothers, with none of them reporting high levels of DP. Linear regression analysis significantly predicted higher EE scores of mothers with more than one disabled child while lower EE scores were significantly predicted in highly educated mothers and mothers who spent more time in caregiving. Higher PA scores were also significantly predicted for highly educated mothers. DP scores were significantly predicted to be higher in mothers who had highly educated husband/guardian, employed mothers and those living in joint families whereas they were significantly predicted to be lower in highly educated mothers.ConclusionWe have identified that mothers who are less educated, have more than one child with disability and who live in joint families will need extra support and input to prevent burnout.
Kynurenic acid in neurodegenerative disorders—unique neuroprotection or double‐edged sword?
Authors: Ostapiuk Aleksandra , Urbanska Ewa M. 
Published: December 2021

AbstractAimsThe family of kynurenine pathway (KP) metabolites includes compounds produced along two arms of the path and acting in clearly opposite ways. The equilibrium between neurotoxic kynurenines, such as 3‐hydroxykynurenine (3‐HK) or quinolinic acid (QUIN), and neuroprotective kynurenic acid (KYNA) profoundly impacts the function and survival of neurons. This comprehensive review summarizes accumulated evidence on the role of KYNA in Alzheimer's, Parkinson's and Huntington's diseases, and discusses future directions of potential pharmacological manipulations aimed to modulate brain KYNA.DiscussionThe synthesis of specific KP metabolites is tightly regulated and may considerably vary under physiological and pathological conditions. Experimental data consistently imply that shift of the KP to neurotoxic branch producing 3‐HK and QUIN formation, with a relative or absolute deficiency of KYNA, is an important factor contributing to neurodegeneration. Targeting specific brain regions to maintain adequate KYNA levels seems vital; however, it requires the development of precise pharmacological tools, allowing to avoid the potential cognitive adverse effects.ConclusionsBoosting KYNA levels, through interference with the KP enzymes or through application of prodrugs/analogs with high bioavailability and potency, is a promising clinical approach. The use of KYNA, alone or in combination with other compounds precisely influencing specific populations of neurons, is awaiting to become a significant therapy for neurodegenerative disorders.
Perception of Happening: How the Brain Deals with the No‐History Problem
Authors: White Peter A. 
Published: December 2021

AbstractIn physics, the temporal dimension has units of infinitesimally brief duration. Given this, how is it possible to perceive things, such as motion, music, and vibrotactile stimulation, that involve extension across many units of time? To address this problem, it is proposed that there is what is termed an “information construct of happening” (ICOH), a simultaneous representation of recent, temporally differentiated perceptual information on the millisecond time scale. The main features of the ICOH are (i) time marking, semantic labeling of all information in the ICOH with ordinal temporal information and distance from what is informationally identified as the present moment, (ii) vector informational features that specify kind, direction, and rate of change for every feature in a percept, and (iii) connectives, information relating vector informational features at adjacent temporal locations in the ICOH. The ICOH integrates products of perceptual processing with recent historical information in sensory memory on the subsecond time scale. Perceptual information about happening in informational sensory memory is encoded in semantic form that preserves connected semantic trails of vector and timing information. The basic properties of the ICOH must be supported by a general and widespread timing mechanism that generates ordinal and interval timing information and it is suggested that state‐dependent networks may suffice for that purpose. Happening, therefore, is perceived at a moment and is constituted by an information structure of connected recent historical information.
Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase
Authors: Kang Jihyun , Kim Andrew HyoungJin , Jeon Inseung , Oh Jaeseong , Jang In‐Jin , Lee SeungHwan , Cho Joo‐Youn 
Published: December 2021

AbstractFive‐fluorouracil (5‐FU) is a chemotherapeutic agent that is mainly metabolized by the rate‐limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5‐FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography‐quantitative time‐of‐flight‐mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q‐value < 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency.
The role of the IAC Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy and the ACR Breast Imaging‐Reporting and Data System in the evaluation of breast lesions
Authors: Sundar Preethi Muthusamy , Shanmugasundaram Sakthisankari , Nagappan Elango 
Published: December 2021

AbstractBackgroundStratification of breast lesions for appropriate management is achieved through an integration of clinical examination, imaging, and fine needle aspiration biopsy (FNAB). The current study aimed to evaluate the combined effectiveness of the widely used Breast Imaging‐Reporting and Data System (BI‐RADS) with the recently proposed International Academy of Cytology (IAC) Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy Cytopathology.MethodsA retrospective analysis was done on all breast FNABs from 2016 through 2020. The cases were categorised according to the IAC Yokohama System. Histopathological correlation of the BI‐RADS and IAC Yokohama System was performed. The rate of malignancy (ROM) for each category of the BI‐RADS and IAC Yokohama System was calculated.ResultsThe ROM values for categories I to V were 38%, 0.6%, 21.9%, 100%, and 97%, respectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FNAB with category III assumed as malignant were 98.9%, 85%, 76.1%, 99.3%, and 89.5%, respectively. With category III assumed as benign, these indices were 90.8%, 98.9%, 97.5%, 95.7%, and 96.2%, respectively. The sensitivity, specificity, PPV, NPV and accuracy of BI‐RADS were 91.5%, 81.9%, 72%, 95%, and 85.1%, respectively.ConclusionsFNAB is still an indispensable test in the evaluation of breast lesions. The utilisation of the IAC Yokohama reporting system for breast cytology in conjunction with ACR BI‐RADS aids in better stratification of lesions.
Mutualistic coupling of vocabulary and non‐verbal reasoning in children with and without language disorder
Authors: Griffiths Sarah , Kievit Rogier A. , Norbury Courtenay 
Published: December 2021

AbstractMutualism is a developmental theory that posits positive reciprocal relationships between distinct cognitive abilities during development. It predicts that abilities such as language and reasoning will influence each other's rates of growth. This may explain why children with Language Disorders also tend to have lower than average non‐verbal cognitive abilities, as poor language would limit the rate of growth of other cognitive skills. The current study tests whether language and non‐verbal reasoning show mutualistic coupling in children with and without language disorder using three waves of data from a longitudinal cohort study that over‐sampled children with poor language at school entry (N = 501, 7–13 years). Bivariate Latent Change Score models were used to determine whether early receptive vocabulary predicted change in non‐verbal reasoning and vice‐versa. Models that included mutualistic coupling parameters between vocabulary and non‐verbal reasoning showed superior fit to models without these parameters, replicating previous findings. Specifically, children with higher initial language abilities showed greater growth in non‐verbal ability and vice versa. Multi‐group models suggested that coupling between language and non‐verbal reasoning was equally strong in children with language disorder and those without. This indicates that language has downstream effects on other cognitive abilities, challenging the existence of selective language impairments. Future intervention studies should test whether improving language skills in children with language disorder has positive impacts on other cognitive abilities (and vice versa), and low non‐verbal IQ should not be a barrier to accessing such intervention.
Current provision and HCP experiences of remote care delivery and diabetes technology training for people with type 1 diabetes in the UK during the COVID‐19 pandemic
Authors: Forde Hannah , Choudhary Pratik , Lumb Alistair , Wilmot Emma , Hussain Sufyan 
Published: December 2021

AbstractBackgroundThe COVID‐19 pandemic has led to the rapid implementation of remote care delivery in type 1 diabetes. We studied current modes of care delivery, healthcare professional experiences and impact on insulin pump training in type 1 diabetes care in the United Kingdom (UK).MethodsThe UK Diabetes Technology Network designed a 48‐question survey aimed at healthcare professionals providing care in type 1 diabetes.ResultsOne hundred and forty‐three healthcare professionals (48% diabetes physicians, 52% diabetes educators and 88% working in adult services) from approximately 75 UK centres (52% university hospitals, 46% general and community hospitals), responded to the survey. Telephone consultations were the main modality of care delivery. There was a higher reported time taken for video consultations versus telephone (p < 0.001). Common barriers to remote consultations were patient familiarity with technology (72%) and access to patient device data (67%). We assessed the impact on insulin pump training. A reduction in total new pump starts (73%) and renewals (61%) was highlighted. Common barriers included patient digital literacy (61%), limited healthcare professional experience (46%) and time required per patient (44%). When grouped according to size of insulin pump service, pump starts and renewals in larger services were less impacted by the pandemic compared to smaller services.ConclusionThis survey highlights UK healthcare professional experiences of remote care delivery. While supportive of virtual care models, a number of factors highlighted, especially patient digital literacy, need to be addressed to improve virtual care delivery and device training.
‘Is insulin right for me?’: Feasibility of a pilot randomised controlled trial and acceptability of a web‐based intervention to reduce psychological barriers to insulin therapy among adults with type 2 diabetes
Authors: Holmes‐Truscott Elizabeth , Holloway Edith E. , Husin Hanafi M. , Furler John , Hagger Virginia , Skinner Timothy C. , Speight Jane 
Published: December 2021

AbstractAimsAcceptable and accessible interventions are needed to address ‘psychological insulin resistance’, which is a common barrier to insulin uptake among adults with type 2 diabetes (T2D). Our aim was to test the feasibility of a randomised controlled trial (RCT) study design and acceptability of a theoretically grounded, psycho‐educational, web‐based resource to reduce negative insulin appraisals among adults with T2D.MethodsA double‐blinded, parallel group, two‐arm pilot RCT (1:1), comparing intervention with active control (existing online information about insulin). Eligible participants were Australian adults with T2D, taking oral diabetes medications. Exclusion criteria: prior use of injectable medicines; being ‘very willing’ to commence insulin. Primary outcomes: study feasibility (recruitment ease, protocol fulfilment, attrition, data completeness); secondary outcomes: intervention acceptability (intervention engagement, user feedback) and likely efficacy (negative Insulin Treatment Appraisal Scale [ITAS] scores at follow‐up). Online surveys completed at baseline and 2 weeks.ResultsDuring 4‐week recruitment, 76 people expressed interest: 51 eligible and 35 enrolled (intervention = 17, control = 18; median[interquartile range] age = 62[53, 69] years; 17 women). Protocol fulfilment achieved by 26 (74%) participants (n = 13 per arm), with low participant attrition (n = 6, 17%). Intervention acceptability was high (>80% endorsement, except format preference = 60%). ITAS negative scores differed between‐groups at follow‐up (M diff = −6.5, 95% confidence interval: −10.7 to −2.4), favouring the intervention.ConclusionsThis novel web‐based resource (“Is insulin right for me?”) is acceptable and associated with a likely reduction in negative insulin appraisals, relative to existing resources. This pilot shows the study design is feasible and supports conduct of a fully powered RCT.