bluuebunny/crossref_metadata_2025 huggingface dataset:
Theta patterns of stimulation induce synaptic and intrinsic potentiation in O-LM interneurons
Authors: Sammari Malika , Inglebert Yanis , Ankri Norbert , Russier Michaël , Incontro Salvatore , Debanne Dominique
Published: October 2022

Brain oscillations have long-lasting effects on synaptic and cellular properties. For instance, synaptic stimulation at theta (θ) frequency induces persistent depression of both excitatory synaptic transmission and intrinsic excitability in CA1 principal neurons. However, the incidence of θ activity on synaptic transmission and intrinsic excitability in hippocampal GABAergic interneurons is unclear. We report here the induction of both synaptic and intrinsic potentiation in oriens-lacunosum moleculare (O-LM) interneurons following stimulation of afferent glutamatergic inputs in the θ frequency range (∼5 Hz). Long-term synaptic potentiation (LTP) is induced by synaptic activation of calcium-permeable AMPA receptors (CP-AMPAR), whereas long-term potentiation of intrinsic excitability (LTP-IE) results from the mGluR1-dependent down-regulation of Kv7 voltage-dependent potassium channel and hyperpolarization activated and cyclic nucleotide-gated (HCN) channel through the depletion of phosphatidylinositol-4,5-biphosphate (PIP2). LTP and LTP-IE are reversible, demonstrating that both synaptic and intrinsic changes are bidirectional in O-LM cells. We conclude that synaptic activity at θ frequency induces both synaptic and intrinsic potentiation in O-LM interneurons, i.e., the opposite of what is typically seen in glutamatergic neurons.
Loss of the repressor REST affects progesterone receptor function and promotes uterine leiomyoma pathogenesis
Authors: Cloud Ashley S. , Koohestani Faezeh , McWilliams Michelle M. , Ganeshkumar Sornakala , Gunewardena Sumedha , Graham Amanda , Nothnick Warren B. , Chennathukuzhi Vargheese M.
Published: October 2022

Uterine leiomyomas (UL) are benign tumors that arise in the myometrial layer of the uterus. The standard treatment option for UL is hysterectomy, although hormonal therapies, such as selective progesterone receptor modulators, are often used as temporary treatment options to reduce symptoms or to slow the growth of tumors. However, since the pathogenesis of UL is poorly understood and most hormonal therapies are not based on UL-specific, divergent hormone signaling pathways, hallmarks that predict long-term efficacy and safety of pharmacotherapies remain largely undefined. In a previous study, we reported that aberrant expression of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes activate UL growth due to the near ubiquitous loss of REST. Here, we show that ablation of the
Rest
gene in mouse uterus leads to UL phenotype and gene-expression patterns analogous to UL, including altered estrogen and progesterone signaling pathways. We demonstrate that many of the genes dysregulated in UL harbor
cis
-regulatory elements bound by REST and progesterone receptor (PGR) adjacent to each other. Crucially, we identify an interaction between REST and PGR in healthy myometrium and present a putative mechanism for the dysregulation of progesterone-responsive genes in UL ensuing in the loss of REST. Using three
Rest
conditional knockout mouse lines, we provide a comprehensive picture of the impact loss of REST has in UL pathogenesis and in altering the response of UL to steroid hormones.
Morphological growth dynamics, mechanical stability, and active microtubule mechanics underlying spindle self-organization
Authors: Fukuyama Tatsuya , Yan Lucan , Tanaka Masahito , Yamaoka Megumi , Saito Kei , Ti Shih-Chieh , Liao Chung-Chi , Hsia Kuo-Chiang , Maeda Yusuke T. , Shimamoto Yuta
Published: October 2022

The spindle is a dynamic intracellular structure self-organized from microtubules and microtubule-associated proteins. The spindle’s bipolar morphology is essential for the faithful segregation of chromosomes during cell division, and it is robustly maintained by multifaceted mechanisms. However, abnormally shaped spindles, such as multipolar spindles, can stochastically arise in a cell population and cause chromosome segregation errors. The physical basis of how microtubules fail in bipolarization and occasionally favor nonbipolar assembly is poorly understood. Here, using live fluorescence imaging and quantitative shape analysis in
Xenopus
egg extracts, we find that spindles of varied shape morphologies emerge through nonrandom, bistable self-organization paths, one leading to a bipolar and the other leading to a multipolar phenotype. The bistability defines the spindle’s unique morphological growth dynamics linked to each shape phenotype and can be promoted by a locally distorted microtubule flow that arises within premature structures. We also find that bipolar and multipolar spindles are stable at the steady-state in bulk but can infrequently switch between the two phenotypes. Our microneedle-based physical manipulation further demonstrates that a transient force perturbation applied near the assembled pole can trigger the phenotypic switching, revealing the mechanical plasticity of the spindle. Together with molecular perturbation of kinesin-5 and augmin, our data propose the physical and molecular bases underlying the emergence of spindle-shape variation, which influences chromosome segregation fidelity during cell division.
ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit
Authors: Riella Cristian V. , McNulty Michelle , Ribas Guilherme T. , Tattersfield Calum F. , Perez-Gill Chandra , Eichinger Felix , Kelly Jessica , Chun Justin , Subramanian Balajikarthick , Guizelini Dieval ,   Nephrotic Syndrome Study Network (NEPTUNE), Alper Seth L. , Pollak Martin R. , Sampson Matthew G. , Friedman David J. , Massengill S , Dell K , Sedor J , Martin B , Lemley K , Sharma S , Srivastava T , Markus K , Sethna C , Vento S , Canetta P , Pradhan A , Greenbaum L , Wang CS , Yun E , Adler S , LaPage J , Atkinson M , Williams M , McCarthy E , Fervenza F , Hogan M , Lieske J , Selewski D , Conley C , Kaskel F , Ross M , Flynn P , Kopp J , Malaga-Dieguez L , Zhdanova O , Pace B , Almaani S , Lafayette R , Dave S , Lee I , Quinn-Boyle S , Shah S , Reich H , Hladunewich M , Ling P , Romano M , Brakeman P , Podoll A , Fornoni A , Bidot C , Kretzler M , Gipson D , Williams A , Klida C , Derebail V , Gibson K , Froment A , Ochoa-Toro F , Holzman L , Meyers K , Kallem K , Swenson A , Sharma K , Sambandam K , Wang Z , Rogers M , Jefferson A , Hingorani S , Tuttle K , Manahan L , Pao E , Kuykendall K K , Lin JJ , Baker Stefanie , Dharnidharka V
Published: October 2022

APOL1
risk variants are associated with increased risk of kidney disease in patients of African ancestry, but not all individuals with the
APOL1
high-risk genotype develop kidney disease. As APOL1 gene expression correlates closely with the degree of kidney cell injury in both cell and animal models, the mechanisms regulating APOL1 expression may be critical determinants of risk allele penetrance. The APOL1 messenger RNA includes Alu elements at the 3′ untranslated region that can form a double-stranded RNA structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting on RNA (ADAR)–mediated adenosine-to-inosine (A-to-I) editing, potentially impacting gene expression. We studied the effects of ADAR expression and A-to-I editing on APOL1 levels in podocytes, human kidney tissue, and a transgenic APOL1 mouse model. In interferon-γ (IFN-γ)–stimulated human podocytes, ADAR down-regulates APOL1 by preventing melanoma differentiation-associated protein 5 (MDA5) recognition of dsRNA and the subsequent type I interferon (IFN-I) response. Knockdown experiments showed that recognition of APOL1 messenger RNA itself is an important contributor to the MDA5-driven IFN-I response. Mathematical modeling suggests that the IFN–ADAR–APOL1 network functions as an incoherent feed-forward loop, a biological circuit capable of generating fast, transient responses to stimuli. Glomeruli from human kidney biopsies exhibited widespread editing of APOL1 Alu-dsRNA, while the transgenic mouse model closely replicated the edited sites in humans. APOL1 expression in mice was inversely correlated with Adar1 expression under IFN-γ stimuli, supporting the idea that ADAR regulates APOL1 levels in vivo. ADAR-mediated A-to-I editing is an important regulator of APOL1 expression that could impact both penetrance and severity of APOL1-associated kidney disease.
SWAP1-SFPS-RRC1 splicing factor complex modulates pre-mRNA splicing to promote photomorphogenesis in
Arabidopsis
Authors: Kathare Praveen Kumar , Xin Ruijiao , Ganesan Abirama Sundari , June Viviana M. , Reddy Anireddy S. N. , Huq Enamul
Published: October 2022

Light signals perceived by a group of photoreceptors have profound effects on the physiology, growth, and development of plants. The red/far-red light–absorbing phytochromes (phys) modulate these aspects by intricately regulating gene expression at multiple levels. Here, we report the identification and functional characterization of an RNA-binding splicing factor, SWAP1 (SUPPRESSOR-OF-WHITE-APRICOT/SURP RNA-BINDING DOMAIN-CONTAINING PROTEIN1). Loss-of-function
swap1-1
mutant is hyposensitive to red light and exhibits a day length–independent early flowering phenotype. SWAP1 physically interacts with two other splicing factors, (SFPS) SPLICING FACTOR FOR PHYTOCHROME SIGNALING and (RRC1) REDUCED RED LIGHT RESPONSES IN CRY1CRY2 BACKGROUND 1 in a light-independent manner and forms a ternary complex. In addition, SWAP1 physically interacts with photoactivated phyB and colocalizes with nuclear phyB photobodies. Phenotypic analyses show that the
swap1sfps
,
swap1rrc1,
and
sfpsrrc1
double mutants display hypocotyl lengths similar to that of the respective single mutants under red light, suggesting that they function in the same genetic pathway. The
swap1sfps
double and
swap1sfpsrrc1
triple mutants display pleiotropic phenotypes, including sterility at the adult stage. Deep RNA sequencing (RNA-seq) analyses show that SWAP1 regulates the gene expression and pre–messenger RNA (mRNA) alternative splicing of a large number of genes, including those involved in plant responses to light signaling. A comparative analysis of alternative splicing among single, double, and triple mutants showed that all three splicing factors coordinately regulate the alternative splicing of a subset of genes. Our study uncovered the function of a splicing factor that modulates light-regulated alternative splicing by interacting with photoactivated phyB and other splicing factors.
RUFY1 binds Arl8b and mediates endosome-to-TGN CI-M6PR retrieval for cargo sorting to lysosomes
Authors: Rawat Shalini , Chatterjee Dhruba , Marwaha Rituraj , Charak Gitanjali , Kumar Gaurav , Shaw Shrestha , Khatter Divya , Sharma Sheetal , de Heus Cecilia , Liv Nalan , Klumperman Judith , Tuli Amit , Sharma Mahak
Published: October 2022

Arl8b, an Arf-like GTP-binding protein, regulates cargo trafficking and positioning of lysosomes. However, it is unknown whether Arl8b regulates lysosomal cargo sorting. Here, we report that Arl8b binds to the Rab4 and Rab14 interaction partner, RUN and FYVE domain-containing protein (RUFY) 1, a known regulator of cargo sorting from recycling endosomes. Arl8b determines RUFY1 endosomal localization through regulating its interaction with Rab14. RUFY1 depletion led to a delay in CI-M6PR retrieval from endosomes to the TGN, resulting in impaired delivery of newly synthesized hydrolases to lysosomes. We identified the dynein-dynactin complex as an RUFY1 interaction partner, and similar to a subset of activating dynein adaptors, the coiled-coil region of RUFY1 was required for interaction with dynein and the ability to mediate dynein-dependent organelle clustering. Our findings suggest that Arl8b and RUFY1 play a novel role on recycling endosomes, from where this machinery regulates endosomes to TGN retrieval of CI-M6PR and, consequently, lysosomal cargo sorting.
Hemicentin-mediated type IV collagen assembly strengthens juxtaposed basement membrane linkage
Authors: Gianakas Claire A. , Keeley Daniel P. , Ramos-Lewis William , Park Kieop , Jayadev Ranjay , Kenny Isabel W. , Chi Qiuyi , Sherwood David R.
Published: October 2022

Basement membrane (BM) matrices surround and separate most tissues. However, through poorly understood mechanisms, BMs of adjacent tissue can also stably link to support organ structure and function. Using endogenous knock-in fluorescent proteins, conditional RNAi, optogenetics, and quantitative live imaging, we identified extracellular matrix proteins mediating a BM linkage (B-LINK) between the uterine utse and epidermal seam cell BMs in Caenorhabditis elegans that supports the uterus during egg-laying. We found that hemicentin is secreted by the utse and promotes fibulin-1 assembly to jointly initiate the B-LINK. During egg-laying, however, both proteins’ levels decline and are not required for B-LINK maintenance. Instead, we discovered that hemicentin recruits ADAMTS9/20, which facilitates the assembly of high levels of type IV collagen that sustains the B-LINK during the mechanically active egg-laying period. This work reveals mechanisms underlying BM–BM linkage maturation and identifies a crucial function for hemicentin and fibulin-1 in initiating attachment and type IV collagen in strengthening this specialized form of tissue linkage.
Bearing fault diagnosis method using a spatio-temporal neural network based on feature transfer learning
Authors: Song Mengmeng , Zhang Zexiong , Xiao Shungen , Xiong Zicheng , Li Mengwei
Published: October 2022

An intelligent bearing fault diagnosis method based requires a large quantity of labeled data. However, in an actual engineering environment, only a tiny amount of unlabeled data can be collected. To solve this problem, we construct a spatio-temporal neural network (STN) model by multi-layer fusion of convolutional neural network (CNN) and long-term memory network features. Then, a model based on feature migration is constructed and a STN is applied as the feature extractor of the network. Finally, the Case Western Reserve University bearing dataset is employed to verify the performance of our proposed model, and the influence of different neural network feature extractors (CNN, recurrent neural network, long- and short-term memory network, STN) and several feature transfer measures [correlation alignment, multiple kernel maximum mean discrepancy, joint maximum mean discrepancy, discriminative joint probability maximum mean discrepancy (DJP-MMD) on the accuracy of the model were compared. The results show that the diagnostic accuracy of the proposed method is over 98%, and the diagnostic accuracy can be maintained at around 99% in most cases when the signal to noise ratio (SNR) is 10 dB. When the SNR is lower than 2 dB, the accuracy of the STN-DJPMMD model is still over 88%.
Construction and remote demonstration of an inexpensive but efficient linear differential variable transformer (LVDT) for physics or electronics teaching during COVID-19 pandemic
Authors: Roy Arijit , Roy Durjoy , Mallick Abhishek
Published: October 2022

A linear variable differential transformer is termed as LVDT in short. A simple miniature and inexpensive LVDT was constructed for laboratory teaching. Starting from the fundamental physics of LVDT, a complete demonstration was presented. The heart of an LVDT is three coils that were taken from the electrical ‘Ding-dong’ doorbell. A universal laboratory experiment kit named ‘ExpEyes-17’ is used to drive the LVDT and display the input and output signals on a laptop screen. Thus, a compact LVDT system was developed. Displacement experiments were conducted, and the well-known V-shape response for our LVDT was obtained. The theory and experiment were presented with a high degree of clarity for ease of understanding. A complete demonstration was given to a group of students while teaching the theory of LVDT, and an excellent response from the group was obtained. Moreover, online demonstration of LVDT experiments using our kit was easily achievable. The authors have used the setup for remote demonstration the experiment to the students during COVID-19 pandemic lockdown.
Teaching remote laboratories using smart phone sensors: determining the density of air
Authors: Wye Steven
Published: October 2022

During the COVID-19 pandemic and subsequent lockdown, both schools and universities faced significant challenges in moving teaching from an in-situ setting to a remote one, this included laboratory experiments. This paper presents an experiment developed to use a phone’s in built pressure sensor, common to most smart phones. By using this sensor to measure the pressure at a series of known heights, the density of air was calculated with an accuracy of approximately ±0.03 kg m−3. This was completed as part of a first year undergraduate course.
Weak cosmic censorship conjecture in Myers-Perry black hole with separability
Authors: Gwak Bogeun
Published: October 2022

We investigate the weak cosmic censorship conjecture in Myers-Perry black holes with arbitrary rotations in general dimensions based on the scattering of a massless scalar field. From the fluxes of the scalar field flowing into the black hole, the changes in mass and angular momenta of the black hole are obtained. However, the extremal and near-extremal black holes with the aforementioned changes are still black holes in the final state. Hence, the conjecture is valid for our investigation. Furthermore, we analyze the changes in the black hole from a thermodynamic perspective to highlight that the laws of thermodynamics support the conjecture.
A Fast and High-precision Alignment Method for IFU Based on Optical Interferometry and Fresnel Diffraction
Authors: Wang Anzhi , Wang Jiabin , Yang Xingyu , Wang Shengjia , Yan Yunxiang , Yan Qi , Lu Chunlian , Li Song , Geng Tao , Sun Weimin , Chen Shuang , Zhong Yue , Xu Zhi , Qu Zhongquan
Published: October 2022

High-precision alignment between the microlens array and the fiber-positioning microplate is of great significance in developing fiber-based integrated field units (IFU). In this paper, we propose a method combining optical interference and a Fresnel diffraction model to realize fast and accurate alignment. The minimum resolution angles of the tip and tilt in the optical interference-assisted alignment experiment are 2.6 × 10−4° and 1.3 × 10−4°, respectively. The errors in the remaining four degrees of freedom, x, y, z, and roll, are simulated by the Fresnel diffraction model. Finally, the output energy of 96.7% of the number of fibers is within a tolerance error of 10% and the relative energy reaches its highest level, which meets the IFU requirement.
Characterizing the quantumness of mixed-state ensembles via the coherence of Gram matrix with generalized α-z-relative Rényi entropy
Authors: Yuan Wendao , Wu Zhaoqi , Fei Shao-Ming
Published: October 2022

The Gram matrix of an ensemble of pure states can be regarded as a quantum state, and the quantumness of the ensemble can be quantified by the coherence of the Gram matrix. By using the affinity between mixed states, the concept of Gram matrix of pure-state ensembles can be extended to the one of mixed-state ensembles. By utilizing the generalized α-z-relative Rényi entropy of coherence of Gram matrices, we present a new quantifier of quantumness of mixed-sate ensembles and further reveal its peculiar properties. To illustrate our quantumness of mixed-sate ensembles, we also calculate the quantumness for some detailed mixed-sate ensembles by deriving their analytical formulae.
Understanding fast ion dynamics in sodiated Li4Na
x
Ti5O12: from interfacial to extended Li+ and Na+ dynamics in its mixed-conducting solid solutions
Authors: Posch Patrick , Lunghammer Sarah , Wilkening Alexandra , Hogrefe Katharina , Wilkening H Martin R
Published: October 2022

Climate change and energy crises require the development of new sustainable materials to realise reliable electrochemical energy storage devices. Spinel-type Li4Ti5O12 (LTO) is one of the most promising anode materials not only for Li-based batteries, but also for those relying on sodium. While Li+ ion dynamics at the early stages of lithiation has been studied already previously, almost no data on the diffusion properties of Na+ ions can be found in the literature. Here, we used nucleus-specific 7Li and 23Na nuclear magnetic resonance (NMR) spectroscopy to quantify the motional processes in mixed-conducting Li4Na
x
Ti5O12 with x = 0.1, 0.5 and 1.5 on the angstrom length scale. Most importantly, our results reveal a strong increase in Li+ diffusivity in the early stages of chemical sodiation that is accompanied by a sharp decrease in activation energy when x reaches 0.5. The two-component 7Li NMR spectra point to the evolution of an interfacial solid solution at very low sodiation levels (x = 0.1). At x = 0.5, these regions emerge over almost the entire crystallite area, enabling rapid 8a-16c-8a Li+ exchange (0.4 eV), which leads to facile long-range ion transport. We direct the attention of the reader towards the initial formation of solid solutions in LTO-based anode materials and their capital impact on overall ion dynamics. In contrast to macroscopic electrochemical testing, NMR is uniquely positioned to detect and to resolve these exceptionally fast ion dynamics during the initial stages of sodiation. As these processes crucially determine the fast-charging performance of LTO-type batteries, our study lays the atomistic foundations to establish a general understanding of why two-phase materials such as LTO can act as an impressive insertion host for both Li and Na ions.
177 GENOME-WIDE ASSOCIATION ANALYSIS OF THE FRAILTY PHENOTYPE IN UK BIOBANK HIGHLIGHTS CARDIOMETABOLIC AND AUTOIMMUNE SIGNATURES IN AGEING
Authors: McElheron M , Romero-Ortuno R , Kenny RA , O'Halloran A , Bourke N
Published: October 2022

Background

Frailty is a state of advanced biological age that is characterized by multisystem physiological decline and advanced risk to adverse health outcomes. One approach to defining frailty is using the Fried frailty phenotype, a five-point list of health-related criteria used to score individuals as non-frail, pre-frail, or frail. The biological basis of frailty is not fully understood, nor why some experience frailty at younger ages. Between 30%-45% of frailty risk is estimated to be genetic. This study aimed to investigate the genetic basis of frailty phenotype risk using data from UK Biobank.

Methods

UK Biobank is a large-scale biomedical database of community dwelling adults (n = 502,529, age range: 37-73 years, 54% female). UK Biobank has genome-wide genotyping (approx. 93 million variants), health, and demographic data for all participants. A genome-wide association study (GWAS) of the frailty phenotype was performed on British and Irish adults aged 60 to 70 years (n = 157,720) to identify heritable factors which predict frailty progression in later life. Functional mapping was performed to determine genes and biological pathways enriched in GWAS results.

Results

95 single nucleotide polymorphisms (SNPs) from three independent genomic risk loci were significantly associated (p < 5e-8) with the frailty phenotype in UK Biobank participants. Three genes, PPP1R3A, LONRF2, and AIF1 were statistically enriched with genetic variants. Tissue-specific expression analysis indicated genes differentially expressed in blood vessels were enriched. Linkage Disequilibrium Score Regression (lambda = 1.2005, intercept = 1.0006) indicated GWAS test statistic inflation resulting from polygenicity. SNP-based heritability was estimated to be 6.34% (SE: 0.36%).

Conclusion

SNP-based heritability of the frailty phenotype was lower than expected in comparison to previous reports of 30%-45%. Statistically significant genomic risk loci, genes, and tissue-enrichment pointed towards dysregulation of cardiometabolic, cardiovascular, and immunological processes in frailty risk, contrasting to brain pathways enriched in previous genomic analyses of the frailty index.
195 THE IMPACT OF COVID-19 RESTRICTIONS ON PATIENTS ATTENDING A FALLS ASSESSMENT SERVICE
Authors: Pierpoint R , Keating J , McElwaine P
Published: October 2022

Background

Covid-19 impacted older peoples’ confidence and mobility. Restrictions from March 2020 on our cohort of patients (> 65 years) reduced movement and social interactions leading to deconditioning and brain health implications. In our falls assessment service the clinical nurse specialist conducts a multifactorial assessment. We aimed to see if a difference existed in assessments of similar cohorts of patients’ pre and post restrictions.

Methods

A retrospective review of assessment measures for patients attending the falls service between October – December 2019 and 2021. Measures compared included gender, age, Fear-of-Falling (FOF), Timed Up and Go (TUG), Fracture Risk Assessment tool (FRAX), Vitamin D levels, grip strength and Body Mass Index (BMI).

Results

Twenty-two patient charts were reviewed from 2019 and 2021. Both years had similar female and male patient data reviewed (14/22 female 2019, 15/22 female 2021). FOF was noted in 38% (8/21) of patients in 2019, versus 45% (10/22) in 2021. In 2021 the average age of our patient cohort had decreased by three years. The TUG average time increased by 2 seconds in 2021 (median time decreased by 2.5 seconds). The major osteoporotic average percentage decreased in 2021 by 1.1%, (median drop 9%), the hip fracture percentage decreased by 2.5% in 2021 (median drop 10.5%). The average vitamin D level decreased by 1mmol in 2021 (median decreased 54mmol), while BMI average increased by 2kg/m² (median increased by 6kg/m²). The average grip strength results in 2021 dropped by 11.5kg (median decreased by 10.5kg).

Conclusion

Potential trends are observed in this data. We intend to examine a larger timeline/number of patients to be able to validate these findings, particularly FOF.
286 PERCEPTIONS OF RESEARCH AMONGST OLDER ADULTS
Authors: Davey N , Connolly E , McFeely A , Bambrick P , Pope G , Mulcahy R , Cooke J , O'Regan N
Published: October 2022

Background

Older adults are often excluded from healthcare research, particularly those with cognitive impairment. It is crucial that study participants have given informed consent and partake in research of their own free will. People with cognitive impairment are not always able to engage in the informed consent process. This can lead to under-representation of this cohort in studies. Understanding older people’s perceptions of research is important to better design policies and research studies that are inclusive of older adults. This pilot study aimed to gain a better understanding of older adults’ views about healthcare research and what they imagine their wishes would be if they were unable to consent themselves due to memory problems.

Methods

In this prospective observational study, participants were recruited from outpatient clinics. Consenting participants were surveyed over the phone to ascertain their perceptions of healthcare research.

Results

Twenty-five interviews were conducted. Median age was 76.24 years (range 68-85 years). Most respondents reached at least second level education (80%), and most volunteered knowing very little about healthcare research. All participants had a nominated next of kin. Of 23 participants who had not previously been involved in healthcare research, none had been asked to do so.

Most participants would be interested or very interested in participating in research if the study involved either survey questions (64%), chart review (88%), or additional investigations (68%), however only a minority were interested or very interested in partaking in research involving a trial drug (16%). Most participants (88%) would be happy or very happy for their next of kin to ‘consent’ on their behalf (if they themselves were unable to do so).

Conclusion

In this study, older adults had clear views about healthcare research and a keenness to participate. This group of older adults expressed trust in their next of kin to make decisions on their behalf regarding research participation. More research is required to explore this area further.
335 AN AUDIT OF ANTI-COAGULATION AND ANTI-PLATELET PRESCRIBING POST-INTRACEREBRAL HEMORRHAGE
Authors: Hanrahan C , Hyland N , Kitt K
Published: October 2022

Background

Choosing if, and when antithrombotic therapy should be re-started after Intracerebral Haemorrhage (ICH) is a decision commonly faced by clinicians working in stroke medicine. In spite of this, there is a dearth of international guidelines to support clinicians in decision making. Two recent Randomised-Controlled Trials (RCT), RESTART and SO-START, have indicated that anti-thrombotic therapy may have a better benefit:risk ratio than previously thought for patients post ICH. We conducted an audit of our practice in our tertiary hospital in 2020, a centre dealing with acute stroke.

Methods

Data was sourced from the local HIPE repository and included patients with acute, spontaneous ICH. Data was examined for variables which may influence decision to re-introduce anti-thrombotics such as indication for anti-thrombotic, type of anti-thrombotic, length of time to re-start anti-thrombotic post ICH, survival at discharge, and follow-up imaging. Our practice was compared to the intervention arms of the two previously mentioned RCT's.

Results

Of 56 included patients, 42 patients (75%) survived to discharge. Chi-squared analysis was used to assess for associations between variables. Of patients taking anti-platelets at time of ICH, only 25% were restarted on anti-platelet therapy at one year. Mean time to restarting anti-platelets post ICH was 20 weeks. For patients on oral anti-coagulation, 70% were restarted on oral anti-coagulation at one year. Mean time post ICH for restarting oral-anticoagulation was 14 weeks. No patients with amyloid angiopathy confirmed on MR Brain (n=5), were restarted on anti-thrombotic therapy, which was statistically significant. (p<0.01).

Conclusion

Results of our audit revealed a smaller proportion of patients were re-started on anti-platelet therapy compared to anti-coagulant therapy, despite trial evidence suggesting both are reasonable options for patients post ICH. Confirmed amyloid angiopathy was associated with a reduced rate of re-starting anti-thrombotic therapy. Further research is needed to examine outcomes amongst those restarted on antithrombotic therapy and to develop practice guidelines in this area.
361 EXPLORING THE EXPERIENCES OF HEALTHCARE PROFESSIONALS (HCPS) WORKING IN ACUTE STROKE DURING THE COVID-19 PANDEMIC: A QUALITATIVE STUDY
Authors: Donohue N , Galvin R , Horgan F
Published: October 2022

Background

The COVID-19 pandemic had a significant impact on the delivery of stroke care internationally. The INAS (Irish National Audit for Stroke) report 2020, found that there was no significant disruption to stroke services as a result of the COVID-19 pandemic. Little is known about the experiences of Health-Care Professionals (HCPs) who were working in stroke care during the COVID-19 pandemic. This study explored the experiences of HCPs working in acute stroke care in an Irish hospital group during the COVID-19 pandemic.

Methods

A qualitative descriptive study was conducted. Using a combination of purposive and snowball sampling, 16 semi-structured interviews of healthcare professionals from six specialities (Medicine, Nursing, Physiotherapy, Occupational therapy, Speech and Language Therapy and Medical Social Work) in two model three hospitals and one model four hospital were conducted. Interviews were virtual. Analysis was completed using the Braun and Clarke six-step method. This research was approved by the Royal College of Surgeons Research Ethics committee and permission was secured from the Stroke Clinical lead at each site to conduct interviews.

Results

Two main themes emerged: (i) Disruption of the end-to-end acute stroke pathway and (ii) Opportunities of the pandemic to develop a new model of care. Theme (i) suggests challenges were experienced in emergency care, access to Stroke Units (SU) beds and multidisciplinary teams (MDT). In theme (ii) participants described opportunities in telemedicine, the development of new rehabilitation and existing Early Supported Discharge (ESD) pathways.

Conclusion

This study highlights the lived experience of HCPs, the disruption to the stroke pathway and the opportunities as a result of the pandemic. It demonstrates the need for further exploration of, telemedicine, alternative rehabilitation pathways in stroke care and the need for a wider stroke education programme for HCPs working outside stroke. Finally, this study highlights the unwavering resilience and empathy of HCPs working in Stroke.
The Jurisdictional Vacuum: Transnational Corporate Human Rights Claims in Common Law Home States
Authors: Ahmad Hassan M
Published: October 2022

Private MNCs that operate in developing host states through overseas subsidiaries are regularly accused of human rights and environmental violations. Host state plaintiffs who then seek redress in home states where a corporate parent is domiciled face a number of doctrinal limitations. Focusing on the United States, the United Kingdom, and Canada, this Article outlines the current state of common law doctrines that consistently inhibit host state plaintiffs from advancing transnational home state claims. Cumulatively, the doctrines create a ‘jurisdictional vacuum,’ illustrating that domestic legal principles have not kept pace with commerce that spans across state borders. As international business has been able to structure itself to avoid the adjudicative reach of home state courts, harmed host state plaintiffs are unable to utilize domestic common laws to exact civil liability and obtain compensation.

Comprised mainly of transnational claims that originate in commercial activities in the extractive and manufacturing industries, the vacuum’s doctrinal limitations fall within two broad categories. In the first category, home state courts have parochially interpreted corporate legal personality. Adhering to the corporate veil, they have disaggregated otherwise integrated transnational business operations in accordance with the entity theory of liability. They have also disaggregated MNC liability from government and individual liability by, respectively, holding onto ‘statist’ notions of international law and restrictively construing corporate personhood. In the second category, home state courts have taken restrained approaches to transnational corporate claims that implicate foreign relations or trade and investment or, otherwise, impinge on a host state’s judicial system. They have routinely invoked deferential and prudential doctrines, namely forum non conveniens and act of state, and restrictively interpreted the presumption against extraterritoriality. And when they have eschewed restraint in boomerang litigation, the end result has equally thwarted the ability of host state plaintiffs to procure compensatory remedies.
Role of gut-microbiota in disease severity and clinical outcomes
Authors: Yadav Monika , Chauhan Nar Singh
Published: October 2022

A delicate balance of nutrients, antigens, metabolites and xenobiotics in body fluids, primarily managed by diet and host metabolism, governs human health. Human gut microbiota is a gatekeeper to nutrient bioavailability, pathogens exposure and xenobiotic metabolism. Human gut microbiota starts establishing during birth and evolves into a resilient structure by adolescence. It supplements the host's metabolic machinery and assists in many physiological processes to ensure health. Biotic and abiotic stressors could induce dysbiosis in gut microbiota composition leading to disease manifestations. Despite tremendous scientific advancements, a clear understanding of the involvement of gut microbiota dysbiosis during disease onset and clinical outcomes is still awaited. This would be important for developing an effective and sustainable therapeutic intervention. This review synthesizes the present scientific knowledge to present a comprehensive picture of the role of gut microbiota in the onset and severity of a disease.
The LCD-Composer webserver: high-specificity identification and functional analysis of low-complexity domains in proteins
Authors: Cascarina Sean M , Ross Eric D
Published: October 2022

Low-complexity domains (LCDs) in proteins are regions enriched in a small subset of amino acids. LCDs exist in all domains of life, often have unusual biophysical behavior, and function in both normal and pathological processes. We recently developed an algorithm to identify LCDs based predominantly on amino acid composition thresholds. Here, we have integrated this algorithm with a webserver and augmented it with additional analysis options. Specifically, users can (i) search for LCDs in whole proteomes by setting minimum composition thresholds for individual or grouped amino acids, (ii) submit a known LCD sequence to search for similar LCDs, (iii) search for and plot LCDs within a single protein, (iv) statistically test for enrichment of LCDs within a user-provided protein set and (v) specifically identify proteins with multiple types of LCDs.

Availability and implementation

The LCD-Composer server can be accessed at http://lcd-composer.bmb.colostate.edu. The corresponding command-line scripts can be accessed at https://github.com/RossLabCSU/LCD-Composer/tree/master/WebserverScripts.
HaploDMF: viral haplotype reconstruction from long reads via deep matrix factorization
Authors: Cai Dehan , Shang Jiayu , Sun Yanni
Published: October 2022

Motivation

Lacking strict proofreading mechanisms, many RNA viruses can generate progeny with slightly changed genomes. Being able to characterize highly similar genomes (i.e. haplotypes) in one virus population helps study the viruses’ evolution and their interactions with the host/other microbes. High-throughput sequencing data has become the major source for characterizing viral populations. However, the inherent limitation on read length by next-generation sequencing makes complete haplotype reconstruction difficult.

Results

In this work, we present a new tool named HaploDMF that can construct complete haplotypes using third-generation sequencing (TGS) data. HaploDMF utilizes a deep matrix factorization model with an adapted loss function to learn latent features from aligned reads automatically. The latent features are then used to cluster reads of the same haplotype. Unlike existing tools whose performance can be affected by the overlap size between reads, HaploDMF is able to achieve highly robust performance on data with different coverage, haplotype number and error rates. In particular, it can generate more complete haplotypes even when the sequencing coverage drops in the middle. We benchmark HaploDMF against the state-of-the-art tools on simulated and real sequencing TGS data on different viruses. The results show that HaploDMF competes favorably against all others.

Availability and implementation

The source code and the documentation of HaploDMF are available at https://github.com/dhcai21/HaploDMF.

Supplementary information

Supplementary data are available at Bioinformatics online.
Cerebrovascular insulin receptors are defective in Alzheimer’s disease
Authors: Leclerc Manon , Bourassa Philippe , Tremblay Cyntia , Caron Vicky , Sugère Camille , Emond Vincent , Bennett David A , Calon Frédéric
Published: October 2022

Central response to insulin is suspected to be defective in Alzheimer’s disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood–brain barrier and whether alterations of this interaction could contribute to Alzheimer’s disease pathophysiology both remain poorly defined.

Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer’s disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer’s disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood–brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer’s disease neuropathology induces insulin resistance at the level of the blood–brain barrier.

Overall, the present data in post-mortem Alzheimer’s disease brains and an animal model of Alzheimer’s disease indicate that defects in the insulin receptor localized at the blood–brain barrier strongly contribute to brain insulin resistance in Alzheimer’s disease, in association with β-amyloid pathology.
Changes in the Syphilis Rapid Plasma Reagin Titer Between Diagnosis and Treatment
Authors: Pandey Katrina , Fairley Christopher K , Chen Marcus Y , Williamson Deborah A , Bradshaw Catriona S , Ong Jason J , Aung Ei T , Chow Eric P F
Published: October 2022

Background

We compared the rapid plasma reagin (RPR) titer on the day of initial presentation with that on the day of syphilis treatment to inform clinical practice as to whether a repeated RPR test should be recommended.

Methods

We undertook a retrospective study between 1 March 2011 and 31 December 2020 at the Melbourne Sexual Health Centre in Australia among individuals who underwent syphilis serology on the day of initial presentation and the day of treatment, if the latter were within 14 days after initial presentation. We calculated the percentage of individuals with a ≥4-fold change in RPR titer, stratified by the time between initial presentation and treatment and by syphilis stage.

Results

Among the 766 included syphilis cases, the median duration between initial presentation and treatment was 6 days (interquartile range, 5–7 days). Of these cases, 14.8% (n = 113) had a ≥4-fold increase or decrease during this interval. The number of cases with a ≥4-fold increase or decrease in RPR titer increased with increasing time between initial presentation and treatment, from 5.7% (n = 6) 1–3 days after initial presentation to 26.2% (n = 27) at 10–14 days (Ptrend < .001). There was no significant difference in the number of cases with a ≥4-fold increase or decrease in RPR titer between syphilis stages (P = .66).

Conclusions

Our data support the recommendation of repeating the RPR titer if the day of initial presentation and the day of treatment are different, even when treatment is within a few days after initial presentation.
Disjunctive Total Domination In Harary Graphs
Authors: Çiftçi Canan , Aytaç Vecḋ
Published: October 2022

Let $ G $ be a graph. A set $ S $ of vertices in $ G $ is a disjunctive total dominating set of $ G $ if every vertex is adjacent to a vertex of $ S $ or has at least two vertices in $ S $ at distance two from it. The disjunctive total domination number, $ \gamma _t^d(G) $, is the minimum cardinality of such a set. In this paper, we determine disjunctive total domination number of Harary graph $ H_{k,n} $ for all $ k $ and $ n $.
Understanding subjective inequality in China
Authors: Song Xi
Published: October 2022

Rising income inequality is a critical global problem that has rapidly accelerated over the past two decades. Yet most people in China are misinformed about inequality because of the government’s control over media via propaganda and censorship. This paper examines how rising inequality is perceived, publicized, and interpreted in contemporary China, where reporting on inequality is actively framed and consumed in the interests of political stability. Combining automated text analysis of millions of news articles and social media data and metric methods for survey questions on individuals’ attitudes, beliefs, and opinions, I test the formation of public misperception of inequality through two interlocking processes. First, during the production of news, Chinese media suppresses and selectively covers some topics related to inequality. Specifically, media outlets under tighter government control tend to cover more news on Chinese political, rural–urban, and historical inequality, and they focus less on educational and economic inequality and western politics. Second, Chinese media also affects individuals’ perceptions about inequality during the consumption of news. Users of state-owned media tend to underestimate the level of inequality compared with users of marketized or social media. These findings call attention to the political roots of the gap between real and perceived inequality.
Iron deficiency and cardiovascular disease
Authors: Savarese Gianluigi , von Haehling Stephan , Butler Javed , Cleland John G F , Ponikowski Piotr , Anker Stefan D
Published: October 2022

Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials.
Can people afford to pay for health care? Evidence on inequity in financial protection in Europe
Authors:   Organised by: WHO Europe,   Moderator: Natasha Azzopardi Muscat (WHO Europe)
Published: October 2022

Governments have repeatedly affirmed their commitment to meeting the goals of universal health coverage (UHC) – to ensure that everyone can use the quality health services they need without experiencing financial hardship. In spite of strong political commitment to UHC, research from the WHO Regional Office for Europe shows that:

This session aims to raise awareness about the most prevalent gaps in coverage in European health systems, the policies that cause them and what countries can do to address them. It will draw on findings from an updated version of the WHO study ‘Can people afford to pay for health care? New evidence on financial protection in Europe’, which covers over 35 countries in Europe, including all EU member states and many middle-income countries

The session will highlight common gaps in coverage that systematically harm people with low incomes:

The session will focus on how to make progress by:

Keynote speaker:

Charles Normand

Trinity College Dublin, Dublin, Ireland

Panellists:

Sarah Thomson

WHO Europe

Kaisa Immonen

European Patients' Forum (EPF)