bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal calcium dysregulation in mice at an early stage of tauopathy and its alleviation by a tau antibody
Authors: Ji Changyi , Lin Yan , Sigurdsson Einar M. 
Published: December 2022

AbstractBackgroundTau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. How tau antibodies restore neuronal function remains unknown. Neuronal activity can be monitored by two‐photon calcium imaging in awake and behaving animals. Using this method, we observed altered neuronal calcium activity in the motor cortex of 12‐month‐old JNPL3 tauopathy mice during quiet wakefulness or forced running (Wu Q et al, Neurobiol. Dis. 2021). We also demonstrated that a mouse monoclonal antibody, targeting phosphorylated tau‐Ser396/Ser404, significantly restored the abnormal calcium activity and decreased pathological tau levels in these mice. Analysis of possible neuronal functional deficits and tau antibody efficacy in younger tauopathy mice warrants further investigation.MethodsSomatic calcium activity in the motor cortex of 6‐month‐old JNPL3 mice were assessed by two‐photon microscopy when animals were either resting or running on a treadmill. At this age, JNPL3 mice are in their early stage of tauopathy. The frequency, amplitude and total activity of calcium transients were analyzed and compared between wild‐type and JNPL3 mice. After the first imaging session, two doses (100 µg each) of a tau antibody were administered intravenously to JNPL3 mice four days apart. The somatic calcium activity was assessed again in these animals four days later, and compared to their neuronal calcium activity profile before tau antibody treatment.ResultsWe found abnormal cortical calcium activity in resting and running JNPL3 mice at 6 months of age. Brain levels of pathological tau correlated with the degree of calcium dysfunction. Acute treatment with a tau antibody attenuated these changes, whereas littermate JNPL3 mice treated with control IgG showed no improvements.ConclusionThese findings revealed neuronal calcium dysregulation in JNPL3 mice at an early stage of tauopathy that was partially corrected by an acute tau antibody treatment, analogous to our prior findings at a later stage of tauopathy. Together, these results indicate that neuronal dysfunction correlates with tau pathology at various stages of tauopathy, which can be consistently alleviated by a tau antibody treatment. This type of functional evaluation in vivo is a valuable way to study tau pathogenesis, and assess therapeutic efficacy at different stages of tauopathy.
Advancing the Science of Recruitment and Retention in Alzheimer’s disease Clinical Studies among Spanish‐speaking immigrant Latino/Hispanic communities
Authors: Diaz‐Santos Mirella , Eliseo Stephanie G Ovalle , Ryan Gery W. , Talamantes Efrain , Bookheimer Susan Y. , Moreno Gerado 
Published: December 2022

AbstractBackgroundWhile Latinos/Hispanics living with Alzheimer’s are projected to grow 832% by the year 2060, they make up approximately 7.5% of research participants across 32 federally funded Alzheimer’s Disease Research Centers. Our previous work presented at AAIC 2020 highlighted how the Human Connectome Project’s study design automatically excluded 94% of potential Latino/Hispanic community members in Southern California due to language. As a result, the individuals recruited and retained were mostly bilingual white Latinos/Hispanics with higher education and occupational attainment and high levels of research literacy, resembling the well‐known WEIRD sample (e.g., White, Educated, Industrialized, Rich, and Democratic). In the current study, we sought to understand the role of Latino/Hispanic community stakeholders in involving community members more representative of Southern California (Spanish‐Speaking, low income, immigrants, Afro‐Latinx, Indigenous Natives).MethodDuring the COVID‐19 pandemic, we recruited 11 community stakeholders from Southern California to complete a 1‐hour semi‐structured interview via an HIPPA compliant zoom platform. All participants were involved in Latino healthy aging and Alzheimer’s Disease organizations. We conducted a preliminary reflexive thematic analysis from the interviews.ResultThe overarching theme surrounded the exclusion of Latinx/Hispanic community stakeholders from leadership conversations about Alzheimer’s disease clinical research priorities. The systematic exclusion of community stakeholders from leadership tables lead to non‐inclusive community engagement and research practices. They were solely used for outreach (“find me your people”), as well as for the translation of recruitment materials, and/or for the sole administration of poorly translated and non‐culturally adapted outcome measures. These practices lead to the exclusion of Spanish‐speaking, immigrant communities through language and cultural isolation, triggering negative cognitive schemas and negative beliefs from previous traumatic experiences of exclusionary practices in the United States.ConclusionOur findings highlight how the Alzheimer’s disease clinical research enterprise continues to propagate multi‐level systematic exclusionary practices, accounting for the lack of equitable representation of high‐risk Latinx/Hispanic communities in research. To advance the science of recruitment and retention, and brain health equity, we need to systematically employ transformative community engagement and inclusive science models where Latinx/Hispanic community stakeholders are essential in decision‐making research process with equal‐power and shared governance.
Amyloid beta deposition in the lumbosacral spinal circuit impairs both the short‐term and long‐term neuroplasticity of locomotion.
Authors: Huang Ruyi 
Published: December 2022

AbstractBackgroundLocomotion deficits have emerged as a novel predictor of the pathological progression of the Alzheimer’s disease (AD). In this study, we hypothesize that spinal cord is impacted by the protein pathogenic in the AD.MethodTo rule out the impact of the supraspinal structures, we transected spinal cord completely at thoracic level 10 to cut off all connections between the lumbosacral spinal cord and all the rostral parts of the central nervous system (CNS). The short‐term plasticity of the lumbosacral locomotor circuit was evaluated by an instrumental learning model, paw withdrawal paradigm (PaWL) and the long‐term plasticity was investigated by weekly bipedal treadmill stepping paradigm, which lasted for seven weeks.ResultBoth 4mon and 13mon J20 mice showed significant decreases in the PaWL compared to their WT littermates (p = 0.0075). The spontaneous bipedal locomotion recovery was also blocked in spinal J20 mice when compared to WT littermates (p = 0.0031). These impairments of lumbar circuit plasticity were reversed by the administration of a gamma‐secretase inhibitor (Benzodiazepine‐type LY‐411575) in the spinal J20 mice, suggesting the generation of amyloid beta in local spinal cord circuit contribute to the locomotor deficits.ConclusionThe soluble beta amyloid expression levels in the lumbar spinal cord impair both the the long‐term and short‐term neuroplasticity of locomotion.
Sleep medication use and falls risk among African Americans with dementia
Authors: Anderson Loretta R. , Wennberg Alexandra MV 
Published: December 2022

AbstractBackgroundSleep disturbances and falls are frequent in older adults and risk increases with increasing age (M. Ohayon, 2002; World Health Organization, 2007), especially for those people living with dementia (PLWD). While existing research sheds light on the difference between high‐ and low‐ frequency sleep medication use in people with and without dementia (L. Anderson, 2021), little evidence exists in the nature of racial differences. This study seeks to determine the differential effect of high versus low frequency sleep medication use in non‐Hispanic Blacks with dementia.MethodWe used data from the 2011 National Health and Aging Trends Study (n = 8,245) to create logistic regression models examining the association high‐ versus low‐ frequency sleep medication use with falls in community‐dwelling non‐Hispanic Blacks living with dementia. High‐frequency sleep medication use was defined as 5 or more nights per week, while low‐frequency sleep medication use was defined as 4 or fewer nights per week.ResultIn our fully adjusted model, non‐Hispanic Blacks living with dementia (n = 121) who were high‐frequency sleep medication users were much more likely to fall compared to non‐Hispanic Blacks living with dementia who were low‐frequency sleep medication users (OR = 7.59, 95% CI: 2.86, 20.13). Fully adjusted model controlled for sociodemographic characteristics, anxiety, depression, arthritis, diabetes, and hypertension.ConclusionAfter controlling for potential confounders, non‐Hispanic Blacks living with dementia and having high‐frequency sleep medication usage are over 7 times more likely to fall compared with non‐Hispanic Blacks with dementia who have low‐frequency sleep medication usage. Reducing sleep medication use in this population may help reduce the risk of falls and fall‐related outcomes.
Spreading of Tau and other corrupted proteins through the gut‐brain axis
Authors: Martin‐Peña Alfonso , Lopez‐Scarim Joshua , Tansey Malu Gamez 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. However, although the clinical and pathological aspect of the disease are thoroughly characterized, the pathophysiological mechanism underlying the progressive neurodegenerative process is not well understood. In consequence, there is no cure and a disease‐modifying treatment is lacking. It is therefore imperative to identify the earliest signs of disease pathology to pave the way to identify the triggering molecular factors of the disease and the mechanisms underlying molecular spreading of toxic assemblies. Our search for these key clues in the periphery is founded on the fact that peripheral dysfunction, particularly in the gastrointestinal (GI) system, can arise decades before the onset of the classic symptoms in neurodegenerative disorders. In fact, the risk of AD increases significantly in patients with inflammatory bowel disease (IBD) when compared with the non‐IBD population. Furthermore, Tau accumulates in Crohn’s Disease guts and in sigmoid colon of AD and FTD patients. Therefore, we are investigating the physiological and molecular mechanisms that support Tau spreading in the prodromal stages and, particularly, along the gut‐brain axis.MethodTo test whether corrupted proteins expressed in the gut will spread to the brain, we employed the Gal4/UAS system and expressed wild type human Tau in selected populations of gut epithelium cells. We then monitor behavior on aging flies expressing Tau in the gut epithelium using Drosophila activity monitors (DAM) and analyzed their circadian patterns of activity along with several sleep parameters.ResultWe observed that flies selectively expressing full length (2N4R) human Tau in enteroendocrine cells of the gut exhibited a significant impairment in their daily activity pattern that specifically affected their behavior during the light phase (day) but not during the dark period (night). Interestingly, these flies also showed an increased sleepiness during the day without affecting their nocturnal sleep pattern. The onset of these behavioral changes appears to occur as early as 10 days after eclosion.ConclusionOur results support the presence of spreading mechanisms for Tau from gut epithelial cells to the brain; hence, affecting the neuronal physiology that sustain daily activity patterns.
SORL1‐retromer regulates endosomal recycling and helps explain Alzheimer’s regional vulnerability
Authors: Small Scott A. 
Published: December 2022

AbstractThe importance of the endosomal recycling pathway for cellular health was recognized ever since its reverse trafficking itinerary, clathrin‐dependent endocytosis, was described. Vital for synaptic function, a recent study found that neurons are endowed with a distinct unit dedicated to the recycling pathway. Akin to how endocytosis is regulated by a functional unit formed by the clathrin coat interacting with low‐density lipoprotein‐related receptors (LDLRs), recent studies will be reviewed suggesting that endosomal recycling in neurons is regulated by a functional unit comprised of a neuronal‐enriched retromer coat that interacts with the sortilin‐related receptor SORL1. Genetic studies suggest that rare truncating mutations in SORL1, inducing SORL1 haploinsuffiency, acts a causal event in triggering Alzheimer’s disease (AD). In agreement with this interpretation, recent studies will be reviewed showing that SORL1 haploinsufficiency can trigger AD’s cardinal pathologies, including showing in mice that it leads to selective atrophy in the trans‐entorhinal cortex. These studies suggest that SORL1‐retromer recycling is a causal pathway in AD that when disrupted can trigger AD’s molecular, cellular, and anatomical pathologies. When interpreted together with a collection of other studies this recent insight suggests why the trans‐entohrinal cortex is so dependent on SORL1‐retromer recycling, why the trans‐entorhinal cortex is differentially vulnerable even to ‘sporadic’ AD, and why AD anatomically ‘spreads’ over time.
Single cell biology to analyse cellular heterogeneity in the response to amyloid plaques in Alzheimer’s Disease
Authors: De Strooper Bart 
Published: December 2022

AbstractMicroglial activation and neuroinflammation are crucial in the pathogenesis of Alzheimer’s disease. However, studies in mouse models and human postmortem samples have yielded divergent results regarding transcriptional programs in microglia elicited by exposure to amyloid‐b pathology. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for AD. Human microglia adopt a different, more complex spectrum of cell states than mouse microglia. Besides a disease associated (DAM) profile, human microglia show a pronounced HLA‐response related to antigen presentation in response to amyloid‐b plaques, which is absent in mouse. Furthermore, oligomeric amyloid‐β present in this model induces a distinctive pro‐inflammatory CRM response characterized by the expression of cytokines and chemokines, also not seen in mice. TREM2 and APOE polymorphisms modulate the response of microglia to amyloid‐b plaques, much less to oligomeric Aβ. In conclusion, human microglia mount a multipronged ARM response to amyloid pathology in Alzheimer’s disease. This implies that therapeutic strategies targeting microglia need to analyse carefully the effect on these different cell states some of which seem protective.
Lifestyle impacts on insulin transport at the blood‐brain barrier in mice
Authors: Rhea Elizabeth 
Published: December 2022

AbstractBackgroundThe blood‐brain barrier (BBB) is a regulatory interface, controlling the blood‐to‐brain transport of many substances, resulting in nutrient delivery to the central nervous system (CNS) and communication between the periphery and CNS. There are structural and functional changes within the BBB in Alzheimer’s disease, which may contribute to the detrimental effects occurring within the CNS. CNS insulin resistance is one of many detrimental features of Alzheimer’s disease. As the BBB is responsible for the delivery of insulin to the CNS, alterations in insulin BBB transport could be a cause of CNS insulin resistance. Indeed, various lifestyle factors are known to impact insulin BBB pharmacokinetics, including diet and exercise, which have also been shown to impact Alzheimer’s disease progression.MethodsUtilizing sensitive radiotracer methods of substrate transport at the BBB in young male and female mice, we investigated the impact of exposure to a voluntary running wheel and what role CNS insulin resistance has on insulin BBB pharmacokinetics.ResultsAcute exercise increased insulin BBB transport and CNS insulin resistance decreased insulin brain uptake.ConclusionCNS insulin resistance decreases insulin BBB transport in mice, particularly in females. We found a lifestyle intervention, such as exercise, is able to enhance insulin BBB transport, which may be able to attenuate CNS insulin resistance. Future work is necessary to determine if exercise can reverse the insulin BBB transport deficiencies observed due to CNS insulin resistance.
Shell‐type supernova remnants and very high energy cosmic rays
Authors: Sinitsyna Vera G. , Sinitsyna Vera Y. 
Published: December 2022

AbstractThe investigation of very high energy (VHE) γ‐ray sources by any methods, including mirror Cherenkov telescopes, touches on the problem of the cosmic‐ray origin and, accordingly, the role of the Galaxy in their generation. The SHALON observations have yielded the results on Galactic supernova remnants (SNR) of different ages. Among them are: the shell‐type SNRs Tycho's SNR, Cas A, IC 443, γCygni SNR, G166.0+4.3. For each of SNRs, the observation results are presented with spectral energy distribution by SHALON in comparison with other experiment data and images by SHALON in together with data from X‐ray by Chandra and radio‐data by CGPS. The experimental data presented here have confirmed the prediction of the theory about the hadronic generation mechanism of VHE 800 GeV–100 TeV γ‐rays in Tycho's SNR, Cas A and IC 443, and also the collected experimental data help to make clear the origin of TeV γ‐ray emission in the older SNRs like γCygni SNR and G166.0+4.3.
Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1
Authors: Lajmi Yosra , Loeuillet Laurence , Petrilli Giulia , Egloff Charles , Nectoux Juliette , Molac Clémence , Roux Nathalie , Pannier Emmanuelle , Achaiaa Amale , Arkoub Zaina Ait , Chuon Sophie , Coussement Aurélie , Dupont Jean Michel , Malan Valérie , Spaggiari Emmanuel , Razavi Ferechte , Amiel Jeanne , Bessières Bettina , Grotto Sarah , Attié‐Bitach Tania 
Published: December 2022

AbstractBackgroundHereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases.CasesIn our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation.ConclusionCystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.
Design, Synthesis, Insecticidal Activities and Molecular Docking of Sulfonamide Derivatives Containing Propargyloxy or Pyridine Groups
Authors: Zhu Jian‐Jun , Guo Tao , Zhang Zi‐Wei , Qian Hao , Tian Peng , Yu Ke‐Yin , Wu Wen‐Jun , Zhang Ji‐Wen 
Published: December 2022

AbstractThe discovery of new highly active molecules from natural products is a common method to create new pesticides. Celangulin V targeting Mythimna separate (M. separate) midgut V‐ATPase  H subunit, has received considerable attention for its excellent insecticidal activity and unique mechanism of action. Therefore, combined with our preliminary work, thirty‐seven sulfonamide derivatives bearing propargyloxy or pyridine groups were systematically synthesized to search for insecticidal candidate compounds with low cost and high efficiency on the  H subunit of V‐ATPase. Bioactive results showed that compounds A2‐A4 and A6‐A7 exhibited a better bioactivity with median effective concentration (LC50) values (2.78, 3.11, 3.34, 3.54 and 2.48 mg/mL, respectively) against third‐instar larvae of M. separate than Celangulin V (LC50=18.1 mg/mL). Additionally, molecular docking experiments indicated that these molecules may act on the H subunit of V‐ATPase. Based on the above results, these compounds provide new ideas for the discovery of insecticides.
Benedikt syndrome in a 74‐year‐old hypertensive woman: A case report
Authors: Adhikari Abhishek , Bhattarai Ayush Mohan , Pandit Ayushma , Rokaya Pooja , Khadka Manoj , Shahi Manoj , Baiju Swastika , Poudel Raju 
Published: December 2022

AbstractBenedikt syndrome is a rare neurological disorder of the midbrain. Herein, we present a case of Benedikt syndrome, who presented with left‐sided body weakness, right oculomotor nerve palsy, cerebellar ataxia, and Holmes tremor in the left upper limb following midbrain infarction. She was treated with aspirin, clopidogrel, and amiodarone.
Influence of High Hydrostatic Pressure and Pulsed Electric Field Treatment on Moisture Absorption of Wheat Grains
Authors: Shorstkii Ivan , Mounassar Emad Hussein Ali , Bindrich Ute , Heinz Volker , Aganovic Kemal 
Published: December 2022

AbstractThe effect of high pressure (0.1–600 MPa) and pulsed electric field (E = 3 and 6 kV cm−1) pretreatments on the moisture absorption properties of non‐hulled wheat grains were investigated. Microwave sensor was used as a non‐invasive technique for determination of the moisture content. The results demonstrated that high pressure soaking (>100 MPa) of wheat grains significantly increased the water uptake. High pressure soaking (600 MPa) decreased the water uptake due to the starch gelatinization and as a result appearance of structural changes. Compared to control samples, PEF‐pretreated samples showed a sharp increase of water absorption at the initial process with a further reduction of equilibrium water content. Peleg's water absorption model was adapted to the measured data of non‐hulled wheat grains. Results showed a good prediction of Peleg's equation in all experiments, which gave the possibility for estimation of initial water absorption rate and equilibrium moisture content.
The Facets of Diversity: The EFMC Perspective**
Authors: Borsari Chiara , Matagne Brieuc , Goncharenko Kristina , Moreira Rui , Auberson Yves P. 
Published: December 2022

AbstractDiversity in science refers to cultivating talent, while promoting full inclusion across the community. In medicinal chemistry and chemical biology, it enhances creativity and encourages contributions from multiple perspectives, leading to better decision making and broader scientific impact. The European Federation for Medicinal chemistry and Chemical biology (EFMC) embraces and promotes diversity, to ensure representation of all talents, and enable equality of opportunity through fairness and transparency. EFMC has historically paid continuous attention to diversity in terms of culture, geography and equilibrium between academia and industry, with over the last few years a focus on increasing gender balance, aiming at a fair representation of the scientific community and equal opportunities independently of gender. EFMC promotes cultural diversity as it reinforces openness and mutual respect. All scientific organizations of a scope compatible with its remit are welcome within EFMC, where their members benefit from a welcoming, psychologically safe, and stimulating environment. Herein, we describe the state of diversity within the EFMC, how the situation has evolved over the years and where diversity should be further encouraged.