bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep extractive denitrogenation with Cu‐based ionic liquids and mechanistic insights
Authors: Wu Peiwen , Wang Bangzhu , Li Hongping , Ma Shaojie , Chen Linlin , Liu Jixing , Chao Yanhong , Zhu Wenshuai , Xu Chunming 
Published: January 2025

AbstractA major challenge in the extractive denitrogenation (EDN) of fuel oils lies in achieving high nitrogen removal efficiency with minimal extractant usage. To address this, a series of Cu‐based ionic liquids (ILs) ([Bmim]Cl/CuCl2‐X) with different cation‐to‐anion ratios were synthesized and characterized. The cation‐to‐anion ratio was found to be crucial in determining the predominant anions present in the ILs. Among the synthesized Cu‐based ILs, [Bmim]Cl/CuCl2‐1 exhibited outstanding EDN performance, achieving 100% nitrogen removal with minimal ionic liquid consumption. The anion [CuCl3]− was identified as playing a key role in the EDN process, where the unoccupied orbitals of Cu and the chloridion in [CuCl3]− facilitate effective coordination with nitrogen atoms in organic nitrogen compounds. This coordination forms Lewis acid–base interactions, which are essential for deep EDN. The study not only introduces an efficient Cu‐based ionic liquid but also provides insights into optimizing ionic liquid design for better extraction performance.
Risk of Raynaud's Phenomenon Among Workers in the Occupational Disease Surveillance System
Authors: Yeo Ryann E. , Eros Fanni R. , Demers Paul A. , Sritharan Jeavana 
Published: January 2025

ABSTRACTIntroductionRaynaud's phenomenon (RP) is linked to occupational exposures such as vibration, cold temperature, and chemicals. However, large cohort studies examining RP by occupation and sex are scarce. To address this gap, this study aimed to assess risk of RP by both occupation and sex in a large cohort of workers in Ontario, Canada.MethodsWorkers with accepted lost‐time compensation claims were linked to physician billing records to identify diagnoses of RP between 2002 and 2020. A 3‐year washout (disease‐free) period was applied, and follow‐up was limited to 5 years. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for diagnoses of RP, adjusted for age at start of follow‐up, birth year, and stratified by sex.ResultsA total of 7,131 RP cases were identified among 810,739 workers. Among men, higher risks were observed for truck drivers (HR = 1.23, 95% CI = 1.08–1.41), driver‐salesmen (HR = 2.54, 95% CI = 1.21–5.34), those in mining and quarrying‐related cutting, handling, and loading (HR = 2.57, 95% CI = 1.29–5.15), and construction trades laboring and elemental work (HR = 1.70, 95% CI = 1.24–2.34). Among women, higher risks were observed for those working in waitressing and related (HR = 1.70, 95% CI = 1.22–2.38), food and beverage preparation (HR = 1.34, 95% CI = 1.02–1.76), and electrical equipment fabricating and assembling (HR 1.96, 95% CI = 1.08–3.55).ConclusionStudy findings show elevated risks of RP among various occupations, with notable differences between men and women. These differences may be attributable to variations in potential exposures and susceptibility to RP. Findings underscore the need for large cohort studies to examine RP across various occupational groups and both sexes.
Osteoporosis Caused by Monoallelic Variant of WNT1 Gene in Four Pediatric Patients
Authors: Wang Qiao , Liu Min , Cao Bing‐Yan , Su Chang , Meng Xi , Ding Yuan , Ren Xiao‐Ya , Gong Chun‐Xiu 
Published: January 2025

ABSTRACTPediatric patients of autosomal dominant early onset osteoporosis conferred by heterozygous mutation in the WNT1 (OMIM: 615221) were rarely reported, and therapy in pediatrics is relatively inexperienced. The clinical and genotypic characteristics and treatment process of four children with osteoporosis caused by WNT1 monoallelic variation were analyzed. The patients admitted from June 2023 to January 2024. All patients presented multiple vertebral compression fracture, two of them experienced recurrent peripheral fragility fractures. The age of the first fractures occur between 2 years and 12 years. Lumber BMD by dual‐energy X‐ray absorptiometry were decreased (height adjusted z score of −8.06 to −3.50). Four monoallelic variants in WNT1 (c.505G>T, c.616G>A, c.677C>T and c. 506G>A with transcript ID. NM_005430.4) were identified in the probands, and relatives carrying mutations presented with a bone phenotype, consistent with autosomal dominant inheritance. Novel variant c.616G>A was analyzed by 3D protein structural modeling. Subsequent to the treatment of zelodronic acid on all four patients, lumbar BMD improvement by 0.061–0.251 g/cm2. Our data showed that the age of onset of osteoporosis by monoallelic variants in WNT1 is significantly earlier than the age of onset in the general population. Severe osteoporosis is also exhibited in pediatric patients, not just in aging patients with WNT1 variant. Zoledronic acid treatment is effective in short‐term observation for pediatric patients with improvement of bone pain and BMD, and no more facture during treatment.
Discovery and Characterization Small Molecule Modulators of Striatal‐Enriched Protein Tyrosine Phosphatase (STEP) for Alzheimer’s Disease Therapeutics
Authors: Wu Jiaqian , Han Ye Na , Cosford Nicholas , Tautz Lutz 
Published: January 2025

AbstractBackgroundA pathological hallmark of Alzheimer’s disease (AD) is the accumulation of amyloid‐beta peptide (Aß). Potential treatments targeting Aß production such as γ‐secretase inhibitors have had limited success. A promising alternative approach involves addressing early synaptic dysfunction by modulating molecules like striatal‐enriched protein tyrosine phosphatase (STEP), whose levels and activity are upregulated by Aß. The current model of STEP function is that it opposes the development of synaptic strengthening, and that high levels of STEP contribute to the cognitive deficits in AD. Importantly, genetic reduction or chemical inhibition of STEP reverses the cognitive and cellular deficits in an AD mouse model, validating STEP as a drug target in AD.MethodUsing 19F nuclear magnetic resonance (NMR) spectroscopy, a library of 1,000 fluorine‐containing fragments was screened to identify novel STEP binders. Initial hits were validated using a combination of biophysical binding assays including 19F NMR, 1D WaterLOGSY NMR, microscale thermophoresis (MST), and isothermal titration calorimetry (ITC). Based on a potent and selective fragment, STEP‐targeted protein degraders were designed, synthesized, and characterized in cellular experiments.ResultSeveral potent and selective fragments were identified and validated. Based on the most potent binder, five proteolysis targeting chimera (PROTAC) molecules were initially synthesized and characterized. These compounds demonstrated degradation of STEP in SH‐SY5Y neuroblastoma cells. One STEP PROTAC was able to penetrate the blood‐brain barrier and showed potent degradation efficacy in vivo.ConclusionOur fragment‐based discovery platform to identify novel STEP binders for the development of specific degrader molecules has yielded first‐in‐class STEP PROTACs. By targeting STEP and thus synaptic dysfunction, our research could provide valuable insights into the early stages of AD pathogenesis and contribute to the development of effective therapeutic strategies for this devastating disease.
Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N‐(pyridin‐3‐ylmethyl)quinoline derivative targeting synaptic plasticity
Authors: ZUCCARELLO ELISA , Zhang Hong , Acquarone Erica , Deng Shi‐Xian , Landry Donald W. , Arancio Ottavio , Fiorito Jole 
Published: January 2025

AbstractBackgroundThere are no cures for Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by elevation of beta‐amyloid and tau proteins besides neuronal death and causing cognitive impairment. Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate‐degrading enzyme involved in numerous biological pathways including those relevant to memory formation. PDE5 inhibition offers the potential to attenuate AD progression by acting at the downstream level of beta‐amyloid and tau elevation. None of the existing PDE5 inhibitors has been developed to be used in CNS diseases or possesses the selectivity required for chronic administration to an elderly population with comorbid conditions such as AD patients. We now propose to find PDE5 inhibitors (PDE5Is) that are tailored to the use in AD patientsMethodOur strategy used a combination of drug discovery, biochemical and electrophysiological techniques. We identified the quinoline scaffold of our lead compound 7a, 4‐((3‐chloro‐4‐methoxybenzyl)amino)‐8‐cyclopropyl‐3‐(hydroxymethyl)quinoline‐6‐carbonitrile, as a starting scaffold for a structure activity relationship study aimed at identifying the suitable isosteric substitutions, with the purpose of obtaining new PDE5Is that are more stable than compound 7a, while maintaining potency and selectivity towards other PDE isoforms. The most potent PDE5Is, showing an IC50 in the nano‐molar range, were advanced toward an in vitro metabolic stability assay, and compounds with the highest potency and microsomal stability were tested for phase I and II metabolic identification. Out of these small molecules, the most potent and stable quinoline derivate, compound 4b, was tested in electrophysiological experiments assessing long‐term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation.ResultThe characterization of compound 7a properties revealed high PDE5 potency (IC50 = 0.27 nM) and great selectivity, but low in vitro human microsomal metabolic stability (half‐life = 20.5min). The second‐generation PDE5Is, compound 4b (8‐cyclopropyl‐3‐(hydroxymethyl)‐4‐(((6‐methoxypyridin‐3‐yl)methyl)amino)quinoline‐6‐carbonitrile), (IC50 = 20 nM) had improved in vitro microsomal stability (t1/2 = 44.6 min), and an outstanding phase I and II metabolic profile. Both compounds ameliorated the deficit in LTP, a cellular surrogate of memory, after exposure of hippocampal slices to tau oligomers.ConclusionThese data suggest that compounds 7a and 4b are important leads in the pharmacologic restoration of cell‐to‐cell communication and memory in AD.
Synergistic influence of education and marriage on the risk for cognition loss among the older people in China
Authors: Sun Ning 
Published: January 2025

AbstractBackgroundThe study was aim to prove that both rationality and emotion are indispensable for older people to maintain their ability to live independently during the twilight of their lives.MethodThe resilience of older people to dementia were investigated by considering the interactions between educational levels and marriage status. Four sociodemographic variables (age, sex, educational level, and marital status) were collected from 1177 older Chinese participants, whose mini‐mental state examination scores (MMSE scores) were measured.ResultA lower educational level coupled with being widowed caused a greater risk for severe cognitive impairment (relative risk [RR] 1.48; 95% confidence interval [CI] 1.20‐1.82; p < 0.001) for high‐aged older participants (age range: ≥80) than for their low‐aged counterparts (age range: ≥60 and <80). In contrast, a higher educational level coupled with being married leveled this age‐related risk for cognitive loss (RR 0.91; 95% CI 0.65‐1.27; p = 0.62).ConclusionFurther findings suggest that the synergistic influence of education and marriage was observed only among high‐aged older people. Being both well‐educated and married is associated with a delayed cognitive function for older people. However, longevity is a prerequisite for realizing this benefit.
Latent atrophy factors in Primary Progressive Aphasia due to Alzheimer´s disease and linguistic features, across different cultural settings
Authors: Calandri Ismael Luis , Groot Colin , Wesseling Alex J. , Garcia Florentina Morello , Allegri Ricardo , Barkhof Frederik , Jonkman Laura E. , Pijnenburg Yolande A.L. , Ossenkoppele Rik 
Published: January 2025

AbstractBackgroundPrimary Progressive Aphasia (PPA) is a clinical entity that encompasses various neurodegenerative etiologies. Based on differential linguistic profiles, PPAhas been classified into three phenotypes (i.e., semantic [svPPA], non‐fluent [nfvPPA] and logopenic [lvPPA]), each characterized by unique atrophy patterns. Linguistic classification encounters a cultural barrier, as, e.g., certain features (like surface dyslexia) are difficult to objectify across languages, limiting the classification's generalizability. Our aim is to create an atrophy pattern detection model to predict PPA subtypes, independent of the cultural context that modifies linguistic features.MethodsWe extract latent gray matter atrophy factors (LF) in a cohort of 134 Dutch‐speaking individuals with a clinical diagnosis of PPA. We use a data‐driven Bayesian modeling framework using latent Dirichlet allocation, and uncovered four LF’s from standardized gray matter density images (adjusted for age, sex, and MRI scanner). For each subject, the probability of belonging to each of the four LF’s was calculated. The probability assignment to each LF was compared against the linguistic phenotype assigned by a neurologist and AD biomarker status. The model was also applied to post‐mortem MRI data from 4 subjects to examine their neuropathological correlates.Resultsthe 4 LF’s are shown in Figure 1. LF1 (“svPPA‐like”) showed left‐predominant temporo‐polar atrophy; LF2 (“nfvPPA‐like”) left‐predominant fronto‐opercular and insular atrophy; LF3 (“lvPPA‐like") left‐predominant posterior‐parietal involvement; LF4 (“other”) parieto‐occipital. Higher LF1 probability was significantly associated with a clinical svPPA diagnosis (non‐standarized b=11, 95%CI[7.2‐15.0], p<0.001), higher LF2probability with a nfvPPA diagnosis (7.2[4.0‐11.0], p<0.001), and higher LF3 probability with lvPPA (9.0[5.9‐13], p<0.001). Higher LF3 probability was associated with a higher frequency of positive AD biomarkers (7[4.6‐11], p<0.001; Figure 2). Model generalizability will be tested by classifying 35 Spanish‐speaking subjects with PPA from Argentina based on their atrophy pattern (data presented at the conference).ConclusionOur model demonstrates a strong ability to predict phenotypic classification and AD pathology through MRI. It can contribute to standardizing diagnostic performance across different cultural settings.
Communicating with patients about the new disease‐modifying treatment(s) for Alzheimer’s disease: the perspective of memory clinic professionals
Authors: Visser Leonie N.C. , Fluitman Tjeerd , van Gils Aniek M. , van der Veere Pieter J. , van Harten Argonde C. , Vijverberg Everard G.B. , van der Flier Wiesje M. 
Published: January 2025

AbstractBackgroundThe first disease‐modifying treatments (DMTs) for Alzheimer’s disease (AD) have been approved in the USA, marking profound changes in AD‐diagnosis and treatment. This will bring new challenges in terms of clinician‐patient communication. We aimed to collect the perspectives of memory clinic professionals regarding the most important topics to address and what (tools) would support professionals and their patients and care partners to engage in a meaningful conversation on whether (or not) to initiate treatment.MethodsSemi‐structured interviews were conducted with 16 professionals (10 neurologists, 4 geriatricians, 2 other; 7 female) with >5 years of experience in various Dutch memory clinics. We described the context of (at the time hypothetical) EMA approval, and asked questions such as ‘How would you communicate with patients about DMTs?’(Table 1). The transcribed audio‐recordings were analyzed by means of thematic analysis using MaxQDA software.ResultsA first overarching theme concerned the ambivalence that professionals expressed towards DMTs. On the one hand, they considered approval of the first DMTs as a hopeful development. On the other hand, they expressed caution considering expected effects, risks of (serious) side effects, and burdensome procedures. Professionals therefore emphasized the need for shared decision‐making (SDM) with patients and care partners. Second, to enable SDM, they stressed that professionals and patients must comprehend essential information, including the mechanisms of AD and DMTs, benefits, and potential negative aspects, and that patients/care partners express their needs, expectations, and personal circumstances. Third, professionals anticipated challenges, including the required consultation time and insufficient knowledge/experience with DMTs and/or SDM. They would therefore value education and communication tools, also for patients and care partners, to help them prepare for consultations and increase understanding (Table 2).ConclusionA broad representation of memory clinic professionals emphasized that initiating DMT for AD is a preference‐sensitive decision. SDM is not a new concept in memory clinics, yet professionals considered SDM imperative and more complex in the DMT‐context, because of the uncertainties regarding effects, risk of side effects, and burden of DMT‐administration/monitoring. To support professionals and patients in having a meaningful conversation about DMT‐initiation, educational materials and communication tools are needed.
Association of Acquired Immunodeficiency Syndrome with Alzheimer`s Disease‐Related Dementia in HIV‐Infected Individuals
Authors: Lee Young‐gun , Lee Eunyoung , Bang Jihwan 
Published: January 2025

AbstractBackgroundCognitive decline often follows human immunodeficiency virus (HIV) infection, yet the specific risk factors for developing Alzheimer’s disease and related dementia (ADRD) in HIV patients remain elusive.MethodTo investigate the association between acquired immune deficiency syndrome (AIDS) status at the time of HIV diagnosis and the risk of ADRD, we conducted a retrospective cohort study using data from a nationwide claim database spanning 2008 to 2021. During the study period, 13,289 patients were newly diagnosed with HIV infection and were prescribed antiretroviral therapy (ART). Among them, a total of 3,929 individuals over 40 years old, with a follow‐up exceeding 3 years and without dementia diagnosed within two months post‐HIV diagnosis, were included. Cox proportional hazards regression models for ADRD requiring medication such as anti‐cholinesterase inhibitor or memantine were performed using baseline presence of AIDS as a predictor, after adjusting for age, sex, insurance type, and comorbidities.ResultAmong the 3,929 participants (median age: 45 [IQR 15] years; 90.9% male), with a median follow‐up of 7.6 (IQR 5.0) years, 114 patients were diagnosed with ADRD. HIV individuals with AIDS at baseline had a higher risk of ADRD (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.51 – 3.31) compared to those without AIDS. The risk was more prominent in individuals under 50 years old (HR, 5.39; 95% CI, 2.22 – 13.05) than in those 50 years or older (HR, 1.68; 95% CI, 1.07 – 2.63; P for interaction = 0.03).ConclusionThis study underscores the need to stratify the management of cognitive impairment in newly diagnosed HIV patients based on their baseline AIDS status and age.
The effectiveness of psychological therapies for anxiety or depression, for people living with atypical dementia
Authors: Baou Celine El , Saunders Rob , Buckman Joshua , Richards Marcus , Cooper Claudia , Bell Georgia , Fearn Caroline , Pilling Stephen , Crutch Sebastian J , Zimmermann Nikki , Brotherhood Emilie V , John Amber , Stott Joshua 
Published: January 2025

AbstractBackgroundPrior research has highlighted that people living with dementia experiencing depression or anxiety can benefit from psychological therapies delivered in primary care. Yet, studies have mainly focused on common dementia types, leaving a gap in evidence for more atypical dementias, and especially those that are not memory‐led. This evaluation is crucial, given the unique challenges posed by these subtypes, such as syndrome‐specific symptoms of changes in personality or visual processing. This study assesses the effectiveness of psychological therapies provided in primary care settings for individuals with atypical dementia subtypes.MethodLinked national data from over 2 million individuals in the UK who received a course of therapy in NHS Talking Therapies for Anxiety and Depression services were used to identify 523 individuals with atypical dementias who attended therapy between 2012 and 2019. We compared their depression and anxiety outcomes to a cohort of individuals with no diagnosis of dementia.ResultPeople with atypical dementia had similar outcomes compared to people with typical dementia [Reliable improvement from depression and anxiety symptoms: AdjOR 1.08 (0.86; 1.36) p = 0.4850], but their therapy outcomes were poorer when compared to the matched cohort without dementia [Reliable improvement: AdjOR 0.70 (0.53; 0.91) p = 0.0150].ConclusionPeople with atypical dementia who experience depression or anxiety may benefit from psychological therapies provided in primary care. Their outcomes are poorer than those of people who do not have dementia. These results suggest a need to increase access to psychological therapies for people with atypical dementia and offer interventions that are better tailored to their specific experiences.
Deriving meaningful within‐patient change thresholds for the ADCS‐ADL in trials of early and mild‐to‐moderate Alzheimer’s disease ‐ a caregiver‐rated, anchor‐based analysis of the Tauriel and Lauriet trials
Authors: Ritchie Marina , Datta Seema , Lansdall Claire J , Monteiro Cecilia , Toth Balazs , Teng Edmond 
Published: January 2025

AbstractBackgroundClinical outcome assessments (COAs) that measure functional capacities are key tools to evaluate efficacy in Alzheimer’s disease (AD) clinical trials. The Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) scale is frequently used to assess changes in both basic and instrumental activities of daily living, but there is no clear consensus on what magnitude of change on this scale may be considered clinically meaningful. To address this question, we conducted anchor‐based analyses (as recommended by the FDA) to explore meaningful within‐patient/participant change thresholds on the ADCS‐ADL.MethodsOur anchor‐based analyses (and supportive distribution‐based analyses) used data from two phase 2 semorinemab trials, Tauriel (NCT03289143; early AD) and Lauriet (NCT03828747; mild‐to‐moderate AD). The Caregiver Global Impression of Change‐Alzheimer’s Disease (CaGI‐Alz), a caregiver‐reported measure on subjective change in participant function, served as the anchoring scale. To determine if anchor‐based analyses were appropriate, we first examined correlations between the ADCS‐ADL change scores and CaGI‐Alz ratings at Weeks 25 and 49 for both trials, along with Week 61 for Lauriet, and Week 73 for Tauriel. To determine meaningful change thresholds, we analyzed the mean changes on the ADCS‐ADL for participants rated as performing “somewhat worse” on CaGI‐Alz. Those rated as demonstrating“no‐change” were used for comparison.ResultsCorrelations between the ADCS‐ADL and the CaGI‐Alz scales were consistently stronger at Week 49 and later time points (Table 1). For those rated as “somewhat worse,” mean decline on the ADCS‐ADL ranged from approximately 5 to 8 points across time points, and uniformly exceeded distribution‐based thresholds. Larger declines on the ADCS‐ADL were associated with “somewhat worse” ratings in patients in Lauriet (mild‐to‐moderate AD) compared to Tauriel (early AD) and at later time points in both trials (Table 2). Patients rated as “no change” by the caregiver experienced some decline on the ADCS‐ADL, although generally less than the declines seen in those rated “somewhat worse.”ConclusionThe anchor‐ and distribution‐based approaches suggest that clinically meaningful change on the ADCS‐ADL may be greater than the 2 points that has previously been postulated (Dysken et al., 2014). Higher change thresholds may be required to reflect meaningful changes perceptible to caregivers.