bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort
Authors: Chen Jiachen , Doyle Margaret F. , Fang Yuan , Mez Jesse , Crane Paul K. , Scollard Phoebe ,   ADSP Data Harmonization Consortium Cognitive Harmonization Core, Satizabal Claudia L. , Alosco Michael L. , Qiu Wei Qiao , Murabito Joanne M. , Lunetta Kathryn L. 
Published: August 2023

AbstractInflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well‐characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia‐free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross‐sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all‐cause and AD dementia during up to 20 years of follow‐up were tested. APOE genotype‐stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF‐R, TWEAK, CCL19, IL‐17C, MCP‐4, and TGF‐alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all‐cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.
AAV‐Mediated nuclear localized PGC1α4 delivery in muscle ameliorates sarcopenia and aging‐associated metabolic dysfunctions
Authors: Guo Mingwei , Zhang Jun , Ma Ying , Zhu Zhenzhong , Zuo Hui , Yao Jing , Wu Xia , Wang Dongmei , Yu Jian , Meng Meiyao , Liu Caizhi , Zhang Yi , Chen Jiangrong , Lu Jian , Ding Shuzhe , Hu Cheng , Ma Xinran , Xu Lingyan 
Published: August 2023

AbstractSarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC‐1α4, a short isoform of PGC‐1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS‐PGC1α4 and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus. Indeed, NLS‐PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV‐NLS‐PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size and molecular phenotypes, and alleviate age‐associated adiposity, insulin resistance and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS‐PGC‐1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA‐seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS‐PGC‐1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle. Together, our results revealed that NLS‐PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging‐associated metabolic diseases.
Chronic administration of a norepinephrine antagonist prevents and partially reverses escalation of cocaine self‐administration
Authors: Beldjoud Hassiba , Avelar Alicia , de Guglielmo Giordano , Kallupi Marsida , Sedighim Sharona , Velarde Nathan , Boomhower Brent , Rizo Nathan , Carrette Lieselot L. G. , George Olivier 
Published: August 2023

AbstractAnxiety is a critical component of the development and maintenance of drug addiction; however, anti‐anxiety medications such as benzodiazepines and beta‐blockers (β‐adrenergic receptor antagonists) are not used for the treatment of substance use disorder, except for the management of acute withdrawal syndrome. Preclinical studies have shown that beta‐blockers may reduce stress‐induced relapse; however, the effect of beta blockers on the escalation and maintenance of drug intake has not been tested. To address this issue, we chronically administered the β‐adrenergic receptor antagonist propranolol during the escalation or maintenance of cocaine intake in a model of extended access (6 h) to cocaine self‐administration (0.5 mg/kg). The behavioural specificity of propranolol was tested using a non‐drug reward (saccharin). Daily administration of propranolol (15 mg/kg) prevented the development of escalation of cocaine self‐administration and partially reversed self‐administration after the establishment of escalation of intake. Moreover, propranolol dose‐dependently decreased the motivation for cocaine tested under a progressive ratio schedule of reinforcement during the development of escalation and after maintenance. Finally, propranolol administration had no effect on the escalation and maintenance of saccharin self‐administration. These results demonstrate that chronic treatment with propranolol provides therapeutic efficacy in reducing cocaine self‐administration during the development and after the establishment of escalation of cocaine self‐administration in an animal model relevant to cocaine use disorder. These results suggest that beta blockers should be further investigated as a target for medication development for the treatment of cocaine use disorder.
Self‐control fluctuates from day to day and is linked to subjective well‐being within and between persons
Authors: Schmid Johanna , Moschko Tomasz , Riccio Matthew , Snyder Kenzie Aryn , Gawrilow Caterina , Stadler Gertraud 
Published: August 2023

AbstractThe psychological trait of self‐control has been linked to interindividual differences in subjective well‐being: Individuals with higher self‐control report less negative affect, more positive affect, and higher life satisfaction. However, less is known about how much self‐control fluctuates from day to day and how these fluctuations are related to subjective well‐being. This intensive longitudinal study describes day‐to‐day fluctuations in self‐control and investigates whether and how they are related to subjective well‐being. A sample of 64 undergraduate students at the entry phase of university (M = 22.55 years, SD = 6.51, range = 18–53, 97% female) provided 1459 reports of their self‐control and subjective well‐being, collected every evening across three 9‐day measurement bursts over 6 months. Participants' self‐control fluctuated substantially from day to day with less than 40% of the variability in daily self‐control being attributable to interindividual differences in self‐control. On days with higher self‐control, participants reported less negative affect, more serenity, and higher life satisfaction. We found no relationship between self‐control and vigor. The findings suggest that researchers need to go beyond current assessment practices and theories treating self‐control as a stable trait to help develop tailored well‐being interventions for everyday life.
A first‐in‐human study of the novel immunology antibody–drug conjugate, ABBV‐3373, in healthy participants
Authors: D'Cunha Ronilda , Kupper Hartmut , Arikan Dilek , Zhao Weihan , Carter David , Blaes Jonas , Ruzek Melanie , Pang Yinuo 
Published: August 2023

AimsABBV‐3373, an immunology antibody–drug conjugate composed of adalimumab conjugated to a proprietary glucocorticoid receptor modulator (the small‐molecule payload), has the potential to treat immune‐mediated inflammatory diseases. This first‐in‐human study investigated the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) using a safety PD marker, and safety/tolerability of ABBV‐3373 in healthy adults.MethodsFifty‐five participants were randomly assigned to single‐dose subcutaneous (SC; 30, 100 or 300 mg) or intravenous (IV; 30, 300 or 900 mg) ABBV‐3373 or placebo. Eight additional participants received a single dose of 10 mg oral prednisone for evaluation of systemic glucocorticoid effects. Blood samples were collected for up to 85 days postdose for PK, anti‐drug antibody and serum cortisol (safety PD marker) assessments.ResultsABBV‐3373 and total antibody displayed antibody‐like SC/IV PK profiles and the unconjugated/free payload in circulation exhibited formation rate‐limited kinetics with exposure several fold lower than ABBV‐3373 or total antibody. Treatment‐emergent anti‐drug antibody incidence was 69%, with loss of exposure in 6% (SC) and 5% (IV) of participants, but without any impact on safety. ABBV‐3373 up to 300 mg SC/IV had no apparent impact on serum cortisol, and only caused a transient decrease at 900 mg IV. Treatment‐emergent adverse events were primarily mild in severity, and no pattern emerged with respect to dose or route of administration.ConclusionsABBV‐3373 had favourable PK profiles, manageable immunogenicity, and was generally well‐tolerated. Except for a transient effect at 900 mg IV, there was no apparent impact on serum cortisol. Study results supported further clinical development of ABBV‐3373.
Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in sub‐Saharan Africa (the BIOCADRE study)
Authors: Ranque Brigitte , Diaw Mor , Dembele Abdoul Karim , Lapoumeroulie Claudine , Offredo Lucile , Tessougue Oumar , Gueye Serigne Mourtalla , Diallo Dapa , Diop Saliou , Colin‐Aronovicz Yves , Jouven Xavier , Blanc‐Brude Olivier , Tharaux Pierre‐Louis , Le Jeune Sylvain , Connes Philippe , Romana Marc , Le Van Kim Caroline 
Published: August 2023

SummarySickle cell anaemia (SCA) is a monogenic disease with a highly variable clinical course. We aimed to investigate associations between microvascular function, haemolysis markers, blood viscosity and various types of SCA‐related organ damage in a multicentric sub‐Saharan African cohort of patients with SCA. In a cross‐sectional study, we selected seven groups of adult patients with SS phenotype in Dakar and Bamako based on the following complications: leg ulcer, priapism, osteonecrosis, retinopathy, high tricuspid regurgitant jet velocity (TRV), macro‐albuminuria or none. Clinical assessment, echocardiography, peripheral arterial tonometry, laboratory tests and blood viscosity measurement were performed. We explored statistical associations between the biological parameters and the six studied complications. Among 235 patients, 58 had high TRV, 46 osteonecrosis, 43 priapism, 33 leg ulcers, 31 retinopathy and 22 macroalbuminuria, whereas 36 had none of these complications. Multiple correspondence analysis revealed no cluster of complications. Lactate dehydrogenase levels were associated with high TRV, and blood viscosity was associated with retinopathy and the absence of macroalbuminuria. Despite extensive phenotyping of patients, no specific pattern of SCA‐related complications was identified. New biomarkers are needed to predict SCA clinical expression to adapt patient management, especially in Africa, where healthcare resources are scarce.
A new case of platelet‐type von Willebrand disease supports the recent findings of gain‐of‐function GP1BA variants outside the C‐terminal disulphide loop enhances affinity for von Willebrand factor
Authors: Monteiro Catarina , Gonçalves Ana , Pereira Mónica , Lau Catarina , Morais Sara , Santos Rosário 
Published: August 2023

SummaryPlatelet‐type von Willebrand disease (PT‐VWD) is a rare autosomal dominant bleeding disorder characterized by an increased ristocetin‐induced platelet aggregation (RIPA) and enhanced affinity of platelet glycoprotein Ibα (GPIbα) to von Willebrand factor (VWF). To date, only seven variants have been described with this gain‐of‐function effect, most of them located in the C‐terminal disulphide loop of the VWF‐binding domain of GPIbα. We herein describe a patient with moderate bleeding symptoms, mild thrombocytopenia and increased RIPA. By direct sequencing of GP1BA, a novel leucine‐rich repeat heterozygous variant was identified (c.580C>T; predictably p.Leu194Phe), strongly suggestive as being the underlying cause for the PT‐VWD phenotype of our patient.
Congenital fibrinogen disorders: Strengthening genotype–phenotype correlations through novel genetic diagnostic tools
Authors: Ramanan Radha , McFadyen James D. , Perkins Andrew C. , Tran Huyen A. 
Published: August 2023

SummaryCongenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.
Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model
Authors: van Leeuwen L. Leonie , Ruigrok Mitchel J. R. , Kessler Benedikt M. , Leuvenink Henri G. D. , Olinga Peter 
Published: August 2023

AbstractBackground and PurposeFibrosis in kidney allografts is a major post‐transplant complication that contributes to graft failure. Lately, multiple potent inhibitors of fibrosis‐related pathways have been developed such as galunisertib, an inhibitor of the transforming growth factor‐beta (TGF‐β/TGFβ1) signalling pathway. This drug, however, poses risks for adverse effects when administered systemically. Therefore, we devised a new repurposing strategy in which galunisertib is administered ex vivo. We combined machine perfusion and tissue slices to explore the antifibrotic effects of galunisertib in renal grafts.Experimental ApproachPorcine kidneys were subjected to 30 min of warm ischaemia, 24 h of oxygenated hypothermic machine perfusion and 6 h of normothermic machine perfusion with various treatments (i.e. untreated control, TGFβ1, galunisertib or TGFβ1 + galunisertib; n = 8 kidneys per group). To determine whether effects persisted upon ceasing treatment, kidney slices were prepared from respective kidneys and incubated for 48 h.Key ResultsGalunisertib treatment improved general viability without negatively affecting renal function or elevating levels of injury markers or by‐products of oxidative stress during perfusion. Galunisertib also reduced inflammation and, more importantly, reduced the onset of fibrosis after 48 h of incubation.Conclusions and ImplicationsOur findings demonstrate the value of using machine perfusion for administering antifibrotic drugs such as galunisertib, proving it to be an effective example of repurposing.
Understanding gender inequality in children's reading behavior: New insights from digital behavioral data
Authors: Smith Emil , Reimer David 
Published: August 2023

AbstractThis study examined gender differences in reading behavior of 2652 Danish 5th‐grade students (age 10–12 years, girls 51%, 14% immigrant background) observed for 218 days in 2019/2020, using data from a popular reading app. Reading behavior was operationalized as time spent reading. Analyses of timing of reading behavior and models of day‐to‐day reading time were employed to investigate the gender gap in reading behavior. Results show that girls read more than boys. This differential can be attributed to girls reading more outside school hours, during weekends and holidays than boys while there are no gender differences in reading activity during school hours. Results suggest that girls with positive academic attitudes were more inclined to read than boys with similar attitudes.
First clinical experience of a ring‐configured cadmium zinc telluride camera: A comparative study versus conventional gamma camera systems
Authors: Cerić Andelius Irma , Minarik David , Persson Eva , Mosén Henrik , Valind Kristian , Trägårdh Elin , Oddstig Jenny 
Published: August 2023

AbstractBackgroundA novel semiconductor cadmium zinc telluride (CZT) gamma camera system using a block sequential regularized expectation maximization (BSREM) reconstruction algorithm is now clinically available. Here we investigate how a multi‐purpose ring‐configurated CZT system can be safely applied in clinics and describe the initial optimization process.MethodSeventy‐six patients (bone‐, cardiac‐ and lung scan) were scanned on a conventional gamma camera (planar and/or single‐photon emission computed tomography [SPECT]/SPECT‐CT) used in clinical routine and on the ring‐configurated CZT camera Starguide (GE Healthcare). These data were used to validate and optimize the Starguide system for routine clinical use.ResultsComparable image quality for the Starguide system, to that of the conventional gamma camera, was achieved for bone scan (4 min/bed position [BP] using a relative difference prior [RDP] with gamma 2 and beta 0.4, along with 10 iterations and 10 subsets), cardiac scan (8 min [stress] and 3 min 20 s [rest] using median root prior [MRP] with beta 0.07 non attenuation corrected and 0.008 attenuation corrected and 50 interations and 10 subsets for both stress and rest) and lung scan (10 min [vent] and 5 min [perf] using RDP with gamma 0.5 and beta 0.03 [vent] and 0.02 [perf] and 20 interations and 10 subsets for both vent and perf).ConclusionsIt was possible to transition from a conventional gamma camera to the Starguide system as part of the clinical routine, with acceptable image quality. Images from the Starguide system were deemed to be at least as good as those from a conventional gamma camera.
A phase I, randomized, ascending‐dose study to assess safety, pharmacokinetics, and activity of GDC‐8264, a RIP1 inhibitor, in healthy volunteers
Authors: Jones Nicholas S. , Kshirsagar Smita , Mohanan Vishnu , Ramakrishnan Vidya , Di Nucci Flavia , Ma Ling , Mao Jialin , Ding Hao , Klabunde Sha , Vucic Domagoj , Pan Lin , Lekkerkerker Annemarie N. , Chen Yuan , Rothenberg Michael E. 
Published: August 2023

AbstractReceptor‐interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)‐α, Toll‐like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1‐mediated inflammation and cell death. GDC‐8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo‐controlled, double‐blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single‐ (5–225 mg) and multiple‐ (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC‐8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC‐8264. All adverse events in GDC‐8264‐treated subjects in both stages were mild. GDC‐8264 exhibited dose‐proportional increases in systemic exposure; the mean terminal half‐life ranged from 10–13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC‐8264 had minimal renal excretion at all doses. A high‐fat meal had no significant effect on the PKs of GDC‐8264. In an ex vivo stimulation assay of whole blood, GDC‐8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK‐PD modeling, the GDC‐8264 half‐maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC‐8264 support its further development for treatment of RIP1‐driven diseases.
Generalized early inflammatory morphea mimicking interstitial T‐cell lymphoma: A diagnostic pitfall
Authors: Go Janelle , Wu Yu‐Hung 
Published: August 2023

AbstractEarly generalized morphea can clinically mimic mycosis fungoides. The microscopic features of early inflammatory morphea may show variable degrees of infiltration and do not have the characteristic dermal collagen sclerosis. We report the case of a 63‐year‐old female patient who presented with a 2‐month history of an asymptomatic skin rash. Physical examination revealed multiple erythematous to dusky patches on the trunk and thighs, resembling the patch stage of mycosis fungoides. Two skin biopsies were performed, both of which showed prominent interstitial lymphoid infiltration in the reticular dermis without dermal sclerosis. Small lymphocyte exocytosis and lining along the dermal–epidermal junction were observed focally in the epidermis. Small clusters of plasma cells and eosinophils were observed in perivascular areas. Although no predominant clonality was found for CD4 and CD8 stains, 50% loss of CD5 antigen and 90% loss of CD7 antigen expression were apparent in immunohistochemical studies. Subsequent blood tests showed a normal blood cell count and positive human T‐lymphotropic virus Type 1 antibodies. The overall findings suggested interstitial mycosis fungoides or early adult T‐cell lymphoma–leukemia. The patient refused aggressive treatment, and 3 months later, she presented with indurated plaques from the previous rash. A repeat biopsy revealed the typical features of morphea. This report discussed the pitfalls in the clinical and histopathological diagnosis of early generalized inflammatory morphea that both clinicians and pathologists should consider.