bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penetration of Topically Applied Polymeric Nanoparticles across the Epidermis of Thick skin
Authors: Antony Andrea , Raju Gayathri , Job Ahina , Joshi Meet , Shankarappa Sahadev 
Published: August 2023

AbstractThe natural barrier function of the epidermal skin layer poses a significant challenge to nanoparticle-mediated topical delivery. A key factor in this barrier function is the thickness of the stratum corneum (SC) layer within the epidermis, which varies across different anatomical sites. The epidermis from the palms and soles, for instance, have thicker SC compared to those from other areas. Previous studies have attempted to bypass the SC layer for nanoparticle penetration by using physical disruption; however, these studies have mostly focused on non-thick skin. In this study, we investigate the role of mechano-physical strategies on SC of thick skin for transdermal nanoparticle penetration. We characterize and compare two mechano-physical strategies, namely tape-stripping and microneedle abrasion, for epidermal disruption in both thick and thin skin. Furthermore, we examine the impact of SC disruption in thick and thin skin on the penetration of topically applied 100 nm sized polystyrene nanoparticles using an ex-vivo model. Our findings show that tape-stripping reduced the overall thickness of SC in thick skin by 87%, from 67.4 ± 17.3 µm to 8.2 ± 8.5 µm, whereas it reduced thin skin SC by only 38%, from 9.9 ± 0.6 µm to 6.2 ± 3.2 µm. Compared to non-thick skin, SC disruption in thick skin resulted in higher nanoparticle diffusion. Tape-stripping effectively reduces SC thickness of thick skin and can be potentially utilized for enhanced penetration of topically applied nanoparticles in skin conditions that affect thick skin.
Structural flexibility of apolipoprotein E-derived arginine-rich peptides improves their cell penetration capability
Authors: Takechi-Haraya Yuki , Ohgita Takashi , Usui Akiko , Nishitsuji Kazuchika , Uchimura Kenji , Abe Yasuhiro , Kawano Ryuji , Konaklieva Monika I. , Reimund Mart , Remaley Alan T. , Sato Yoji , Izutsu Ken-ichi , Saito Hiroyuki 
Published: August 2023

AbstractAmphipathic arginine-rich peptide, A2-17, exhibits moderate perturbation of lipid membranes and the highest cell penetration among its structural isomers. We investigated the direct cell-membrane penetration mechanism of the A2-17 peptide. We designed structurally constrained versions of A2-17, stapled (StpA2-17) and stitched (StchA2-17), whose α-helical conformations were stabilized by chemical crosslinking. Circular dichroism confirmed that StpA2-17 and StchA2-17 had higher α-helix content than A2-17 in aqueous solution. Upon liposome binding, only A2-17 exhibited a coil-to-helix transition. Confocal microscopy revealed that A2-17 had higher cell penetration efficiency than StpA2-17 in HeLa cells. Partitioning into lipid membranes was more prominent for StchA2-17 than for A2-17 or StpA2-17; StchA2-17 remained on the cell membrane without cell penetration. Tryptophan fluorescence analysis suggested that A2-17 and its analogs had similar membrane-insertion positions between the interface and hydrophobic core. Atomic force microscopy demonstrated that A2-17 reduced the mechanical rigidity of liposomes to a greater extent than StpA2-17 and StchA2-17. Finally, electrophysiological analysis showed that A2-17 induced a higher charge influx through transient pores in a planer lipid bilayer than StpA2-17 and StchA2-17. These findings indicate that structural flexibility, which enables diverse conformations of A2-17, leads to a membrane perturbation mode that contributes to cell membrane penetration.
CYP2C19 and effect of clopidogrel for secondary prevention of major ischemic events: systematic review and meta-analysis
Authors: Kremers Femke C.C. , van den Biggelaar Jochem , Lingsma Hester F. , van Schaik Ron H.N. , Roozenbeek Bob , Dippel Diederik W.J. 
Published: August 2023

AbstractBackgroundCarriers of the CYP2C19 Loss of Function (LoF) allele may experience decreased efficacy of clopidogrel in secondary prevention after cardiovascular events. Randomized clinical trials of clopidogrel in patients with known CYP2C19 carrier status provided inconsistent results. Our aim was to pool the evidence on the effect of clopidogrel on outcome, according to CYP2C19 LoF status, in a meta-analysis.MethodsA systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of clopidogrel according to CYP2C19 LoF status in patients with cardiovascular disease and recent TIA or stroke was performed. The primary outcomes were 1) ischemic stroke and 2) major adverse cardiac events (MACE). We used random effects analysis to estimate the effect of clopidogrel as a pooled odds ratio (OR) in carriers and non-carriers of the LoF variant and tested for interaction between clopidogrel and CYP2C19.ResultsWe included six RCTs with a total of 15,141 participants comparing combined clopidogrel and aspirin therapy to aspirin monotherapy. The effect of clopidogrel on MACE was OR=0.70 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.13). In patients with a recent TIA or minor ischemic stroke, the OR for the effect of clopidogrel on MACE was OR=0.52 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.02) while in patients with cardiovascular disease the difference in effect was not evident (non-variant carriers OR=0.76, variant carriers OR= 0.84, pinteraction=0.50).ConclusionOur meta-analysis could not establish that overall, clopidogrel is less effective in patients with a recent MI, minor stroke or TIA and a CYP2C19 LoF genotype. However, the size and direction of the difference in effect warrants further research.Registration - URL:https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021242993.
Occupational Farm Work Activities Influence Workers’ Indoor Home Microbiome
Authors: Dalton Kathryn R. , Lee Mikyeong , Wang Ziyue , Zhao Shanshan , Parks Christine G. , Beane-Freeman Laura E. , Motsinger-Reif Alison A. , London Stephanie J. 
Published: August 2023

AbstractBackgroundFarm work entails a heterogeneous mixture of exposures that vary considerably across farms and farmers. Farm work is associated with various health outcomes, both adverse and beneficial. One mechanism by which farming exposures can impact health is through the microbiome, including the indoor built environment microbiome. It is unknown how individual occupational exposures shape the microbial composition in workers’ homes.ObjectivesWe investigated associations between farm work activities, including specific tasks and pesticide use, and the indoor microbiome in the homes of 468 male farmers.MethodsParticipants were licensed pesticide applicators, mostly farmers, enrolled in the Agricultural Lung Health Study from 2008-2011. Vacuumed dust from participants’ bedrooms underwent whole-genome shotgun sequencing for indoor microbiome assessment. Using questionnaire data, we evaluated 6 farm work tasks (processing of either hay, silage, animal feed, fertilizer, or soy/grains, and cleaning grain bins) and 19 pesticide ingredients currently used in the past year, plus 7 persistent banned pesticide ingredients ever used.ResultsAll 6 work tasks were associated with increased within-sample microbial diversity, with a positive dose-response for the sum of tasks (p=0.001). All tasks were associated with altered overall microbial compositions (weighted UniFrac p=0.001) and with higher abundance of specific microbes, including soil-based microbes such asHaloterrigena. Among the 19 pesticides, only current use of glyphosate and past use of lindane were associated with increased within-sample diversity (p=0.02-0.04). Ten currently used pesticides and all 7 banned pesticides were associated with altered microbial composition (p=0.001-0.04). Six pesticides were associated with differential abundance of certain microbes.DiscussionSpecific farm activities and exposures can impact the dust microbiome inside homes. Our work suggests that occupational farm exposures could impact the health of workers and their families through modifying the indoor environment, specifically the microbial composition of house dust, offering possible future intervention targets.
Ready-To-Use Investigational Stem Cells in Patients with recent Acute Myocardial Infarction
Authors: Ueng KC , Tsai CF , Chuang YT , Huang JY , Liu JTK 
Published: August 2023

AbstractBACKGROUNDCardiovascular diseases are a major health concern, and stem cell therapy holds promise as a potential treatment. However, obtaining stem cells from patients who are already ill poses challenges, as does limited access to specialized laboratories. We aimed to assess the safety and preliminary effectiveness of a read-to-use investigational stem cell product, MiSaver, in patients with recent acute myocardial infarction (AMI).METHODSWe enrolled 10 participants with AMI and reduced left ventricular ejection fraction (LVEF ≤45%). Group A (n=5) received a low dosage of 0.5×107cells/kg, and Group B (n=5) received a high dosage of 1.6×107cells/kg of cells. Additionally, 20 control patients who received standard care were included for statistical analysis. The primary outcome was the occurrence of side effects or graft-versus-host disease (GVHD) associated with the stem cell treatment. Secondary outcomes included changes in LVEF.RESULTSDuring the 12-month follow-up period, no study-related adverse effects or GVHD were observed. Baseline LVEF values for Group A and Group B were 42.0% and 41.3%, respectively, increasing to 53.0% and 53.7% at 12 months. Furthermore, no signs or symptoms of graft-versus-host disease (GVHD) were reported. Significant improvements in LVEF were observed in non-morbidly obese treated patients (cases 1-9), with baseline values of 41.3% and 12-month values of 53.7%, compared to the control group with baseline and 12-month values of 42.35% and 47.5%, respectively (p<0.05).CONCLUSIONSThis trial demonstrated the safety and tolerability of MiSaver stem cells in patients with recent AMI. Preliminary evidence suggests efficacy in improving outcomes in non-morbidly obese participants.
Prevalence and Prescribers’ Knowledge of Psychotropic Polypharmacy in the Bono, Bono East, and Ahafo Regions, Ghana
Authors: Dumba James , Barimah Antwi Joseph , Ibrahim Mohammed Mohammed , Allotey Solomon Saka , Alorvi Semefa , Appertey William , Sopaal Luke , Acheampong Frank , Niriwa Benjamin Pulle 
Published: August 2023

AbstractThe use of psychotropic medications for treating simple and complex psychological and emotional problems is common and relevant among prescribers. This, therefore, come with the tendency to prescribe many medications to a patient on a single visit due to varied reasons. The study, therefore, sought to ascertain the prevalence and prescribers’ knowledge of psychotropic polypharmacy. A quantitative, descriptive study was conducted using a simple random approach to select and review the prescription records of three hundred and ten (309) patients’ folders retrospectively within seven (7) mental health units across the study area to ascertain the prevalence of Psychotropic Polypharmacy (PP). Fifty-eight (58) prescribers were also selected using probability method (simple random) to respond to the study questionnaire. Psychotropic Polypharmacy was prevalent (66.0%) in the study area with antipsychotic polypharmacy (74.0%) being the common form with the co-prescription of Chlorpromazine (CPZ) + Hadol (70.0%) being frequent. This was more predominant among male patients (78.0%) than female patients (22.0%). Prescribers had high (82.8%) knowledge of Psychotropic Polypharmacy and the majority (68.9%) disagreed that the practice of Psychotropic Polypharmacy should be promoted. The continuous training of prescribers (i.e. mental health officers) on rational prescriptions would help reduce the prevalence of Psychotropic Polypharmacy.
The Metabolic Usage and Glycan Destinations of GlcNAz inE. coli
Authors: Eddenden Alexander , Dooda Manoj K. , Morrison Zachary A. , Subramanian Adithya Shankara , Howell P. Lynne , Troutman Jerry M. , Nitz Mark 
Published: August 2023

ABSTRACTBacteria use a diverse range of carbohydrates to generate a profusion of glycans, with amino sugars such asN-acetylglucosamine (GlcNAc) being prevalent in the cell wall and in many exopolysaccharides. The primary substrate for GlcNAc-containing glycans, UDP-GlcNAc, is the product of the bacterial hexosamine pathway, and a key target for bacterial metabolic glycan engineering. Using the strategy of expressing NahK, to circumvent the hexosamine pathway, it is possible to directly feed the analogue of GlcNAc,N-azidoacetylglucosamine (GlcNAz), for metabolic labelling inE. coli. The cytosolic production of UDP-GlcNAz was confirmed using fluorescence assisted polyacrylamide gel electrophoresis. The key question of where GlcNAz is incorporated, was interrogated by analyzing potential sites including: peptidoglycan (PGN), the biofilm-related exopolysaccharide poly-β-1,6-N-acetylglucosamine (PNAG), lipopolysaccharide (LPS) and the enterobacterial common antigen (ECA). The highest levels of incorporation were observed in PGN with lower levels in PNAG and no observable incorporation in LPS or ECA. The promiscuity of the PNAG synthase (PgaCD) towards UDP-GlcNAzin vitroand lack of undecaprenyl-pyrophosphoryl-GlcNAz intermediates generatedin vivoconfirmed the incorporation preferences. The results of this work will guide the future development of carbohydrate-based probes and metabolic engineering strategies.
Left Out: The Effect of Handedness on fMRI Activation in Memory Paradigms
Authors: Goulding Loriana , Hamm Isaac , Kirwan C. Brock 
Published: August 2023

AbstractAbout 11% of the population is left-handed, a significant minority of the potential participant pool for functional MRI (fMRI) studies. However, convention in fMRI research dictates these potential participants be excluded due to the supposition that left-handed (LH) people may have different lateralization of neural functioning than right-handed (RH) people. This difference in lateralization may cause different areas of the brain to be activated by the same task. The current study investigates the lateralization differences between N=49 LH and N=50 RH during encoding and recognition memory tasks for verbal and non-verbal stimuli. Additionally, we measured participants’ laterality index by administering a semantic fluency task. We found no difference between groups for memory encoding activation for either verbal or non-verbal stimuli. Similarly, we found no group differences for verbal retrieval activation. There were quantitative differences between groups in non-verbal retrieval activation, primarily driven by greater spatial extent of activation in the RH group rather than by differences in lateralization in the LH group. To measure if including LH in fMRI studies would dilute results, we calculated memory effects ina prioriregions of interest (ROI) for the RH group only and then examined the effect of substituting in progressively more LH for RH. We found significant memory effects in 14a prioriROIs, 10 of which retained significant effects when adding LH participants. The remaining ROIs had significant memory-related activation in more than 80% of simulations with statistically likely numbers of LH participants. Taken together, these results indicate that the inclusion of left-handed participants does not have a strong detrimental effect on memory-related fMRI activation. On this basis we advocate for the inclusion of left-handed participants in cognitive neuroscience of memory research.
Cryo-EM of soft-landedβ-galactosidase: Gas-phase and native structures are remarkably similar
Authors: Esser Tim K. , Böhning Jan , Önür Alpcan , Chinthapalli Dinesh K. , Eriksson Lukas , Grabarics Marko , Fremdling Paul , Konijnenberg Albert , Makarov Alexander , Botman Aurelien , Peter Christine , Benesch Justin L. P. , Robinson Carol V. , Gault Joseph , Baker Lindsay , Bharat Tanmay A. M. , Rauschenbach Stephan 
Published: August 2023

AbstractNative mass spectrometry (native MS) is a powerful technique that provides information on stoichiometry, interactions, homogeneity and shape of protein complexes. However, the extent of deviation between protein structures in the mass spectrometer and in solution remains a matter of debate. Here, we uncover the gas-phase structure ofβ-galactosidase using single particle electron cryomicroscopy (cryo-EM) down to 2.6 Å resolution, enabled by soft-landing of mass-selected protein complexes onto cold TEM grids and in-situ ice coating. We find that large parts of the secondary and tertiary structure are retained from solution, with dehydration-driven subunit reorientation leading to consistent compaction in the gas phase. Our work enables visualizing the structure of gas-phase protein com-plexes from numerous experimental scenarios at side-chain resolution and demonstrates the possibility of more controlled cryo-EM sample preparation.One Sentence SummaryElectrospray ion-beam deposition on cold grids and in-vacuum ice growth enable cryo-EM of mass-selected proteins at 2.6 Å.
Central and peripheral tau retention modulated by an anti-tau antibody
Authors: Solorzano Alexander , Brady Molly , Bhatt Nemil , Johnson Angelique , Burgess Brooke , Leyva Hannah , Puangmalai Nicha , Jerez Cynthia , Wood Ronald , Kayed Rakez , Deane Rashid 
Published: August 2023

AbstractTau protein blood levels dependent on its distribution to peripheral organs and possible elimination from the body. Thus, the peripheral distribution of CSF-derived tau protein was explored, especially since there is a transition to blood-based biomarkers and the emerging idea that tau pathology may spread beyond brain. Near infrared fluorescence (NIRF) was mainly used to analyze tau (tau-NIRF) distribution after its intracisternal or intravenous injection. There was a striking uptake of blood- or CSF-derived tau-NIRF protein by the skeletal structures, liver, small intestine (duodenum), gall bladder, kidneys, urinary bladder, lymph nodes, heart, and spleen. In aging and in older APP/PS1 mice, tau uptake in regions, such as the brain, liver, and skeleton, was increased. In bone (femur) injected tau protein was associated with integrin-binding sialoprotein (IBSP), a major non-collagenous glycoprotein that is associated with mineralization. Tau-NIRF was cleared slowly from CSF via mainly across the cribriform plate, and cervical lymph nodes. In brain, some of the CSF injected tau protein was associated with NeuN-positive and PDGFRý-positive cells, which may explain its retention. The presence of tau in the bladders suggested excretion routes of tau. CSF anti-tau antibody increased CSF tau clearance, while blood anti-tau antibody decreased tau accumulation in the femur but not in liver, kidney, and spleen. Thus, the data show a body-wide distribution and retention of CSF-derived tau protein, which increased with aging and in older APP/PS1 mice. Further work is needed to elucidate the relevance of tau accumulation in each organ to tauopathy.
PP2A Dephosphorylates Phytochrome-Interacting Factor 3 to Modulate Photomorphogenesis inArabidopsis
Authors: Cai Xingbo , Lee Sanghwa , Gomej-Jaime Andrea , Tang Wenqiang , Sun Yu , Huq Enamul 
Published: August 2023

AbstractThe phytochrome (phy) family of sensory photoreceptors modulates developmental programs in response to ambient light. phys control gene expression in part by directly interacting with the bHLH class of transcription factors, phytochrome-interacting factors (PIFs), and inducing their rapid phosphorylation and degradation. Several kinases have been shown to phosphorylate PIFs and promote their degradation. However, the phosphatases that dephosphorylate PIFs are less investigated. Here we describe the identification of four regulatory subunits ofArabidopsisprotein phosphatase 2A (PP2A) family (B’α, B’β, B’’α and B’’β) that interacted with PIF3 in yeast-two-hybrid,in vitroandin vivoassays. Thepp2ab’’αβandb’’αβ/b’αβdisplayed short hypocotyls, while the overexpression of the B subunits induced longer hypocotyls compared to wild type under red light. The light-induced degradation of PIF3 was faster inb’’αβ/b’αβquadruple mutant compared to wild type. Consistently, immunoprecipitated PP2A A and B subunits directly dephosphorylated PIF3-MYCin vitro. RNA-seq analyses showed that B’’α and B’’β alter global gene expression in response to red light.PIFs (PIF1, PIF3, PIF4andPIF5)are epistatic to these four B subunits in regulating hypocotyl elongation under red light. Collectively, these data show an essential function of PP2A in dephosphorylating PIF3 to modulate photomorphogenesis inArabidopsis.
Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes
Authors: Hernáez Álvaro , Skåra Karoline H. , Page Christian M. , Mitter Vera R. , Hernández Marta H. , Magnus Per , Njølstad Pål R. , Andreassen Ole A. , Corfield Elizabeth C. , Havdahl Alexandra , Næss Øyvind , Brumpton Ben , Åsvold Bjørn Olav , Lawlor Deborah A. , Fraser Abigail , Magnus Maria Christine 
Published: August 2023

ABSTRACTBackgroundAdverse pregnancy outcomes (APO) may unmask a woman’s underlying risk for coronary heart disease (CHD). To test this, we estimated associations between genetically predicted liability for CHD and risk of APOs in mothers and their male partners. We hypothesized that associations would be found for women, but not their partners (negative controls).MethodsWe studied up to 83,969 women (and up to 55,568 male partners) participating in the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and information on history of any APO in their pregnancies (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis.ResultsOne standard deviation increase in the GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96 to 1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98 to 1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners’ GRS and restricting analyses to stable couples. Associations for miscarriage, gestational diabetes, and spontaneous preterm birth were close to the null. In male partners, there was weak evidence of an association with spontaneous preterm birth (OR 1.02 [0.99 to 1.05]), but not with other APOs.ConclusionsHypertensive disorders of pregnancy, small for gestational age and stillbirth unmask women with a genetically predicted existing propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth needs further exploration.