bluuebunny/crossref_metadata_2025_split huggingface dataset:
Superoxide anions mediate veratridine‐induced cytochrome c release and caspase activity in bovine chromaffin cells
Authors: Jordán Joaquín , Galindo María F , Tornero Daniel , Benavides Amparo , González Constancio , Agapito María T , González‐Garcia Carmen , Ceña Valentín 
Published: November 2002

Mitochondrial mechanisms involved in veratridine‐induced chromaffin cell death have been explored.
Exposure to veratridine (30 μM, 1 h) produces cytochrome c release to the cytoplasm that seems to be mediated by superoxide anions and that is blocked by cyclosporin A (10 μM), MnTBAP (10 nM), catalase (100 IU ml−1) and vitamin E (50 μM).
Following veratridine treatment, there is an increase in caspase‐like activity, blocked by vitamin E (50 μM) and the mitochondrial permeability transition pore blocker cyclosporin A (10 μM).
Superoxide anions open the mitochondrial permeability transition pore in isolated mitochondria, an effect that is blocked by vitamin E (50 μM) and cyclosporin A (10 μM), but not by the Ca2+ uniporter blocker ruthenium red (5 μM).
These results strongly suggest that under the stress situation caused by veratridine, superoxide anions become important regulators of mitochondrial function in chromaffin cells.
Exposure of isolated bovine chromaffin mitochondria to Ca2+ results in mitochondrial swelling. This effect was prevented by ruthenium red (5 μM) and cyclosporin A (10 μM), while it was not modified by vitamin E (50 μM).
Veratridine (30 μM, 1 h) markedly decreased total glutathione and GSH content in bovine chromaffin cells.
In conclusion, superoxide anions seem to mediate veratridine‐induced cytochrome c release, decrease in total glutathione, caspase activation and cell death in bovine chromaffin cells.

British Journal of Pharmacology (2002) 137, 993–1000. doi:10.1038/sj.bjp.0704953
The intracellular pathway of the acetylcholine‐induced contraction in cat detrusor muscle cells
Authors: An J Y , Yun H S , Lee Y P , Yang S J , Shim J O , Jeong J H , Shin C Y , Kim J H , Kim D S , Sohn U D 
Published: November 2002

The present study was aimed to investigate intracellular pathways involved in acetylcholine (ACh)‐induced contraction in cat detrusor muscle cells
Contraction was expressed as per cent shortening of length of individually isolated smooth muscle cells obtained by enzymatic digestion. Dispersed intact and permeabilized cells were prepared for the treatment of drugs and antibody to enzymes, respectively. Using Western blot, we confirmed the presence of related proteins.
The maximal contraction to ACh was generated at 10−11 M. This response was preferentially antagonized by M3 muscarinic receptor antagonist ρ‐fluoro‐hexahydrosiladifenidol (ρF‐HSD) but not by the M1 antagonist pirenzepine and the M2 muscarinic receptor antagonist methoctramine. We identified G‐proteins Gq/11, Gs, G0, Gi1, Gi2 and Gi3 in the bladder detrusor muscle. ACh‐induced contraction was selectively inhibited by Gq/11 antibody but not to other G subunit.
The phosphatidylinositol‐specific phospholipase C (PI‐PLC) inhibitor neomycin reduced ACh‐induced contraction. However, the inhibitors of the phospholipase D, the phospholipase A2 and protein kinase C did not attenuate the ACh‐induced contraction. ACh‐induced contraction was inhibited by antibody to PLC‐β1 but not PLC‐β3 and PLC‐γ. Thapsigargin or strontium, which depletes or blocks intracellular calcium release, inhibited ACh‐induced contraction. Inositol 1,4,5‐triphosphate (IP3) receptor inhibitor heparin reduced ACh‐induced contraction.
These results suggest that in cat detrusor muscle contraction induced by ACh is mediated via M3 muscarinic receptor‐dependent activation of Gq/11 and PLC‐β1 and IP3‐dependent Ca2+ release.

British Journal of Pharmacology (2002) 137, 1001–1010. doi:10.1038/sj.bjp.0704954
Effects of the selective inhibition of platelet thromboxane synthesis on the platelet‐subendothelium interaction
Authors: De La Cruz J P , Villalobos M A , Escalante R , Guerrero A , Arrebola M M , Sánchez de la Cuesta F 
Published: November 2002

Drugs that inhibit TxA2 synthesis are used to reduce platelet aggregation. The aim of this study was to compare the effects of a cyclo‐oxygenase (COX) inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor (dazoxiben) and a dual TxS inhibitor and TxA2 receptor blocker (DT‐TX 30) on platelet aggregation and the platelet‐subendothelium interaction in flow conditions.
The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B2 and prostaglandin E2 production and leucocyte production of 6‐keto‐PGF1α. The platelet‐subendothelium interaction was evaluated in rabbit aorta subendothelium preparations exposed to flowing blood at a shear stress of 800 s−1. Morphometric methods were used to calculate the percentage of subendothelium occupied by platelets.
The 50% inhibitory concentration (IC50) of DT‐TX 30 in whole blood was in the range of 10−7 μM (induced with collagen or arachidonic acid) to 10−5 μM (induced with thrombin) or 10−4 (induced with ADP). IC50 values under all experimental conditions were lower with DT–TX 30 than with ASA. For thromboxane B2 the IC50 were: ASA 0.84±0.05 μM, dazoxiben 765±54 μM, DT–TX 30 8.54±0.60 μM. Prostaglandin E2 was inhibited only by ASA (IC50 1.21±0.08 μM). Leucocyte 6‐keto‐PGF1α was inhibited by ASA (IC50 6.58±0.76 μM) and increased by dazoxiben and DT–TX 30. The greatest reduction in percentage subendothelial surface occupied by platelets after blood perfusion was seen after treatment with DT–TX 30 in the range of concentrations that inhibited collagen‐induced platelet aggregation (control group: 31.20±3.8%, DT‐TX 30 at 0.1 μM: 10.71±0.55%, at 1.0 μM: 6.53±0.44%, at 5.0 μM; 1.48±0.07%). All three drugs reduced thrombus formation, although ASA (unlike dazoxiben or DT–TX 30) increased the percentage surface occupied by adhesions.
In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA2 can surpass the effect of ASA in inhibiting the platelet‐subendothelium interaction in flow conditions.

British Journal of Pharmacology (2002) 137, 1082–1088. doi:10.1038/sj.bjp.0704963
Mechanism of nicotine‐evoked release of [3H]‐noradrenaline in human cerebral cortex slices
Authors: Woo Ran‐Sook , Park Eun‐Young , Shin Min‐Soo , Jeong Min‐Suk , Zhao Rong‐Jie , Shin Byuong‐Soo , Kim Chul‐Jin , Park Jin‐Woo , Kim Kee‐Won 
Published: November 2002

The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC) was investigated in human cerebral cortex slices preloaded with [3H]‐noradrenaline.
NIC (10–1000 μM) increased [3H]‐NA release in a concentration‐dependent manner.
NIC (100 μM)‐evoked [3H]‐NA release was largely dependent on external Ca2+, and was attenuated by ω‐conotoxin GVIA (0.1 μM) but not by nitrendipine (1 μM).
Tetrodotoxin (1 μM) and nisoxetine (0.1 μM) attenuated the NIC (100 μM)‐evoked release of [3H]‐NA.
Mecamylamine (10 μM), dihydro‐β‐erythroidine (10 μM) and d‐tubocurarine (30 μM), but not α‐bungarotoxin (α‐BTX, 0.1 μM), attenuated the NIC (100 μM)‐evoked release of [3H]‐NA.
NIC (100 μM)‐evoked release of [3H]‐NA was not affected by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX, 30 μM) and D(−)‐2‐amino‐5‐phosphonopentanoic acid (D‐AP5, 100 μM), but attenuated by MK‐801 (10 μM). MK‐801 (0.1–1000 μM) displaced the specific binding of [3H]‐nisoxetine with Ki values of 91.2 μM. NIC (100, 300 and 1000 μM) did not induce [3H]‐D‐aspartate release in human cerebral cortex slices.
NIC (100 μM)‐evoked release of [3H]‐NA was attenuated by 7‐nitroindazole (10 μM), NG‐nitro‐L‐arginine methyl ester HCl (L‐NAME, 30 μM), NG‐monomethyl‐L‐arginine acetate (L‐NMMA, 300 μM). [3H]‐NA release induced by NIC (100 μM) was attenuated by methylene blue (3 μM) and 1H‐[1,2,4]oxadiazole[4,3‐α]quinoxalin‐1‐one (ODQ, 10 μM), and enhanced by zaprinast (30 μM).
In conclusion, NIC stimulates the release of [3H]‐NA through activation of α‐BTX‐insensitive nicotinic acetylcholine receptors in the human cerebral cortex slices and this action of NIC is associated with modulation of the NO/cGMP pathway.

British Journal of Pharmacology (2002) 137, 1063–1070. doi:10.1038/sj.bjp.0704975
Directions in Evolutionary Biology
Authors: Lewontin R. C. 
Published: November 2002

[Figure: see text] ▪ Abstract  In order to understand both the past and future directions of research in evolutionary biology we need to begin by understanding in what way these programs of research differ from the model of most scientific work. The study of evolutionary processes and, in particular, the genetics of the evolutionary process must confront special difficulties in both the conceptual and the methodological aspects of research. On the conceptual side, unlike for molecular, cellular, and developmental biology, there is no basic mechanism that evolutionists are attempting to elucidate. There is no single cause of the evolutionary change in the properties of members of a species. Natural selection may be involved but so are random events, patterns of migration and interbreeding, mutational events, and horizontal transfer of genes across species boundaries. The change in each character of each species is a consequence of a particular mixture of these causal pathways.
Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population
Authors: Zhao Kun , Shen Xuxiang , Liu Hongwei , Lin Zhennan , Li Jianxin , Chen Shufeng , Liu Fangchao , Huang Keyong , Cao Jie , Liu Xiaoqing , Shen Chong , Yu Ling , Zhao Yingxin , Zhao Liancheng , Li Ying , Hu Dongsheng , Huang Jiangfeng , Lu Xiangfeng , Gu Dongfeng 
Published: January 2024

ImportanceThe genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis of indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different genetic backgrounds, was completely unknown.ObjectiveTo investigate the CHIP profile in a general Chinese cohort by deep sequencing and further explore the association between CHIP and incident CHD considering germline predisposition.Design, Setting, and ParticipantsThis cohort study used data from 3 prospective cohorts in the project Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Participants without cardiovascular disease or cancer at baseline were enrolled in 2001 and 2008 and had a median follow-up of 12.17 years extending into 2021.ExposuresCHIP mutations were detected by targeted sequencing (mean depth, 916×). A predefined CHD polygenic risk score (PRS) comprising 531 variants was used to evaluate germline predisposition.Main Outcomes and MeasuresThe main outcome was first incident CHD.ResultsAmong 6181 participants, the median (IQR) age was 53.83 years (45.35-62.39 years); 3082 participants (49.9%) were female, and 3099 (50.1%) were male. A total of 1100 individuals (17.80%) harbored 1372 CHIP mutations at baseline. CHIP was independently associated with incident CHD (hazard ratio [HR], 1.42; 95% CI, 1.18-1.72; P = 2.82 × 10−4) and presented a risk gradient with increasing VAF (P = 3.98 × 10−3 for trend). Notably, individuals with small clones, nearly half of CHIP carriers, also demonstrated a higher CHD risk compared with non-CHIP carriers (HR, 1.33; 95% CI, 1.02-1.74; P = .03) and were 4 years younger than those with VAF of 2% or greater (median age, 58.52 vs 62.70 years). Heightened CHD risk was not observed among CHIP carriers with low PRS (HR, 1.02; 95% CI, 0.64-1.64; P = .92), while high PRS and CHIP jointly contributed a 2.23-fold increase in risk (95% CI, 1.51-3.29; P = 6.29 × 10−5) compared with non-CHIP carriers with low PRS. Interestingly, the diversity in CHIP-related CHD risk within each PRS group was substantially diminished when removing variants in the inflammatory pathway from the PRS.ConclusionsThis study revealed that elevated CHD risk attributed to CHIP was nonnegligible even for small clones. Inflammation genes involved in CHD could aggravate or abrogate CHIP-related CHD risk.
Factors Affecting Treatment Selection Among Patients With Hidradenitis Suppurativa
Authors: Salame Nicole , Sow Yacine N. , Siira Meron R. , Garg Amit , Chen Suephy C. , Patzer Rachel E. , Kavalieratos Dio , Orenstein Lauren A. V. 
Published: January 2024

ImportanceDespite the US Food and Drug Administration’s approval of adalimumab for the treatment of hidradenitis suppurativa (HS), prescription rates remain low, indicating a critical gap between evidence-based guidelines and clinical practice. Understanding the medical decision-making process that these patients use when considering biologic agents and other HS therapies may uncover opportunities for improved patient-physician communication and HS disease control.ObjectiveTo elucidate factors that affect the medical decision-making process for patients with HS, with an emphasis on biologic therapies.Design, Setting, and ParticipantsOpen-ended semistructured interviews were conducted with English-speaking adults with HS (aged ≥18 years) recruited from 2 dermatology clinics that are part of Emory University School of Medicine in Atlanta, Georgia. All participants had an average 7-day pain score of 1 or higher on a 0- to 10-point numeric rating scale. Surveys were conducted between November 2019 and March 2020, and data were analyzed from December 2021 to August 2022. Data collection continued until thematic saturation was reached at 21 interviews.ResultsA total of 21 participants (median [IQR] age, 38.5 [27.9-43.4] years; 16 females [76%]) were included in the analysis. Almost all participants (96%) had Hurley stage II or III disease, and 15 (71%) had a history of adalimumab use. Suffering threshold, perceptions of treatment risk, treatment fatigue, disease understanding, and sources of information (included dermatologists, the internet, advertisements, and friends and loved ones) were identified as factors affecting participants’ decisions to initiate new treatments for HS.Conclusions and RelevanceResults of this qualitative study suggest that mitigating misconceptions about treatment risk, identifying gaps in disease knowledge, and emphasizing early treatment to prevent scarring and disease progression may empower patients with HS to engage in treatment planning and to try new therapies.
Cumulative Update of a Systematic Overview Evaluating Interventions Addressing Polypharmacy
Authors: Keller Michelle S. , Qureshi Nabeel , Mays Allison M. , Sarkisian Catherine A. , Pevnick Joshua M. 
Published: January 2024

ImportancePolypharmacy is associated with mortality, falls, hospitalizations, and functional and cognitive decline. The study of polypharmacy-related interventions has increased substantially, prompting the need for an updated, more focused systematic overview.ObjectiveTo systematically evaluate and summarize evidence across multiple systematic reviews (SRs) examining interventions addressing polypharmacy.Evidence ReviewA search was conducted of MEDLINE, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects for articles published from January 2017-October 2022, as well as those identified in a previous overview (January 2004-February 2017). Systematic reviews were included regardless of study design, setting, or outcome. The evidence was summarized by 4 categories: (1) medication-related process outcomes (eg, potentially inappropriate medication [PIM] and potential prescribing omission reductions), (2) clinical and functional outcomes, (3) health care use and economic outcomes, and (4) acceptability of the intervention.FindingsFourteen SRs were identified (3 from the previous overview), 7 of which included meta-analyses, representing 179 unique published studies. Nine SRs examined medication-related process outcomes (low to very low evidence quality). Systematic reviews using pooled analyses found significant reductions in the number of PIMs, potential prescribing omissions, and total number of medications, and improvements in medication appropriateness. Twelve SRs examined clinical and functional outcomes (very low to moderate evidence quality). Five SRs examined mortality; all mortality meta-analyses were null, but studies with longer follow-up periods found greater reductions in mortality. Five SRs examined falls incidence; results were predominantly null save for a meta-analysis in which PIMs were discontinued. Of the 8 SRs examining quality of life, most (7) found predominantly null effects. Ten SRs examined hospitalizations and readmissions (very low to moderate evidence quality) and 4 examined emergency department visits (very low to low evidence quality). One SR found significant reductions in hospitalizations and readmissions among higher-intensity medication reviews with face-to-face patient components. Another meta-analysis found a null effect. Of the 7 SRs without meta-analyses for hospitalizations and readmissions, all had predominantly null results. Two of 4 SRs found reductions in emergency department visits. Two SRs examined acceptability (very low evidence quality), finding wide variation in the adoption of polypharmacy-related interventions.Conclusions and RelevanceThis updated systematic overview noted little evidence of an association between polypharmacy-related interventions and reduced important clinical and health care use outcomes. More evidence is needed regarding which interventions are most useful and which populations would benefit most.
Addressing asymmetric saturation in chaotic Chua's circuit switched system: A combined adaptive sliding mode strategy
Authors: Amiri Saeed , Seyed Moosavi Seyed Mohsen , Forouzanfar Mehdi , Aghajari Ebrahim 
Published: January 2024

SummaryThe purpose of this research is to develop a combined adaptive nonlinear feedback integral sliding mode (CANFISM) for the Chua's switched nonlinear circuit systems. The suggested adaptive composite nonlinear technique is improved to provide a robust controller with enhanced performance in the face of uncertainty and asymmetric saturation. The proposed technique has been theoretically validated, and its closed‐loop exponentially boundedly stable has been demonstrated. Meanwhile, CNF (composite nonlinear feedback) parameters are then determined by employing the linear matrix inequality technique, and the notion of robust tracking is performed and compared in Chua's switched nonlinear circuit systems. This method guarantees robustness against the effects of uncertainty and input asymmetric saturation and decreases chattering. The effectiveness and merits of the suggested technique are then achieved by utilizing two simulation examples of Chua's circuit system.
Reconfigurable and Parallel Computable Soft Mechanical Switch by Liquid Metal
Authors: Li Xin‐Yang , Hu Zu‐An , Liu Qian , Xie Tian , Wang Xian‐Wen , Huang Lu , Wu Ying‐Peng 
Published: January 2024

AbstractIntroducing soft materials with deformability and flexibility into mechanical switches may help to develop new types of soft mechanical switches with special properties such as reconfigurable characteristics and parallel computing. However, recently developed soft mechanical switches still have low on/off ratio, slow response time, and insufficient durability. Here, a soft mechanical switch based on liquid metal and a zigzag structure is constructed through strain engineering strategy with high on/off ratio (R/R0 > 107), short response time (~0.2 s), long‐term durability (> 2000 times), and self‐healing performance which is outstanding than the reported ones. With the switch, a mechanical unit is designed and all types of logic gates can be constructed by programming switches. Such multiple switches can also be used to perform parallel computing and achieve intelligent information processing.
Hybrid Cellulose‐Based Systems for Triboelectrification in Aerosol Filtration, Ammonia Abatement and Respiration Monitoring
Authors: Ding Zhaodong , Tian Zhongjian , Ji Xingxiang , Yang Guihua , Sameer Mhatre , Lu Yi , Rojas Orlando J. 
Published: January 2024

AbstractThe dissipation of charges by aging or under the effect of humid conditions considerably impedes a broader utilization of electrostatic fields in aerosol filtration. This study introduces a respiration‐driven air filter (RAF) that continuously generates triboelectric charges within a pair of tribolayers, which facilitates a sustained filtration performance. Such system is integrated in a multilayer unit that is inserted in personal protective equipment (RAFM) to efficiently capture, sense, and degrade airborne pollutants with no need for external power sources. The triboelectric nanogenerator‐based RAF continuously replenishes static charges and maintains an electrostatic field through breathing by the effect of contact‐electrification between two cellulose‐based tribolayers: a cellulose/metal organic framework cryogel (electron donor) and a cellulose–based electrospun membrane (electron acceptor). Notably, the triboelectric field of the RAF's tribolayer pair substantially enhances both the filtration efficiency (up to 93.8% for 0.3 µm particulate matter) and sensing/catalytic degradation (ammonia; degradation >20%). When integrated in a circuit module, the RAFM effectively monitors respiration dynamics, acting as a breathing indicator/regulator. Overall, this study adds to the promise of tribogeneration through cellulose‐based materials and its application in exposure‐risk operations.
Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts
Authors: Wang Leo L. , Tuohy Spencer , Xu Karen L. , Nace Arben , Yang Ruifeng , Zheng Ying , Burdick Jason A. , Cotsarelis George 
Published: January 2024

AbstractJanus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile‐containing baricitinib for drug tethering, which is confirmed with1H and13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod‐induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.