bluuebunny/crossref_metadata_2025_split huggingface dataset:
Essential amino acids in the Plant-Conserved and Class-Specific Regions of cellulose synthases
Authors: Olek Anna T , Rushton Phillip S , Kihara Daisuke , Ciesielski Peter , Aryal Uma K , Zhang Zicong , Stauffacher Cynthia V , McCann Maureen C , Carpita Nicholas C 
Published: October 2022

Abstract
The Plant-Conserved Region (P-CR) and the Class-Specific Region (CSR) are two plant-unique sequences in the catalytic core of cellulose synthases (CESAs) for which specific functions have not been established. Here, we used site-directed mutagenesis to replace amino acids and motifs within these sequences predicted to be essential for assembly and function of CESAs. We developed an in vivo method to determine the ability of mutated CesA1 transgenes to complement an Arabidopsis (Arabidopsis thaliana) temperature-sensitive root-swelling1 (rsw1) mutant. Replacement of a Cys residue in the CSR, which blocks dimerization in vitro, rendered the AtCesA1 transgene unable to complement the rsw1 mutation. Examination of the CSR sequences from 33 diverse angiosperm species showed domains of high-sequence conservation in a class-specific manner but with variation in the degrees of disorder, indicating a nonredundant role of the CSR structures in different CESA isoform classes. The Cys residue essential for dimerization was not always located in domains of intrinsic disorder. Expression of AtCesA1 transgene constructs, in which Pro417 and Arg453 were substituted for Ala or Lys in the coiled-coil of the P-CR, were also unable to complement the rsw1 mutation. Despite an expected role for Arg457 in trimerization of CESA proteins, AtCesA1 transgenes with Arg457Ala mutations were able to fully restore the wild-type phenotype in rsw1. Our data support that Cys662 within the CSR and Pro417 and Arg453 within the P-CR of Arabidopsis CESA1 are essential residues for functional synthase complex formation, but our data do not support a specific role for Arg457 in trimerization in native CESA complexes.
Disturbing NLRP3 acetylation and inflammasome assembly inhibits androgen receptor‐promoted inflammatory responses and prostate cancer progression
Authors: Zhao An‐Ning , Yang Zhan , Wang Dan‐Dan , Shi Bei , Zhang Hong , Bai Yang , Yan Bo‐Wen , Zhang Yong , Wen Jin‐Kun , Wang Xiao‐Lu , Qu Chang‐Bao 
Published: October 2022

AbstractChronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa tumorigenesis and inflammatory response. However, little is known about the AR‐regulated NACHT, LRR, and PYD domain‐containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high‐grade PCa and observed that NLRP3 inflammasome‐associated genes were upregulated in high‐grade PCa compared with that in low‐grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR‐3—a circRNA derived from the AR gene—which is involved in the AR‐regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR‐3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR‐3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression.
Tipping the balance toward stemness in trophoblast: Metabolic programming by Cox6B2
Authors: Saha Sarbani , Bose Rumela , Chakraborty Shreeta , Ain Rupasri 
Published: October 2022

AbstractMetabolic effector(s) driving cell fate is an emerging concept in stem cell biology. Here we showed that Cytochrome C Oxidase Subunit 6B2 (Cox6B2) is essential to maintain the stemness of trophoblast stem (TS) cells. RNA interference of Cox6b2 resulted in decreased mitochondrial Complex IV activity, ATP production, and oxygen consumption rate in TS cells. Furthermore, depletion of Cox6b2 in TS cells led to decreased self‐renewal capacity indicated by compromised BrdU incorporation, Ki67 staining, and decreased expression of TS cell genetic markers. As expected, the consequence of Cox6b2 knockdown was the induction of differentiation. TS cell stemness factor CDX2 transactivates Cox6b2 promoter in TS cells. In differentiated cells, Cox6b2 is post‐transcriptionally regulated by two microRNAs, miR‐322‐5p and miR‐503‐5p, leading to its downregulation as demonstrated by the gain‐in or loss of function of these miRNAs. Cox6b2 transcripts gradually rise in placental trophoblast gestation progresses in both mice and rats with predominant expression in labyrinthine trophoblast. Cox6b2 expression is compromised in the growth‐restricted placenta of rats with reciprocal up‐regulation of miR‐322‐5p and miR‐503‐5p. These data highlight the importance of Cox6B2 in the regulation of TS cell state and uncompromised placental growth.
Insulin stimulates atypical protein kinase C‐mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6‐Rac1 signaling
Authors: Chau Dennis Dik‐Long , Li Wen , Chan Wai Wa Ray , Sun Jacquelyne Ka‐Li , Zhai Yuqi , Chow Hei‐Man , Lau Kwok‐Fai 
Published: October 2022

AbstractNeurite outgrowth is a fundamental process in neurons that produces extensions and, consequently, neural connectivity. Neurite damage and atrophy are observed in various brain injuries and disorders. Understanding the intrinsic pathways of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration. Insulin is a pivotal hormone in the regulation of glucose homeostasis. There is increasing evidence for the neurotrophic functions of insulin, including the induction of neurite outgrowth. However, the associated mechanism remains elusive. Here, we demonstrate that insulin potentiates neurite outgrowth mediated by the small GTPases ADP‐ribosylation factor 6 (ARF6) and Ras‐related C3 botulinum toxin substrate 1 (Rac1) through the neuronal adaptor FE65. Moreover, insulin enhances atypical protein kinase Cι/λ (PKCι/λ) activation and FE65 phosphorylation at serine 459 (S459) in neurons and mouse brains. In vitro and cellular assays show that PKCι/λ phosphorylated FE65 at S459. Consistently, insulin potentiates FE65 S459 phosphorylation only in the presence of PKCι/λ. Phosphomimetic studies show that an FE65 S459E mutant potently activates ARF6, Rac1, and neurite outgrowth. Notably, this phosphomimetic mutation enhances the FE65‐ARF6 interaction, a process that promotes ARF6‐Rac1‐mediated neurite outgrowth. Likewise, insulin treatment and PKCι/λ overexpression potentiate the FE65–ARF6 interaction. Conversely, PKCι/λ knockdown suppresses the stimulatory effect of FE65 on ARF6‐Rac1‐mediated neurite outgrowth. The effect of insulin on neurite outgrowth is also markedly attenuated in PKCι/λ knockdown neurons, in the presence and absence of FE65. Our findings reveal a novel mechanism linking insulin with ARF6‐Rac1‐dependent neurite extension through the PKCι/λ‐mediated phosphorylation of FE65.
CCR2 is expressed by tendon resident macrophage and T cells, while CCR2 deficiency impairs tendon healing via blunted involvement of tendon‐resident and circulating monocytes/macrophages
Authors: Muscat Samantha , Nichols Anne E. C. , Gira Emma , Loiselle Alayna E. 
Published: October 2022

AbstractDuring tendon healing, macrophages are thought to be a key mediator of scar tissue formation, which prevents successful functional restoration of the tendon. However, macrophages are critical for successful tendon healing as they aid in wound debridement, extracellular matrix deposition, and promote fibroblast proliferation. Recent work has sought to better define the multi‐faceted functions of macrophages using depletion studies, while other studies have identified a tendon resident macrophage population. To begin to delineate the functions of tendon‐resident versus circulation‐derived macrophages, we examined the tendon healing phenotype in Chemokine Receptor 2 (CCR2) reporter (CCR2GFP/+), and knockout mice. CCR2 is a chemokine receptor primarily found on the surface of circulating bone marrow‐derived monocytes, with CCR2 being an important mediator of macrophage recruitment to wound environments. Surprisingly, CCR2GFP/+ cells were present in the tendon during adult homeostasis, and single‐cell RNA sequencing identified these cells as tendon‐resident macrophages and T cells. During both homeostasis and healing, CCR2 knockout resulted in a substantial decrease in CCR2GFP+ cells and pan‐macrophages. Additionally, loss of CCR2 resulted in reduced numbers of myofibroblasts and impeded functional recovery during late healing. This study highlights the heterogeneity of tendon‐resident and recruited immune cells and their contributions following injury, and establishes an important role for CCR2 in modulating both the adult tendon cell environment and tendon healing process.
Early‐immediate gene Egr1 is associated with TGFβ1 regulation of epigenetic reader Bromodomain‐containing protein 4 via the canonical Smad3 signaling in hepatic stellate cells in vitro and in vivo
Authors: Tian Haimeng , Xu Feifan , Zhao Feifei , Pan Nachuan , Lu Sidan , Jia Xin , Zhou Yajun 
Published: October 2022

AbstractUpon chronic damage to the liver, multiple cytokines stimulate hepatic stellate cells (HSCs), causing the alterations of gene expression profiles and thus leading to HSC activation, a key step in liver fibrogenesis. Activated HSCs are the dominant contributors to liver fibrosis. Bromodomain containing protein 4 (BrD4), an important epigenetic reader, was demonstrated to concentrate on hundreds of enhancers associated with genes involved in multiple profibrotic pathways, thereby directing HSC activation and the fibrotic responses. The present studies were designed to examine the effect of transforming growth factor beta‐1 (TGFβ1), the most potent pro‐fibrotic cytokine, on BrD4 expression in HSCs and, if so, elucidated the underlying mechanisms in vitro and in vivo. The experiments employed the heterogeneous TGFβ1 knockout (TGFβ1+/−) mice, gene knockdown in vivo, and a model of thioacetamide (TAA)‐induced liver injury. The results revealed that TGFβ1 enhanced BrD4 expression in HSCs, which was mediated, at least, by Smad3 signaling and early‐immediate gene Egr1 (early growth response‐1). TGFβ1‐induced Smad3 signaling increased Egr1 expression and promoted Egr1 binding to BrD4 promoter at a site around −111 bp, promoting BrD4 expression. Egr1 knockdown reduced BrD4 expression in HSCs in a mouse model of TAA‐induced liver injury and lessened liver fibrosis. Double fluorescence staining demonstrated a strong increase in BrD4 expression in activated HSCs in fibrotic areas of the human livers, paralleling the upregulation of p‐Smad3 and Egr1. This research suggested novel molecular events underlying the roles of the master pro‐fibrotic cytokine TGFβ1 in HSC activation and liver fibrogenesis.
Monitoring Drug Safety in Pregnancy with Scan Statistics: A Comparison of Two Study Designs
Authors: Suarez Elizabeth A. , Nguyen Michael , Zhang Di , Zhao Yueqin , Stojanovic Danijela , Munoz Monica , Liedtka Jane , Anderson Abby , Liu Wei , Dashevsky Inna , DeLuccia Sandra , Menzin Talia , Noble Jennifer , Maro Judith C. 
Published: October 2022

Background:
Traditional surveillance of adverse infant outcomes following maternal medication exposures relies on pregnancy exposure registries, which are often underpowered. We characterize the statistical power of TreeScan, a data mining tool, to identify potential signals in the setting of perinatal medication exposures and infant outcomes.

Methods:
We used empirical data to inform background incidence of major congenital malformations and other birth conditions. Statistical power was calculated using two probability models compatible with TreeScan, Bernoulli and Poisson, while varying the sample size, magnitude of the risk increase, and incidence of a specified outcome. We also simulated larger referent to exposure matching ratios when using the Bernoulli model in the setting of fixed N:1 propensity score matching. Finally, we assessed the impact of outcome misclassification on power.

Results:
The Poisson model demonstrated greater power to detect signals than the Bernoulli model across all scenarios and suggested a sample size of 4,000 exposed pregnancies is needed to detect a twofold increase in risk of a common outcome (approximately 8 per 1,000) with 85% power. Increasing the fixed matching ratio with the Bernoulli model did not reliably increase power. An outcome definition with high sensitivity is expected to have somewhat greater power to detect signals than an outcome definition with high positive predictive value.

Conclusions:
Use of the Poisson model with an outcome definition that prioritizes sensitivity may be optimal for signal detection. TreeScan is a viable method for surveillance of adverse infant outcomes following maternal medication use.
Tranexamic Acid Dosing in Craniosynostosis Surgery: A Systematic Review with Meta-analysis
Authors: O’Donnell Devon B. , Vazquez Sima , Greisman Jacob D. , Uddin Anaz , Graifman Gillian , Dominguez Jose F. , Zellner Elizabeth , Muh Carrie R. 
Published: October 2022

Objective:
This study aimed to compare operative time, blood loss, and transfusion requirement in patients receiving a high tranexamic acid (TXA) dose of greater than 10 mg/kg versus those receiving a low dose of 10 mg/kg or less.

Methods:
PubMed, Cochrane Central, and Embase were queried to perform a systematic review with meta-analysis. Studies reporting outcomes of TXA use in craniosynostosis surgery were included. TXA dosing, operative time, blood loss, and transfusion requirement were the primary outcomes studied. Other variables studied included age and types of craniosynostosis.

Results:
In total, 398 individuals in the included articles received TXA for craniosynostosis surgery. TXA loading doses ranged from 10 mg/kg to 50 mg/kg. Overall, administration of TXA was not associated with changes in operative time, but was associated with decreased blood loss and transfusion requirement on meta-analysis. Comparison of high dose TXA (>10 mg/kg) versus low dose (10 mg/kg or less) showed no statistical differences in changes in operative time, blood loss, or transfusion requirement.

Conclusions:
Overall, TXA reduced blood loss and transfusion requirement in patients undergoing surgery for craniosynostosis. There was no difference in outcomes between high dose and low dose regimens amongst those receiving TXA. Low dose TXA appears adequate to achieve clinical efficacy with a low adverse event rate.
Dermal Micro-coring for the Treatment of Moderate to Severe Facial Wrinkles
Authors: Gfrerer Lisa , Kilmer Suzanne L. , Waibel Jill S. , Geronemus Roy G. , Biesman Brian S. 
Published: October 2022

Background:
Micro-coring technology (MCT) removes cores of skin without formation of scars, thereby tightening skin and reducing skin wrinkling. The purpose of this study was to evaluate the safety and efficacy of MCT with the dermal micro-coring device for the treatment of facial wrinkles.

Methods:
This prospective, multicenter clinical trial included fifty-one subjects who underwent MCT treatments of the mid to lower face. The primary study endpoint was change in the Lemperle Wrinkle Severity Scale. Secondary study endpoints were change in Global Aesthetic Improvement Scale (GAIS), participant satisfaction, and evaluation of treatment outcome by an independent review panel. All study endpoints were evaluated at 1, 7, 30, 60, and 150 or 180 days after treatment. Procedure bleeding, pain, and early healing profile were also captured.

Results:
The mean Lemperle Wrinkle Severity Scale change was 1.3 grades. Improvement in the GAIS was reported for 89.7% (87/97) of treated sites, and average improvement of GAIS was 1.5. Participants reported satisfaction with 85.6% of treatment sites. The independent review panel correctly identified 84.2% of the post-treatment photographs as post-treatment. Procedure bleeding and pain was mild with good healing responses and patient-reported average down time of 3 days.

Conclusions:
The results of this study demonstrate the safety and efficacy of MCT with the dermal micro-coring device for the treatment of moderate to severe facial wrinkles. MCT led to significant improvement of facial wrinkles with high patient satisfaction and fast recovery time and should be considered in patients who are seeking minimally invasive treatment for wrinkles of the face.
Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case–control study
Authors: Cayrol Timothée , van den Broeke Emanuel N. , Gerard Eve , Meeus Mira , Mouraux André , Roussel Nathalie , Pitance Laurent 
Published: October 2022

Abstract
Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia—a phenomenon that can be confidently attributed to central sensitization. In this case–control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm2, SD = 28.2) than in the healthy control group (M = 38.4 cm2, SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.
Adenosine causes short-lasting vasodilation and headache but not migraine attacks in migraine patients: a randomized clinical trial
Authors: Thuraiaiyah Janu , Al-Karagholi Mohammad Al-Mahdi , Elbahi Fatima Azzahra , Zhuang Zixuan Alice , Ashina Messoud 
Published: October 2022

Abstract
Migraine is a common disabling disease with a complex pathophysiology. Headache is a frequent side effect after intravenous adenosine administration, although adenosine receptor antagonist, caffeine, relieves migraine headache. These observations suggest a possible involvement of adenosine signaling in headache and migraine pathophysiology. In a randomized, double-blinded, placebo-controlled, crossover study, 18 participants diagnosed with migraine without aura received 120 µg/kg per minute adenosine or placebo over 20 minutes. Headache intensity, migraine-associated symptoms, vital signs, the diameter of the superficial temporal artery (STA), blood flow velocity in the middle cerebral artery (VMCA), and facial skin blood flow were measured at baseline and every 10 minutes until 2 hours after infusion start. The primary end point was the difference in the incidence of migraine attacks after adenosine infusion compared with placebo. Eighteen participants completed the study. We found no difference in the incidence of migraine after adenosine infusion (7 of 18, 39%) compared with placebo (3 of 18, 17%) (P = 0.29). Fourteen participants reported headache after adenosine infusion (14 of 18, 78%) compared with placebo (6 of 18, 33%) (P < 0.01). Adenosine increased heart rate (P < 0.001), facial skin blood flow (P < 0.05), and STA diameter (AUCT0-20min, P = 0.01) and decreased VMCA (AUCT0-20min, P < 0.001) compared with placebo. Adenosine induced headache accompanied by a short-lasting (<30 minutes) dilation of intracerebral and extracerebral arteries. The nonsignificant migraine induction might be because of the presence of several adenosine receptors with counteracting signaling, highlighting the need of more selective modulators to dissect the implication of adenosine in migraine.
Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms
Authors: Potter William Z. 
Published: October 2022

Abstract

Background
The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment.

Method
Narrative commentary drawing on personal positions in both NIH and Industry devoted to translation of CNS compounds from bench to bedside coupled with specific examples of efforts to improve the selection of compounds to take into large clinical trials.

Results
Strategies for increasing R&D productivity in the field of CNS drugs articulated over a decade ago have been implemented over the same period with pre-competitive consortia involved in developing the tools needed to show that before being taken into large trials adequate evidence of postulated brain effects are required. In parallel, the field and the FDA have focused much more on the search for domain specific treatments rather than those depending on traditional measures of efficacy in DSM disorders. NIMH programs such as RDoC and the “Fast-Fail” initiative are provided as efforts which influence and involve partnerships with industry.

Conclusions
The evolution of the field over the last decade is such that there is a shared focus across sources of funding in the public sector, especially NIH brain institutes, on the tools needed to de-risk psychiatric drug development to the degree needed to encourage private sector investment in the clinical trials needed to advance potential new treatments for areas of greatest need. Expansion of funding for translational tool development will have the highest impact on delivering novel treatments.
The Relationship Between Practice Environment Variables and Nurse Manager Perceptions of Workplace Mistreatment to Identify Factors Amenable to Change
Authors: Tarasenko Lindsey Marie , Weston Marla J. , Jones Jacqueline 
Published: October 2022

OBJECTIVE
To examine the relationships between practice environment factors and nurse manager (NM) perceptions of workplace mistreatment (WPM).

BACKGROUND
NMs have a unique perspective of business operations and care delivery and can offer insight into how WPM manifests in clinical settings at the leadership level.

METHODS
Researchers used a cross-sectional correlational design using a nonexperimental causal technique. A convenience sample of 139 NMs completed a survey regarding their perceptions of organizational change, the practice environment, and WPM.

RESULTS
NMs reported experiencing incivility (98%) and bullying (90%). Approximately 20% variance explained mistreatment by relationships with supervisors and budgeted resources (F
4,134 = 9.16, P = 0.000).

CONCLUSIONS
Modifiable factors can be identified to prevent or reduce WPM.