bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPV4 Antagonism Prevents Mechanically Induced Myotonia
Authors: Dupont Chris , Novak Kevin , Denman Kirsten , Myers Jessica H. , Sullivan Jeremy M. , Walker Phillip V. , Brown Nicklaus L. , Ladle David R. , Bogdanik Laurent , Lutz Cathleen M. , A. Voss Andrew , Sumner Charlotte J. , Rich Mark M. 
Published: May 2020

ObjectiveMyotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy.MethodsWe developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness.ResultsAs previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4‐null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%.InterpretationThese data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297–308.
Quantitative Separation of Tremor and Ataxia in Essential Tremor
Authors: Casamento‐Moran Agostina , Yacoubi Basma , Wilkes Bradley J. , Hess Christopher W. , Foote Kelly D. , Okun Michael S. , Wagle Shukla Aparna , Vaillancourt David E. , Christou Evangelos A. 
Published: May 2020

ObjectiveThis study addresses an important problem in neurology, distinguishing tremor and ataxia using quantitative methods. Specifically, we aimed to quantitatively separate dysmetria, a cardinal sign of ataxia, from tremor in essential tremor (ET).MethodsIn Experiment 1, we compared 19 participants diagnosed with ET undergoing thalamic deep brain stimulation (DBS; ETDBS) to 19 healthy controls (HC). We quantified tremor during postural tasks using accelerometry and dysmetria with fast, reverse‐at‐target goal‐directed movements. To ensure that endpoint accuracy was unaffected by tremor, we quantified dysmetria in selected trials manifesting a smooth trajectory to the endpoint. Finally, we manipulated tremor amplitude by switching DBS ON and OFF to examine its effect on dysmetria. In Experiment 2, we compared 10 ET participants with 10 HC to determine whether we could identify and distinguish dysmetria from tremor in non‐DBS ET.ResultsThree findings suggest that we can quantify dysmetria independently of tremor in ET. First, ETDBS and ET exhibited greater dysmetria than HC and dysmetria did not correlate with tremor (R2 < 0.01). Second, even for trials with tremor‐free trajectories to the target, ET exhibited greater dysmetria than HC (p < 0.01). Third, activating DBS reduced tremor (p < 0.01) but had no effect on dysmetria (p > 0.2).InterpretationWe demonstrate that dysmetria can be quantified independently of tremor using fast, reverse‐at‐target goal‐directed movements. These results have important implications for the understanding of ET and other cerebellar and tremor disorders. Future research should examine the neurophysiological mechanisms underlying each symptom and characterize their independent contribution to disability. ANN NEUROL 2020;88:375–387.
The CSF Profile Linked to Cortical Damage Predicts Multiple Sclerosis Activity
Authors: Magliozzi Roberta , Scalfari Antonio , Pisani Anna Isabella , Ziccardi Stefano , Marastoni Damiano , Pizzini Francesca Benedetta , Bajrami Albulena , Tamanti Agnese , Guandalini Maddalena , Bonomi Samuele , Rossi Stefania , Mazziotti Valentina , Castellaro Marco , Montemezzi Stefania , Rasia Sarah , Capra Ruggero , Pitteri Marco , Romualdi Chiara , Reynolds Richard , Calabrese Massimiliano 
Published: May 2020

ObjectiveIntrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear.MethodsWe evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing‐remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated.ResultsForty‐one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p < 0.001). In the multivariate analysis, CXCL13 (hazard ratio [HR] = 1.35; p = 0.0002), LIGHT (HR = 1.22; p = 0.005) and APRIL (HR = 1.78; p = 0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model, including CSF variables, predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C‐index at 4 years = 71% vs 44%). Finally, higher CSF levels of CXCL13 (β = 4.7*10−4; p < 0.001), TNF (β = 3.1*10−3; p = 0.004), LIGHT (β = 2.6*10−4; p = 0.003), sCD163 (β = 4.3*10−3; p = 0.009), and TWEAK (β = 3.4*10−3; p = 0.024) were associated with more severe cortical thinning.InterpretationA specific CSF profile, mainly characterized by elevated levels of B‐cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. ANN NEUROL 2020;88:562–573
Deletion of JNK Enhances Senescence in Joint Tissues and Increases the Severity of Age‐Related Osteoarthritis in Mice
Authors: Loeser Richard F. , Kelley Kathryn L. , Armstrong Alexandra , Collins John A. , Diekman Brian O. , Carlson Cathy S. 
Published: May 2020

ObjectiveTo determine the role of JNK signaling in the development of osteoarthritis (OA) induced by joint injury or aging in mice.MethodsIn the joint injury model, 12‐week‐old wild‐type control, JNK1−/−, JNK2−/−, and JNK1fl/flJNK2−/− aggecan‐CreERT2 double‐knockout mice were subjected to destabilization of the medial meniscus (DMM) (n = 15 mice per group) or sham surgery (n = 9–10 mice per group), and OA was evaluated 8 weeks later. In the aging experiment, wild‐type control, JNK1−/−, and JNK2−/− mice (n = 15 per group) were evaluated at 18 months of age. Mouse knee joints were evaluated by scoring articular cartilage structure, toluidine blue staining, osteophytes, and synovial hyperplasia, by histomorphometric analysis, and by immunostaining for the senescence marker p16INK4a. Production of matrix metalloproteinase 13 (MMP‐13) in cartilage explants in response to fibronectin fragments was measured by enzyme‐linked immunosorbent assay.ResultsThere were no differences after DMM surgery between the wild‐type and the JNK‐knockout mouse groups in articular cartilage structure, toluidine blue, or osteophyte scores or in MMP‐13 production in explants. All 3 knockout mouse groups had increased subchondral bone thickness and area of cartilage necrosis compared to wild‐type mice. Aged JNK‐knockout mice had significantly worse articular cartilage structure scores compared to the aged wild‐type control mice (mean ± SD 52 ± 24 in JNK1−/− mice and 60 ± 25 in JNK2−/− mice versus 32 ± 18 in controls; P = 0.02 and P = 0.004, respectively). JNK1−/− mice also had higher osteophyte scores. Deletion of JNK resulted in increased expression of p16INK4a in the synovium and cartilage in older mice.ConclusionJNK1 and JNK2 are not required for the development of OA in the mouse DMM model. Deletion of JNK1 or JNK2 is associated with more severe age‐related OA and increased cell senescence, suggesting that JNK may act as a negative regulator of senescence in the joint.
The relationship between premarital counselling and marital harmony among families in Lugari, Kakamega County, Kenya
Authors: Muluhya Keverenge Edward , Kipnusu Robert C. , Tarus Prisca , Karimi Jane 
Published: May 2020

AbstractMarriage is the most respected institution in the world, and it contributes to the foundations of procreation, leadership and peace and is the hub of economic stability. Currently, there are marital disharmony cases which have led to marriage being viewed with a negative perception. This trend is common in Lugari, Kakamega County, Kenya, resulting in psychological torture, issues with child development in terms of learning and discipline, and a long‐term effect on their behaviour as adults. Premarital counselling was conceived for the purpose of helping families to re‐evaluate their feelings about marriage and its values in order to experience marital harmony. This study sought to determine the relationship between premarital counselling and marital harmony among families. It was guided by solution‐focused theory (SFT). The target population for the study was married couples and premarital counsellors. Purposive and simple random techniques were used to select a representative sample of 20 men, 20 women and 10 premarital counsellors in Lugari, Kakamega County. There was a statistically significant relationship between premarital counselling services and marital harmony among families with a correlation of .893. Therefore, there should be awareness of the existing services, and couples intending to marry should seek premarital counselling interventions and continue to attend counselling after formalising their marriage to keep up with the changing times.
Investigating the gelling behaviour of ‘waxy' paraffinic mixtures during flow shutdown
Authors: Ehsani Sina , Mehrotra Anil K. 
Published: May 2020

AbstractThe flow of waxy or paraffinic crude oils in a pipeline could be shutdown for a variety of reasons, resulting in their cooling and subsequent gelling. Gel formation from a multicomponent wax‐solvent mixture during flow shutdown was investigated experimentally and analyzed with a transient heat‐transfer model based on the moving boundary problem formulation. The gelling experiments were performed with a 0.10 g/g wax‐solvent mixture in a flow‐loop apparatus, following the formation of a steady‐state deposit layer in turbulent flow regime, at two initial wax‐solvent mixture temperatures, with a constant coolant temperature, and for different shutdown times. The gel formation was found to be a fast process, which continued until the gel fully occupied the deposition tube. Gas chromatographic analyses of the deposit samples (under sheared cooling) and the gel samples (under static cooling during flow shutdown) indicated significant differences in the composition and the total wax content. The deposit samples showed an enrichment of heavier paraffins, whereas the composition of gel samples was comparable to that of the original wax‐solvent mixture. The predictions from the transient model showed that a lower initial oil temperature, a lower coolant temperature, and a smaller pipe diameter would result in a faster blockage of the pipe. The predictions from the moving boundary problem formulation agreed well with the flow shutdown data, which further confirmed that the solid and gel formation from wax‐solvent mixtures is modelled satisfactorily as a heat transfer process.
TBHP‐Mediated Oxidative Decarboxylative Cyclization in Water: Direct and Sustainable Access to Anti‐malarial Polycyclic Fused Quinazolinones and Rutaecarpine
Authors: Chen Xingyu , Xia Fei , Zhao Yifan , Ma Ji , Ma Yue , Zhang Dong , Yang Lan , Sun Peng 
Published: May 2020

Summary of main observation and conclusionPolycyclic fused quinazolinones with anti‐malarial activity were synthesized through tert‐butyl hydroperoxide (TBHP)‐mediated oxidative decarboxylative cyclization between commercially available isatins and cyclic amines in one step. The reaction proceeds smoothly in water without additional transition‐metal catalyst, acid and base. The newly synthesized products were evaluated to exhibit moderate to good anti‐malarial activity against chloroquine drug‐sensitive Plasmodium falciparum 3D7 strain. Additionally, this method also provides direct approach to Rutaecarpine in good yield.
Integrated Catalyst of CuZnAl‐Zr and Nb‐HZSM‐5 for One‐Step Synthesis of Aromatics from Syngas
Authors: Xiao Wentao , Li Minzhe , Nawaz Muhammad Asif , Xu Lichong , Song Guiyao , ShuoYang  , Wang Zihao , Liu Dianhua 
Published: May 2020

Summary of main observation and conclusionThe addition of Zr increased the dispersion and antisinitering of Cu species and Nb adjusted the HZSM‐5 acidity. Bifunctional catalyst increased selectivity of aromatics to 39.8%, and 60.0% for durene in aromatics. A method for resolving the temperature mismatch between Cu‐based catalysts and HZSM‐5 zeolite is provided.
PROTOCOL: Protocol for corporate crime deterrence: An updated systematic review
Authors: Schell‐Busey Natalie , Rorie Melissa , Simpson Sally S. 
Published: May 2020

AbstractThis is the protocol for an updated Campbell review on corporate crime deterrence. Our overall objective is to identify and synthesize the extant empirical literature on formal legal and administrative prevention and control—that is, the actions and programs of government law enforcement agencies, legislative bodies, and regulatory agencies within a specific focus, as further discussed in this study. This review will consider all types of legal and regulatory practices as long as corporate crime prevention is part of the outcome. Other outcomes and information, if relevant, will also be collected.
Pegylation of RNA Spiegelmers by a Novel Widely Applicable Two‐Step Process for the Conjugation of Carboxylic Acids to Amino‐Modified Oligonucleotides
Authors: Bethge Lucas , Vonhoff Stefan 
Published: May 2020

AbstractThe reaction between N‐hydroxy succinimide (NHS) ester−activated carboxylic acids and amino‐modified nucleic acids is commonly used for the post‐synthetic modification of oligonucleotides. Here, we report a two‐step variation of the method in which the NHS ester is replaced by the corresponding parent carboxylic acid. In the first step, the carboxylic acid is activated with a standard peptide coupling reagent like HBTU in an anhydrous water‐miscible aprotic organic solvent. In the second step, the solution of the activated carboxylic acid is added to the amino‐modified oligonucleotide in water. The method is demonstrated using 40‐kDa polyethylene glycol (PEG) carboxylic acid and biotin as examples. Recycling of the carboxylic acid, which is typically used in molar excess over the nucleic acid, is shown for the conjugation with 40‐kDa PEG carboxylic acid. This conjugation method is generally applicable to the conjugation of carboxylic acids to amino‐modified oligonucleotides, thus enabling the attachment of small to large molecular entities such as dyes, tags, peptides, and other macromolecules. © 2020 Wiley Periodicals LLC.Basic Protocol 1: General protocol for the conjugation of an amino‐modified oligonucleotide with a carboxylic acid, exemplified for 40‐kDa PEG carboxylic acidBasic Protocol 2: Biotinylation of an amino‐modified oligonucleotide using the general conjugation protocolBasic Protocol 3: Recycling of the carboxylic acid component from the conjugation reaction, demonstrated for 40‐kDa PEG carboxylic acid using ultrafiltrationSupport Protocol 1: Analytical AEX‐HPLC method used as in‐process control method to monitor the conjugation reaction with 40‐kDa PEG carboxylic acidSupport Protocol 2: Analytical AEX‐HPLC method used as in‐process control method to monitor the conjugation reaction with biotinSupport Protocol 3: Analytical IP‐RP‐HPLC method used as in‐process control method to monitor the conjugation reactionAlternate Protocol: Separation of 40‐kDa PEG carboxylic acid from unreacted and conjugated oligonucleotide by preparative AEX‐HPLC
Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8+ T Cells and Inhibiting Tumor AKT/MAPK Pathway
Authors: Liao Ping , Song Kun , Zhu Zhanwei , Liu Zhaoqian , Zhang Wei , Li Wei , Hu Jiali , Hu Qian , Chen Cuiyu , Chen Bohua , McLeod Howard L. , Pei Haiping , Chen Ling , He Yijing 
Published: May 2020

Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.
Recent Developments in the Application of Flow Cytometry to Advance our Understanding of Mycobacteriumtuberculosis Physiology and Pathogenesis
Authors: Parbhoo Trisha , Sampson Samantha L. , Mouton Jacoba M. 
Published: May 2020

AbstractThe ability of the bacterial pathogen Mycobacterium tuberculosis to adapt and survive within human cells to disseminate to other individuals and cause active disease is poorly understood. Research supports that as M. tuberculosis adapts to stressors encountered in the host, it exhibits variable physiological and metabolic states that are time and niche‐dependent. Challenges associated with effective treatment and eradication of tuberculosis (TB) are in part attributed to our lack of understanding of these different mycobacterial phenotypes. This is mainly due to a lack of suitable tools to effectively identify/detect heterogeneous bacterial populations, which may include small, difficult‐to‐culture subpopulations. Importantly, flow cytometry allows rapid and affordable multiparametric measurements of physical and chemical characteristics of single cells, without the need to preculture cells. Here, we summarize current knowledge of flow cytometry applications that have advanced our understanding of the physiology of M. tuberculosis during TB disease. Specifically, we review how host‐associated stressors influence bacterial characteristics such as metabolic activity, membrane potential, redox status and the mycobacterial cell wall. Further, we highlight that flow cytometry offers unprecedented opportunities for insight into bacterial population heterogeneity, which is increasingly appreciated as an important determinant of disease outcome. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
Association of HLA‐DR‐DQ alleles, haplotypes, and diplotypes with type 1 diabetes in Saudis
Authors: Eltayeb‐Elsheikh Nezar , Khalil Eltahir , Mubasher Mohamed , AlJurayyan Abdullah , AlHarthi Hanan , Omer Waleed H. , Elghazali Inas , Sherbeeni Suphia M. , Alghofely Mohammed A. , Ilonen Jorma , Elghazali Gehad 
Published: May 2020

AbstractAimsType 1 diabetes (T1D) is an autoimmune disease that affects many children worldwide. Genetic factors and environmental triggers play crucial interacting roles in the aetiology. This study aimed to assess the contribution of HLA‐DRB1‐DQA1‐DQB1 alleles, haplotypes, and genotypes to the risk of T1D among Saudis.MethodsA total of 222 children with T1D and 342 controls were genotyped for HLA‐DRB1, ‐DQA1, and ‐DQB1 using reverse sequence‐specific oligonucleotide (rSSO) Lab Type high definition (HD) kits. Alleles, haplotypes, and diplotypes were compared between cases and controls using the SAS statistical package.ResultsDRB1*03:01‐DQA1*05:01‐DQB1*02:01 (32.4%; OR = 3.68; Pc < .0001), DRB1*04:05‐DQA1*03:02‐DQB1*03:02 (6.6%; OR = 6.76; Pc < .0001), DRB1*04:02‐DQA1*03:01‐DQB1*03:02 (6.0%; OR = 3.10; Pc = .0194), DRB1*04:01‐DQA1*03:01‐DQB1*03:02 (3.7%; OR = 4.22; Pc = .0335), and DRB1*04:05‐DQA1*03:02‐DQB1*02:02 (2.7%; OR = 6.31; Pc = .0326) haplotypes were significantly increased in cases compared to controls, whereas DRB1*07:01‐DQA1*02:01‐DQB1*02:02 (OR = 0.41; Pc = .0001), DRB1*13:01‐DQA1*01:03‐DQB1*06:03 (OR = 0.05; Pc < .0001), DRB1*15:01‐DQA1*01:02‐DQB1*06:02 (OR = 0.03; Pc < .0001), and DRB1*11:01‐DQA1*05:05‐DQB1*03:01 (OR = 0.07; Pc = .0291) were significantly decreased. Homozygous DRB1*03:01‐DQA1*05:01‐DQB1*02:01 genotypes and combinations of DRB1*03:01‐DQA1*05:01‐DQB1*02:01 with DRB1*04:05‐DQA1*03:02‐DQB1*03:02, DRB1*04:02‐DQA1*03:01‐DQB1*03:02, and DRB1*04:01‐DQA1*03:01‐DQB1*03:02 were significantly increased in cases than controls. Combinations of DRB1*03:01‐DQA1*05:01‐DQB1*02:01 with DRB1*07:01‐DQA1*02:01‐DQB1*02:02 and DRB1*13:02‐DQA1*01:02‐DQB1*06:04 showed low OR values but did not remain significantly decreased after Bonferroni correction.ConclusionsHLA‐DRB1‐DQA1‐DQB1 alleles, haplotypes, and diplotypes in Saudis with T1D are not markedly different from those observed in Western and Middle‐Eastern populations but are quite different than those of East Asians.