bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)
Authors: Mulvihill Evan , Ardoin Stacy , Thompson Susan D , Zhou Bi , Yu Gakit Richard , King Emily , Singer Nora , Levy D M , Brunner Hermine , Wu Yee Ling , Nagaraja Haikady N , Schanberg Laura Eve , Yu Chack-Yung 
Published: August 2019

ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship betweencomplementand CVD in cSLE.MethodsGene copy numbers (GCNs) for totalC4,C4AandC4Bwere measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2analyses. Effects of totalC4,C4AandC4BGCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of totalC4(p=1.8×10−6). Each copy ofC4gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2C4Bgenes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those withC4Bdeficiency. At the study end, subjects with ≥2C4Band atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN ofC4B; cSLE with ≥2C4Bgenes would benefit from statins therapy to prevent atherosclerosis.
Heightened malpractice risk for hospitalist physicians in the USA: what to know and what to do
Authors: Paterick Zachary R , Paterick Timothy Edward 
Published: August 2019

AbstractHospitalists, nurse practitioners, physician assistants and institutions are all at risk for the potential professional liability issues. The unique relationship between healthcare providers and their sponsoring institution generates complex and evolving legal issues for all participants. The law has played a great role integrating quality care and patient safety with physicians, while providing an avenue for relief when a medical error occurs. The intersection of law and medicine, while allowing for optimal patient care, exposes participating medical providers and the sponsoring institutions to specific professional liability issues. This article addresses the heightened medical practice risk that hospitalist physicians’ encounter in today’s practice of hospital medicine.
Transarticular hinged external skeletal fixation for revision surgery of stifle subluxation associated with multiple ligament injuries in a cat
Authors: Elliott Ross Christopher 
Published: August 2019

Stifle subluxation with multiple ligamentous injuries are a rare but catastrophic injury seen most commonly in cats in the veterinary literature. There is often damage to both cruciate ligaments, the medial and lateral collateral ligaments and the menisci. The long‐term prognosis for this injury is guarded due to the development of marked osteoarthritis after the injury. This paper describes the use of a commercially available range of motion hinge used as a secondary stabilisation for a failed primary anatomical stabilisation. None of the primary implants were removed or augmented at the time of revision surgery. A transarticular fixator was placed and increasing range of motion was allowed by adjusting the hinge at varying intervals over 8 weeks. This allowed fibrous tissue to stabilise the stifle while preventing articular cartilage degeneration. From this case report, transarticular hinge fixation can be considered a method of stabilisation in patients with stifle subluxation.
The Generalized Connectivity of Data Center Networks
Authors: Hao Chen , Yang Weihua 
Published: August 2019

The generalized [Formula: see text]-connectivity of a graph [Formula: see text] is a parameter that can measure the reliability of a network [Formula: see text] to connect any [Formula: see text] vertices in [Formula: see text], which is a generalization of traditional connectivity. Let [Formula: see text] and [Formula: see text] denote the maximum number [Formula: see text] of edge-disjoint trees [Formula: see text] in [Formula: see text] such that [Formula: see text] for any [Formula: see text] and [Formula: see text]. For an integer [Formula: see text] with [Formula: see text], the generalized [Formula: see text]-connectivity of a graph [Formula: see text] is defined as [Formula: see text] and [Formula: see text]. Data centers are essential to the business of companies such as Google, Amazon, Facebook and Microsoft et al. Based on data centers, the data center networks [Formula: see text], introduced by Guo et al. in 2008, have many desirable properties. In this paper, we study the generalized [Formula: see text]-connectivity of [Formula: see text] and show that [Formula: see text] for [Formula: see text] and [Formula: see text].
Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4
Authors: Niu Jixiang , Li Zhen , Li Fuzhou 
Published: August 2019

In recent studies, microRNAs (miRs) have been widely explored as important regulators in tumor suppression. miR-136 has been suggested to participate in tumor inhibition through control of vital cellular processes, such as angiogenesis, proliferation, and apoptosis. This study aimed to evaluate the effects of overexpressed miR-136 by transferring mimics in gallbladder cancer (GBC) and to assess the functional role of miR-136 in GBC cell behaviors with the involvement of the mitogen-activated protein kinase kinase 4 ( MAP2K4)-dependent JNK signaling pathway. Differentially expressed miRs associated with GBC were screened using microarray expression profiles, which identified that miR-136 expression was decreased in GBC. Furthermore, MAP2K4 was validated as a target gene of miR-136. To uncover functional relevance regarding miR-136 and MAP2K4 in GBC, cultured GBC cell lines were prepared to transfect with mimic, inhibitor, siRNA, or vectors. At the same time, the transfected GBC cells were inoculated into nude mice to validate findings in vivo. The obtained results demonstrated that overexpressed miR-136 inhibited angiogenesis and cell proliferation and promoted apoptosis in GBC cell lines in vitro, accompanied by impeded cellular tumorigenicity in nude mice via the suppression of MAP2K4. Moreover, the overexpression of MAP2K4 and the activation of the JNK signaling pathway reversed the inhibitory effects of miR-136 on the angiogenesis and tumorigenicity of GBC cells. Together, our results indicated that overexpressed miR-136 attenuates angiogenesis and enhances cell apoptosis in GBC via the JNK signaling pathway by downregulating the expression of MAP2K4. NEW & NOTEWORTHY This study is based on previous studies suggesting the tumor-suppressive role of microRNA (miR)-136 in various cancers. We aim to clarify whether miR-136 could function as a tumor suppressor in gallbladder cancer (GBC) and an underlying mechanism. In vitro and in vivo assays delineated that the tumor-suppressive role of miR-136 in GBC is achieved through inactivation of the JNK signaling pathway by downregulation of MAP2K4.
Tamoxifen-induced, intestinal-specific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-κB, NLRP3, and gut microbiota
Authors: Sabui Subrata , Skupsky Jonathan , Kapadia Rubina , Cogburn Kyle , Lambrecht Nils W. , Agrawal Anshu , Said Hamid M. 
Published: August 2019

The sodium-dependent multivitamin transporter (SMVT; SLC5A6) is involved in intestinal absorption of vitamin B7 (biotin). We have previously shown that mice with an embryonic intestinal-specific SMVT knockout (KO) develop biotin deficiency and severe spontaneous intestinal inflammation in addition to growth retardation, developmental delays, and death within the first 6–7 wk of life. The profound morbidity and mortality associated with the SMVT-KO has limited our ability to further characterize the intestinal inflammation and other sequelae of this deletion in adult mice with a mature gut microbiota. To overcome this limitation, we generated an intestine-specific, tamoxifen-inducible, conditional SMVT-KO (SMVT-icKO). Our results showed that adult SMVT-icKO mice have reduced body weight, biotin deficiency, shorter colonic length, and bloody diarrhea compared with age- and sex-matched control littermates. All SMVT-icKO mice also developed spontaneous intestinal inflammation associated with induction of calprotectin (S100a8/S100a9), proinflammatory cytokines (IL-1β, TNF-α, IFN-γ, and IL-6), and an increase in intestinal permeability. Additionally, the intestines of SMVT-icKO showed activation of the NF-κB pathway and the nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome. Notably, administration of broad-spectrum antibiotics reduced lethality and led to normalization of intestinal inflammation, proinflammatory cytokines, altered mucosal integrity, and reduced expression of the NLRP3 inflammasome. Overall, these findings support our conclusion that the biotin transport pathway plays an important role in the maintenance of intestinal homeostasis, and that NF-κB and the NLRP3 inflammasome, as well as gut microbiota, drive the development of intestinal inflammation when SMVT is absent. NEW & NOTEWORTHY This study demonstrates that deletion of the intestinal biotin uptake system in adult mice leads to the development of spontaneous gut inflammation and that luminal microbiota plays a role in its development.
Protein arginine methyltransferase biology in humans during acute and chronic skeletal muscle plasticity
Authors: vanLieshout Tiffany L. , Bonafiglia Jacob T. , Gurd Brendon J. , Ljubicic Vladimir 
Published: August 2019

Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins. While dysregulation of PRMTs has been documented in a number of the most prevalent diseases, our understanding of PRMT biology in human skeletal muscle is limited. This study served to address this knowledge gap by exploring PRMT expression and function in human skeletal muscle in vivo and characterizing PRMT biology in response to acute and chronic stimuli for muscle plasticity. Fourteen untrained, healthy men performed one session of sprint interval exercise (SIE) before completing four bouts of SIE per week for 6 wk as part of a sprint interval training (SIT) program. Throughout this time course, multiple muscle biopsies were collected. We found that at basal, resting conditions PRMT1, PRMT4, PRMT5, and PRMT7 were the most abundantly expressed PRMT mRNAs in human quadriceps muscle. Additionally, the broad subcellular distribution pattern of PRMTs suggests methyltransferase activity throughout human myofibers. A spectrum of PRMT-specific inductions, and decrements, in expression and activity were observed in response to acute and chronic cues for muscle plasticity. In conclusion, our findings demonstrate that PRMTs are present and active in human skeletal muscle in vivo and that there are distinct, enzyme-specific responses and adaptations in PRMT biology to acute and chronic stimuli for muscle plasticity. This work advances our understanding of this critical family of enzymes in humans. NEW & NOTEWORTHY This is the first report of protein arginine methyltransferase (PRMT) biology in human skeletal muscle in vivo. We observed that PRMT1, -4, -5, and -7 were the most abundant PRMT mRNAs in human muscle and that PRMT proteins exhibited a broad subcellular localization that included myonuclear, cytosolic, and sarcolemmal compartments. Acute exercise and chronic training evoked PRMT-specific alterations in expression and activity. This study reveals a hitherto unknown complexity to PRMT biology in human muscle.
Placental oxygen transfer reduces hypoxia-reoxygenation swings in fetal blood in a sheep model of gestational sleep apnea
Authors: Almendros Isaac , Martínez-Ros Paula , Farré Nuria , Rubio-Zaragoza Mónica , Torres Marta , Gutiérrez-Bautista Álvaro J. , Carrillo-Poveda José M. , Sopena-Juncosa Joaquín J. , Gozal David , Gonzalez-Bulnes Antonio , Farré Ramon 
Published: August 2019

Obstructive sleep apnea (OSA), characterized by events of hypoxia-reoxygenation, is highly prevalent in pregnancy, negatively affecting the gestation process and particularly the fetus. Whether the consequences of OSA for the fetus and offspring are mainly caused by systemic alterations in the mother or by a direct effect of intermittent hypoxia in the fetus is unknown. In fact, how apnea-induced hypoxemic swings in OSA are transmitted across the placenta remains to be investigated. The aim of this study was to test the hypothesis, based on a theoretical background on the damping effect of oxygen transfer in the placenta, that oxygen partial pressure (Po2) swings resulting from obstructive apneas mimicking OSA are mitigated in the fetal circulation. To this end, four anesthetized ewes close to term pregnancy were subjected to obstructive apneas consisting of 25-s airway obstructions. Real-time Po2 was measured in the maternal carotid artery and in the umbilical vein with fast-response fiber-optic oxygen sensors. The amplitudes of Po2 swings in the umbilical vein were considerably smaller [3.1 ± 1.0 vs. 21.0 ± 6.1 mmHg (mean ± SE); P < 0.05]. Corresponding estimated swings in fetal and maternal oxyhemoglobin saturation tracked Po2 swings. This study provides novel insights into fetal oxygenation in a model of gestational OSA and highlights the importance of further understanding the impact of sleep-disordered breathing on fetal and offspring development. NEW & NOTEWORTHY This study in an airway obstruction sheep model of gestational sleep apnea provides novel data on how swings in oxygen partial pressure (Po2) translate from maternal to fetal blood. Real-time simultaneous measurement of Po2 in maternal artery and in umbilical vein shows that placenta transfer attenuates the magnitude of oxygenation swings. These data prompt further investigation of the extent to which maternal apneas could induce similar direct oxidative stress in fetal and maternal tissues.
Motor unit discharge rate and the estimated synaptic input to the vasti muscles is higher in open compared with closed kinetic chain exercise
Authors: Boccia Gennaro , Martinez-Valdes Eduardo , Negro Francesco , Rainoldi Alberto , Falla Deborah 
Published: August 2019

Conflicting results have been reported on whether closed kinetic chain exercises (such as a leg press) may induce more balanced activation of vastus medialis (VM) and lateralis (VL) muscles compared with open kinetic chain exercise (such as pure knee extension). This study aimed to 1) compare between-vasti motor unit activity and 2) analyze the combined motor unit behavior from both muscles between open and closed kinetic chain exercises. Thirteen participants (four women, mean ± SD age: 27 ± 5 yr) performed isometric knee extension and leg press at 10, 30, 50, 70% of the maximum voluntary torque. High density surface EMG signals were recorded from the VM and VL and motor unit firings were automatically identified by convolutive blind source separation. We estimated the total synaptic input received by the two muscles by analyzing the difference in discharge rate from recruitment to target torque for motor units matched by recruitment threshold. When controlling for recruitment threshold and discharge rate at recruitment, the motor unit discharge rates were higher for knee extension compared with the leg press exercise at 50% [estimate = 1.2 pulses per second (pps), standard error (SE) = 0.3 pps, P = 0.0138] and 70% (estimate = 2.0 pps, SE = 0.3 pps, P = 0.0001) of maximal torque. However, no difference between the vasti muscles were detected in both exercises. The estimates of synaptic input to the muscles confirmed these results. In conclusion, the estimated synaptic input received by VM and VL was similar within and across exercises. However, both muscles had higher firing rates and estimated synaptic input at the highest torque levels during knee extension. Taken together, the results show that knee-extension is more suitable than leg-press exercise at increasing the concurrent activation of the vasti muscles.NEW & NOTEWORTHY There is a significant debate on whether open kinetic chain, single-joint knee extension exercise can influence the individual and combined activity of the vasti muscles compared with closed kinetic chain, multijoint leg press exercise. Here we show that attempting to change the contribution of either the vastus medialis or vastus lateralis via different forms of exercise does not seem to be a viable strategy. However, the adoption of open kinetic chain knee extension induces greater discharge rate and estimated synaptic input to both vasti muscles compared with the leg press.
Skeletal muscle LINE-1 ORF1 mRNA is higher in older humans but decreases with endurance exercise and is negatively associated with higher physical activity
Authors: Roberson Paul A. , Romero Matthew A. , Osburn Shelby C. , Mumford Petey W. , Vann Christopher G. , Fox Carlton D. , McCullough Danielle J. , Brown Michael D. , Roberts Michael D. 
Published: August 2019

The long interspersed nuclear element-1 (L1) is a retrotransposon that constitutes 17% of the human genome and is associated with various diseases and aging. Estimates suggest that ~100 L1 copies are capable of copying and pasting into other regions of the genome. Herein, we examined if skeletal muscle L1 markers are affected by aging or an acute bout of cycling exercise in humans. Apparently healthy younger (23 ± 3 y, n = 15) and older participants (58 ± 8 y, n = 15) donated a vastus lateralis biopsy before 1 h of cycling exercise (PRE) at ~70% of heart rate reserve. Second (2 h) and third (8 h) postexercise muscle biopsies were also obtained. L1 DNA and mRNA expression were quantified using three primer sets [5′ untranslated region (UTR), L1.3, and ORF1]. 5′UTR and L1.3 DNA methylation as well as ORF1 protein expression were also quantified. PRE 5′UTR, ORF1, or L1.3 DNA were not different between age groups ( P > 0.05). ORF1 mRNA was greater in older versus younger participants ( P = 0.014), and cycling lowered this marker at 2 h versus PRE ( P = 0.027). 5′UTR and L1.3 DNA methylation were higher in younger versus older participants ( P < 0.05). Accelerometry data collected during a 2-wk period before the exercise bout indicated higher moderate-to-vigorous physical activity (MVPA) levels per day was associated with lower PRE ORF1 mRNA in all participants ( r = −0.398, P = 0.032). In summary, skeletal muscle ORF1 mRNA is higher in older apparently healthy humans, which may be related to lower DNA methylation patterns. ORF1 mRNA is also reduced with endurance exercise and is negatively associated with higher daily MVPA levels. NEW & NOTEWORTHY The long interspersed nuclear element-1 (L1) gene is highly abundant in the genome and encodes for an autonomous retrotransposon, which is capable of copying and pasting itself into other portions of the genome. This is the first study in humans to demonstrate that certain aspects of skeletal muscle L1 activity are altered with aging. Additionally, this is the first study in humans to demonstrate that L1 ORF1 mRNA levels decrease after a bout of endurance exercise, regardless of age.
Regional differences in Ca2+ entry along the proximal-middle-distal muscle axis during eccentric contractions in rat skeletal muscle
Authors: Tabuchi Ayaka , Eshima Hiroaki , Tanaka Yoshinori , Nogami Shunsuke , Inoue Naoki , Sudo Mizuki , Okada Hidetaka , Poole David C. , Kano Yutaka 
Published: August 2019

Eccentric (ECC) contraction-induced muscle damage is associated with calcium ion (Ca2+) influx from the extracellular milieu through stretch-activated channels. It remains unknown whether Ca2+ influx consequent to repetitive ECC contractions is nonuniform across different muscle regions. We tested the hypothesis that there are regional differences in Ca2+ entry along the proximal-middle-distal muscle axis. Tibialis anterior (TA) muscles of adult male Wistar rats were exposed by reflecting the overlying skin and fasciae and ECC contractions evoked by peroneal nerve stimulation paired with simultaneous ankle extension (50 times/set, 2 protocols: 1 set and 10 sets). During ECC in the proximal, middle, and distal TA, we determined 1) muscle fiber extension by high-speed camera (200 frames/s) and 2) Ca2+ accumulation by in vivo bioimaging (Ca2+-sensitive probe Fura-2-acetoxymethyl ester). Muscle fiber extension from resting was significantly different among regions (i.e., proximal, 4.0%: < middle, 11.2%: < distal, 17.0%; ECC phase length at 500th contraction). Intracellular Ca2+ accumulation after 1 set of ECC was higher in the distal (1.46 ± 0.04, P < 0.05) than the proximal (1.27 ± 0.04) or middle (1.26 ± 0.05) regions. However, this regional Ca2+ accumulation difference disappeared by 32.5 min after the 1 set protocol when the muscle was quiescent and by contraction set 5 for the 10-set protocol. The initial preferential ECC-induced Ca2+ accumulation observed distally was associated spatially with the greater muscle extension compared with that of the proximal and middle regions. Disappearance of the regional Ca2+ accumulation disparity in quiescent and ECC-contracting muscle might be explained, in part, by axial Ca2+ propagation and account for the uniformity of muscle damage across regions evident 3 days post-ECC. NEW & NOTEWORTHY After 1 set of 50 eccentric (ECC) contractions in the anterior tibialis muscle, intracellular Ca2+ ([Ca2+]i) accumulation evinces substantial regional heterogeneity that is spatially coherent with muscle length changes (i.e., distal [Ca2+]i > middle, proximal). However, irrespective of whether 50 or 500 ECC contractions are performed, this heterogeneity is subsequently abolished, at least in part, by axial intracellular Ca2+ propagation. This Ca2+ homogenization across regions is consistent with the absence of any interregional difference in muscle damage 3 days post-ECC.
STING (or SRC) Like an ICB: Priming the Immune Response in Pancreatic Cancer
Authors: Gutiontov Stanley I. , Weichselbaum Ralph R. 
Published: August 2019

Abstract
Pancreatic adenocarcinoma is associated with a poor prognosis and resistance to immune checkpoint blockade. Zhang and colleagues demonstrate that inhibiting DNA repair by pharmacologic blockade or siRNA silencing of ataxia telangiectasia mutated (ATM) increases type I IFN release via a cGAS/STING-independent, SRC-dependent mechanism in models of pancreatic cancer. Furthermore, combining ATM inhibition and radiotherapy amplifies type I IFN signaling, increases programmed death ligand 1 (PD-L1) expression, tumor CD8+ T cells, and proinflammatory tumor macrophages. Finally, the combination of ATM silencing, radiotherapy, and PD-L1 blockade markedly improves in vivo murine tumor responses, supporting further investigation of this promising approach in pancreatic adenocarcinoma.
See related article by Zhang et al., p. 3940