bluuebunny/crossref_metadata_2025_split huggingface dataset:
Butyrate stimulates adipose lipolysis and mitochondrial oxidative phosphorylation through histone hyperacetylation‐associated β3‐adrenergic receptor activation in high‐fat diet‐induced obese mice
Authors: Jia Yimin , Hong Jian , Li Huifang , Hu Yun , Jia Longfei , Cai Demin , Zhao Ruqian 
Published: December 2016

New Findings
What is the central question of this study?
Butyrate can prevent diet‐induced obesity through increasing energy expenditure. However, it is unclear whether β3‐adrenergic receptors (ARβ3) mediate butyrate‐induced adipose lipolysis.

What is the main finding and its importance?
Short‐term oral administration of sodium butyrate is effective in alleviating diet‐induced obesity through activation of ARβ3‐mediated lipolysis in white adipose tissue.

Butyrate can prevent diet‐induced obesity through increasing energy expenditure. However, it is unclear whether ARβ3 mediates butyrate‐induced adipose lipolysis. In this study, weaned mice were were fed control (Con) or high‐fat (HF) diet for 8 weeks to establish obesity. High‐fat diet‐induced obese mice maintained on the HF diet were divided into two subgroups; the HFB group was gavaged with 80 mg sodium butyrate (SB) per mouse every other day for 10 days, whereas the HF group received vehicle. Chromatin immunoprecipitation assay was performed to determine the status of histone H3 lysine 9 acetylation (H3K9Ac) on the promoter of the β3‐adrenergic receptor (ARβ3) gene in epididymal white adipose tissue. It was shown that five gavage doses of SB significantly alleviated HF diet‐induced obesity and restored plasma leptin concentration to the control level. Protein contents of ARβ3 and PKA, as well as ATGL and p‐HSL (Ser563), were significantly upregulated in the HFB group compared with the HF group. Mitochondrial oxidative phosphorylation was enhanced by SB treatment. Sodium butyrate significantly increased the expression of four out of 13 mitochondrial DNA‐encoded genes and significantly upregulated the protein contents of peroxisome proliferator‐activated receptor‐γ coactivator 1α and COX4. Moreover, SB administration enhanced the expression of ARβ3 and its downstream signalling. The G protein‐coupled receptor 43 and p‐CREB (Ser133) were significantly stimulated by SB. In addition, an active transcription marker, H3K9Ac, was significantly enriched on the promoter of the ARβ3 gene. Our results indicate that short‐term oral administration of SB is effective in alleviating diet‐induced obesity through activation of the ARβ3‐mediated lipolysis in the epididymal white adipose tissue.
Metabolic systems biology: a brief primer
Authors: Edwards Lindsay M. 
Published: December 2016

AbstractIn the early to mid‐20th century, reductionism as a concept in biology was challenged by key thinkers, including Ludwig von Bertalanffy. He proposed that living organisms were specific examples of complex systems and, as such, they should display characteristics including hierarchical organisation and emergent behaviour. Yet the true study of complete biological systems (for example, metabolism) was not possible until technological advances that occurred 60 years later. Technology now exists that permits the measurement of complete levels of the biological hierarchy, for example the genome and transcriptome. The complexity and scale of these data require computational models for their interpretation. The combination of these – systems thinking, high‐dimensional data and computation – defines systems biology, typically accompanied by some notion of iterative model refinement. Only sequencing‐based technologies, however, offer full coverage. Other ‘omics’ platforms trade coverage for sensitivity, although the densely connected nature of biological networks suggests that full coverage may not be necessary. Systems biology models are often characterised as either ‘bottom‐up’ (mechanistic) or ‘top‐down’ (statistical). This distinction can mislead, as all models rely on data and all are, to some degree, ‘middle‐out’. Systems biology has matured as a discipline, and its methods are commonplace in many laboratories. However, many challenges remain, especially those related to large‐scale data integration.
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Residual force enhancement is regulated by titin in skeletal and cardiac myofibrils
Authors: Shalabi Nabil , Cornachione Anabelle , de Souza Leite Felipe , Vengallatore Srikar , Rassier Dilson E. 
Published: December 2016

Key pointsWhen a skeletal muscle is stretched while it contracts, the muscle produces a relatively higher force than the force from an isometric contraction at the same length: a phenomenon referred to as residual force enhancement.Residual force enhancement is puzzling because it cannot be directly explained by the classical force–length relationship and the sliding filament theory of contraction, the main paradigms in the muscle field.We used custom‐built instruments to measure residual force enhancement in skeletal myofibrils, and, for the first time, in cardiac myofibrils.Our data report that residual force enhancement is present in skeletal muscles, but not cardiac muscles, and is regulated by the different isoforms of the titin protein filaments.AbstractWhen a skeletal muscle contracts isometrically, the muscle produces a force that is relative to the final isometric sarcomere length (SL). However, when the same final SL is reached by stretching the muscle while it contracts, the muscle produces a relatively higher force: a phenomenon commonly referred to as residual force enhancement. In this study, we investigated residual force enhancement in rabbit skeletal psoas myofibrils and, for the first time, cardiac papillary myofibrils. A custom‐built atomic force microscope was used in experiments that stretched myofibrils before and after inhibiting myosin and actin interactions to determine whether the different cardiac and skeletal titin isoforms regulate residual force enhancement. At SLs ranging from 2.24 to 3.13 μm, the skeletal myofibrils enhanced the force by an average of 9.0%, and by 29.5% after hindering myosin and actin interactions. At SLs ranging from 1.80 to 2.29 μm, the cardiac myofibrils did not enhance the force before or after hindering myosin and actin interactions. We conclude that residual force enhancement is present only in skeletal muscles and is dependent on the titin isoforms.
Relationship Between Fundamental Motor Skill Ability and Body Mass Index in Young Adults
Authors: Jiménez Judith , Morera Maria , Salazar Walter , Gabbard Carl 
Published: December 2016

Purpose:Motor skill competence has been associated with physical activity level, fitness, and other relevant health-related characteristics. Recent research has focused on understanding these relationships in children and adolescents, but little is known about subsequent years. The aim of this study was to examine the relationship between fundamental motor skill (FMS) ability and body mass index (BMI) in young adults.
Method:Participants, 40 men and 40 women (M age = 19.25 yr, SD = 2.48), were assessed for BMI and motor competence with 10 fundamental motor skills (FMSs) using the Test for Fundamental Motor Skills in Adults (TFMSA).
Results:BMI was negatively associated with total motor ability (r = –.257; p = .02) and object control skills (r = –.251; p = .02); the relationship with locomotor skills was marginally insignificant (r = –.204; p = .07). In regard to individual skills, a significant negative association was found for running, jumping, striking, and kicking (ps < .05). Multiple regression analysis indicated that BMI and gender predicted 42% of the variance in total FMS score; gender was the only significant predictor.
Conclusion:Overall, these preliminary findings suggest that young adults with higher FMS ability are more likely to have lower BMI scores.
Principles of auditory processing differ between sensory and premotor structures of the songbird forebrain
Authors: Soyman Efe , Vicario David S. 
Published: December 2016

Sensory and motor brain structures work in collaboration during perception. To evaluate their respective contributions, the present study recorded neural responses to auditory stimulation at multiple sites simultaneously in both the higher-order auditory area NCM and the premotor area HVC of the songbird brain in awake zebra finches ( Taeniopygia guttata). Bird’s own song (BOS) and various conspecific songs (CON) were presented in both blocked and shuffled sequences. Neural responses showed plasticity in the form of stimulus-specific adaptation, with markedly different dynamics between the two structures. In NCM, the response decrease with repetition of each stimulus was gradual and long-lasting and did not differ between the stimuli or the stimulus presentation sequences. In contrast, HVC responses to CON stimuli decreased much more rapidly in the blocked than in the shuffled sequence. Furthermore, this decrease was more transient in HVC than in NCM, as shown by differential dynamics in the shuffled sequence. Responses to BOS in HVC decreased more gradually than to CON stimuli. The quality of neural representations, computed as the mutual information between stimuli and neural activity, was higher in NCM than in HVC. Conversely, internal functional correlations, estimated as the coherence between recording sites, were greater in HVC than in NCM. The cross-coherence between the two structures was weak and limited to low frequencies. These findings suggest that auditory communication signals are processed according to very different but complementary principles in NCM and HVC, a contrast that may inform study of the auditory and motor pathways for human speech processing. NEW & NOTEWORTHY Neural responses to auditory stimulation in sensory area NCM and premotor area HVC of the songbird forebrain show plasticity in the form of stimulus-specific adaptation with markedly different dynamics. These two structures also differ in stimulus representations and internal functional correlations. Accordingly, NCM seems to process the individually specific complex vocalizations of others based on prior familiarity, while HVC responses appear to be modulated by transitions and/or timing in the ongoing sequence of sounds.
Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord
Authors: Song Weiguo , Martin John H. 
Published: December 2016

Spinal cord direct current stimulation (sDCS) has the potential for promoting motor function after injury through its modulatory actions on sensory processing, reflex functions, the motor cortex (M1) motor map, and motor output. Here we addressed systems-level mechanisms underlying sDCS neuromodulation of spinal circuits activated by M1 and peripheral forelimb electrical stimulation in anesthetized healthy rats. We determined the effects of cathodal and anodal sDCS (c- and a-sDCS) on local field potentials (LFP) and single-unit activity recorded at 32 sites simultaneously within the sixth cervical segment using a silicon multielectrode array. M1 stimulation produced distinctive dorsomedial and ventral LFP responses that showed polarity-dependent sDCS modulation. c-sDCS enhanced and a-sDCS depressed significantly ventral M1 responses; neither modulated dorsal responses significantly. Using evoked changes in β- and γ-oscillations to assay network function, c-sDCS enhanced and a-sDCS reduced oscillation power ventrally. c-sDCS increased and a-sDCS decreased background firing and firing synchrony of recorded pairs of single units. Peripheral stimulation produced a region-dependent response that showed polarity-dependent sDCS modulation. The dorsomedial LFP was unaffected by c-sDCS and weakly suppressed with a-sDCS. Peripheral-evoked unit responses showed limited polarity dependence. Our findings stress that ventral motor network behavior is enhanced by the neuromodulatory actions of c-sDCS. The combined actions of c-sDCS on M1-evoked neural responses and network behavior in the cervical spinal cord help explain the reported enhanced motor effects of this neuromodulation approach and inform the mechanisms of sDCS for promoting motor rehabilitation after spinal cord or brain injury. NEW & NOTEWORTHY Spinal cord direct current stimulation (sDCS) modulates spinal functions and shows potential for neural rehabilitation after motor systems injury. Using a multichannel electrode array, we found that cathodal DCS enhanced, and anodal depressed, M1-evoked local field potentials, network oscillations, neuronal activity, and neuronal synchrony, especially in the ventral horn. With this new understanding, it is hoped that sDCS can be developed into a tunable spinal neuromodulatory tool for promoting function after brain or spinal injury.
Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli
Authors: Singh Satish , Houng Aiilyan , Reed Guy L. 
Published: December 2016

Background:
In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of α2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and α2-antiplasmin inactivation on experimental thrombus dissolution and bleeding.

Methods:

Pulmonary embolism was induced by jugular vein infusion of
125
I-fibrin or fluorescein isothiocyanate-fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and α2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism.

Results:

The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal α2-antiplasmin levels treated with an α2-antiplasmin–inactivating antibody (
P
<0.0001). Dissolution of pulmonary emboli by α2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with α2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (
P
<0.001) or α2-antiplasmin inactivation alone (
P
<0.001). Despite greater thrombus dissolution, α2-antiplasmin inactivation alone, or in combination with low-dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA (
P
<0.001).

Conclusions:
Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by α2-antiplasmin. Inactivation of α2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, α2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like α2-antiplasmin, may have unique therapeutic value in pulmonary embolism.
Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage
Authors: Hamming Arend M. , van der Toorn Annette , Rudrapatna Umesh S. , Ma Lisha , van Os Hine J.A. , Ferrari Michel D. , van den Maagdenberg Arn M.J.M. , van Zwet Erik , Poinsatte Katherine , Stowe Ann M. , Dijkhuizen Rick M. , Wermer Marieke J.H. 
Published: December 2016

Background and Purpose—
Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction.

Methods—

Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T
2
-weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test.

Results—

In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (
P
=0.04). Number and duration of SDs, mortality, and neurological function were not statistically significantly different between groups. Lesion growth on magnetic resonance imaging correlated to histological infarct volume (Spearman’s rho =0.83;
P
=0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions.

Conclusions—
In our rat SAH model, valproate treatment significantly reduced brain lesion growth after KCl application. Future studies are needed to confirm that this protective effect is based on SD inhibition.
ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke
Authors: Cui Xu , Chopp Michael , Zhang Zhenggang , Li Rongwen , Zacharek Alex , Landschoot-Ward Julie , Venkat Poornima , Chen Jieli 
Published: December 2016

Background and Purpose—
ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.

Methods—

Middle-aged male specific brain ABCA1–deficient (ABCA1
−B/−B
) and floxed-control (ABCA1
fl/fl
) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1
−B/−B
stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.

Results—

No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1
fl/fl
ischemic mice, ABCA1
−B/−B
ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1
fl/fl
ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1
−B/−B
ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1
−B/−B
-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1
fl/fl
embryos, but not in neurons derived from ABCA1
−B/−B
embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1
−B/−B
embryos.

Conclusions—
ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.
Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation
Authors: Naik Meghna U. , Patel Pravin , Derstine Randall , Turaga Ramya , Chen Xi , Golla Kalyan , Neeves Keith B. , Ichijo Hidenori , Naik Ulhas P. 
Published: December 2016

Key PointsASK1 regulates TxA2 generation through p38 MAPK-dependent phosphorylation of cPLA2. Because of impaired platelet function, Ask1−/− mice are protected from arterial thrombosis and pulmonary thromboembolism.
Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation
Authors: Harder Markus J. , Kuhn Nadine , Schrezenmeier Hubert , Höchsmann Britta , von Zabern Inge , Weinstock Christof , Simmet Thomas , Ricklin Daniel , Lambris John D. , Skerra Arne , Anliker Markus , Schmidt Christoph Q. 
Published: December 2016

Key PointsStrong complement activation overrides the terminal pathway inhibition by the anti-C5 antibody eculizumab. The more powerful complement is activated, the less effective is terminal pathway inhibition by diverse anti-C5 agents.
Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts
Authors: Valent Peter , Akin Cem , Metcalfe Dean D. 
Published: December 2016

Abstract
Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years.