bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced membrane cholesterol after chronic hypoxia limits Orai1-mediated pulmonary endothelial Ca2+entry
Authors: Zhang Bojun , Naik Jay S. , Jernigan Nikki L. , Walker Benjimen R. , Resta Thomas C.
Published: December 2017

Endothelial dysfunction in chronic hypoxia (CH)-induced pulmonary hypertension is characterized by reduced store-operated Ca2+entry (SOCE) and diminished Ca2+-dependent production of endothelium-derived vasodilators. We recently reported that SOCE in pulmonary arterial endothelial cells (PAECs) is tightly regulated by membrane cholesterol and that decreased membrane cholesterol is responsible for impaired SOCE after CH. However, the ion channels involved in cholesterol-sensitive SOCE are unknown. We hypothesized that cholesterol facilitates SOCE in PAECs through the interaction of Orai1 and stromal interaction molecule 1 (STIM1). The role of cholesterol in Orai1-mediated SOCE was initially assessed using CH exposure in rats (4 wk, 380 mmHg) as a physiological stimulus to decrease PAEC cholesterol. The effects of Orai1 inhibition with AnCoA4 on SOCE were examined in isolated PAEC sheets from control and CH rats after cholesterol supplementation, substitution of endogenous cholesterol with epicholesterol (Epichol), or vehicle treatment. Whereas cholesterol restored endothelial SOCE in CH rats, both Epichol and AnCoA4 attenuated SOCE only in normoxic controls. The Orai1 inhibitor had no further effect in cells pretreated with Epichol. Using cultured pulmonary endothelial cells to allow better mechanistic analysis of the molecular components of cholesterol-regulated SOCE, we found that Epichol, AnCoA4, and Orai1 siRNA each inhibited SOCE compared with their respective controls. Epichol had no additional effect after knockdown of Orai1. Furthermore, Epichol substitution significantly reduced STIM1-Orai1 interactions as assessed by a proximity ligation assay. We conclude that membrane cholesterol is required for the STIM1-Orai1 interaction necessary to elicit endothelial SOCE. Furthermore, reduced PAEC membrane cholesterol after CH limits Orai1-mediated SOCE.

NEW & NOTEWORTHY This research demonstrates a novel contribution of cholesterol to regulate the interaction of Orai1 and stromal interaction molecule 1 required for pulmonary endothelial store-operated Ca2+entry. The results provide a mechanistic basis for impaired pulmonary endothelial Ca2+influx after chronic hypoxia that may contribute to pulmonary hypertension.
A novel method for quantitative myocardial contrast echocardiography in mice
Authors: Alvarez E. , Dalton N. D. , Gu Y. , Smith D. , Luong A. , Hoshijima M. , Peterson K. L. , Rychak J.
Published: December 2017

The small size of the mouse heart frequently imparts technical challenges when applying conventional in vivo imaging methods for assessing heart function. Here, we describe the use of high-frequency ultrasound imaging in conjunction with a size-tuned blood pool contrast agent for quantitatively assessing myocardial perfusion in living mice. A perflurocarbon microbubble formulation exhibiting a narrow size distribution was developed, and echogenicity was assessed at 18 MHz in vitro. Adult mice were subjected to permanent ligation of the left anterior descending artery. Ultrasound imaging was performed on day 7, and a cohort of intact mice was used as a control. Parasternal long-axis cine clips were acquired at 18 MHz before and after contrast administration. Reduced ejection fraction and increased end-systolic volume were observed in infarcted compared with control mice. In control animals, washin of the contrast agent was visible in all myocardial segments. Reduced contrast enhancement was observed in apical-posterolateral regions of all infarcted mice. A novel method for reslicing of the imaging data through the time domain provided a two-dimensional presentation of regional contrast agent washin, enabling convenient identification of locations exhibiting altered perfusion. Myocardial segments exhibiting diminished contractility were observed to have correspondingly low relative myocardial perfusion. The contrast agent formulation and methods demonstrated here provide the basis for simplifying routine in vivo estimation of infarct size in mice and may be particularly useful in longitudinal evaluation of revascularization interventions and assessment of peri-infarct ischemia.

NEW & NOTEWORTHY Murine myocardial contrast echocardiography frequently suffers from poor sensitivity to contrast. Here, we formulated a novel size-tuned microbubble contrast agent and validated it for use with ultra-high-frequency ultrasound. A novel data method for evaluating myocardial perfusion based on reslicing the imaging data through the time domain is presented.
Gestational age at time of in utero lipopolysaccharide exposure influences the severity of inflammation-induced diaphragm weakness in lambs
Authors: Karisnan Kanakeswary , Mahzabin Tanzila , Bakker Anthony J. , Song Yong , Noble Peter B. , Pillow J. Jane , Pinniger Gavin J.
Published: December 2017

The preterm diaphragm is functionally immature compared with its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation-induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10 mg lipopolysaccharide (LPS) 2 or 7 days before delivery at 121 days (preterm) or ∼145 days (term) of gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines, diaphragm myosin heavy chain (MHC) isoforms, and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs ( P < 0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2-day LPS exposure was significantly lower than in controls (by ~20%, P < 0.05). In preterm lambs, maximum forces after 2-day and 7-day LPS exposures were significantly lower than in controls (by ~30%, P < 0.05). Peak twitch force after LPS exposure was significantly lower in preterm than in controls, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times, and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7-day versus 2-day LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.
The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis
Authors: Street Jonathan M. , Koritzinsky Erik H. , Bellomo Tiffany R. , Hu Xuzhen , Yuen Peter S. T. , Star Robert A.
Published: December 2017

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.
Effect of isolated ultrafiltration and isovolemic dialysis on myocardial perfusion and left ventricular function assessed with13N-NH3positron emission tomography and echocardiography
Authors: Assa Solmaz , Kuipers Johanna , Ettema Esmée , Gaillard Carlo A. J. M. , Krijnen Wim P. , Hummel Yoran M. , Voors Adriaan A. , van Melle Joost P. , Westerhuis Ralf , Willemsen Antoon , Slart Riemer H. J. A. , Franssen Casper F. M.
Published: December 2017

Hemodialysis is associated with a fall in myocardial perfusion and may induce regional left ventricular (LV) systolic dysfunction. The pathophysiology of this entity is incompletely understood, and the contribution of ultrafiltration and diffusive dialysis has not been studied. We investigated the effect of isolated ultrafiltration and isovolemic dialysis on myocardial perfusion and LV function. Eight patients (7 male, aged 55 ± 18 yr) underwent 60 min of isolated ultrafiltration and 60 min of isovolemic dialysis in randomized order. Myocardial perfusion was assessed by13N-NH3positron emission tomography before and at the end of treatment. LV systolic function was assessed by echocardiography. Regional LV systolic dysfunction was defined as an increase in wall motion score in ≥2 segments. Isolated ultrafiltration (ultrafiltration rate 13.6 ± 3.9 ml·kg−1·h−1) induced hypovolemia, whereas isovolemic dialysis did not (blood volume change −6.4 ± 2.2 vs. +1.3 ± 3.6%). Courses of blood pressure, heart rate, and tympanic temperature were comparable for both treatments. Global and regional myocardial perfusion did not change significantly during either isolated ultrafiltration or isovolemic dialysis and did not differ between treatments. LV ejection fraction and the wall motion score index did not change significantly during either treatment. Regional LV systolic dysfunction developed in one patient during isolated ultrafiltration and in three patients during isovolemic dialysis. In conclusion, global and regional myocardial perfusion was not compromised by 60 min of isolated ultrafiltration or isovolemic dialysis. Regional LV systolic dysfunction developed during isolated ultrafiltration and isovolemic dialysis, suggesting that, besides hypovolemia, dialysis-associated factors may be involved in the pathogenesis of hemodialysis-induced regional LV dysfunction.
Changes in the fluid volume balance between intra- and extracellular water in a sample of Japanese adults aged 15–88 yr old: a cross-sectional study
Authors: Ohashi Yasushi , Joki Nobuhiko , Yamazaki Keisuke , Kawamura Takeshi , Tai Reibin , Oguchi Hideyo , Yuasa Rena , Sakai Ken
Published: December 2017

The fluid volume balance between intracellular water (ICW) and extracellular water (ECW) gradually changes with age and various medical conditions. Comprehension of these physiological changes would aid in clinical decision-making related to body fluid assessments. A total of 1,992 individuals (753 men and 1,239 women) aged ≥15 yr included in this study had their body composition measurements performed at training gyms in 2014. We developed a regression formula to assess the association of age with the ratio of ECW to ICW in these subjects. The mean ages of male and female subjects were 51.2 ± 15.2 and 57.4 ± 15.2 yr, and their mean body mass indexes were 23.4 ± 3.3 and 21.1 ± 2.8 kg/m2, respectively. The total fluid volumes of male and female subjects were 39.6 ± 4.9 and 27.7 ± 3.0 liters, whereas the percent body fat mass per kilogram of body weight were 19 and 26%, respectively. The ECW-to-ICW ratio increased with age because of the steeper decrease in the ICW content than in the ECW content, especially after the age of 70 yr. The regression formulas used for calculating the age-adjusted ECW/ICW ratio were as follows: 0.5857 + 7.4334 × 10−6 × (age)2 in men and 0.6062 + 5.5775 × 10−6 × (age)2 in women. In conclusion, the fluid imbalance between ICW and ECW contents is driven by decreased cell volume associated with aging and muscle attenuation. Therefore, our proposed formula may serve as a useful assessment tool for the calculation of body fluid composition.
Long-duration bed rest modifies sympathetic neural recruitment strategies in male and female participants
Authors: Klassen Stephen A. , De Abreu Steven , Greaves Danielle K. , Kimmerly Derek S. , Arbeille Philippe , Denise Pierre , Hughson Richard L. , Normand Hervé , Shoemaker J. Kevin
Published: December 2017

To understand the impact of physical deconditioning with head-down tilt bed rest (HDBR) on the malleability of sympathetic discharge patterns, we studied 1) baseline integrated muscle sympathetic nerve activity (MSNA; microneurography) from 13 female participants in the WISE-2005 60-day HDBR study (retrospective analysis), 2) integrated MSNA and multiunit action potential (AP) analysis in 13 male participants performed on data collected at baseline and during physiological stress imposed by end-inspiratory apnea in a new 60-day HDBR study, and 3) a repeatability study (control; n = 6, retrospective analysis, 4 wk between tests). Neither baseline integrated burst frequency nor incidence were altered with HDBR (both P > 0.35). However, baseline integrated burst latency increased in both HDBR studies (male: 1.35 ± 0.02 to 1.39 ± 0.02 s, P < 0.01; female: 1.23 ± 0.02 to 1.29 ± 0.02 s, P < 0.01), whereas controls exhibited no change across two visits (1.25 ± 0.02 to 1.25 ± 0.02 s, group-by-time interaction, P = 0.02). With the exception of increased AP latency ( P = 0.03), male baseline AP data did not change with HDBR (all P > 0.19). The change in AP frequency on going from baseline to apnea (∆94 ± 25 to ∆317 ± 55 AP/min, P < 0.01) and the number of active sympathetic clusters per burst (∆0 ± 0.2 to ∆1 ± 0.2 clusters/burst, P = 0.02) were greater post- compared with pre-HDBR. The change in total clusters with apnea was ∆0 ± 0.5 clusters pre- and ∆2 ± 0.7 clusters post-HDBR ( P = 0.07). These data indicate that 60-day HDBR modified discharge characteristics in baseline burst latency and sympathetic neural recruitment during apneic stress.

NEW & NOTEWORTHY Long-duration bed rest did not modify baseline sympathetic burst frequency in male and female participants, but examination of additional features of the multiunit signal provided novel evidence to suggest augmented synaptic delays or processing times at baseline for all sympathetic action potentials. Furthermore, long-duration bed rest increased reflex-sympathetic arousal to apneic stress in male participants primarily by mechanisms involving an augmented firing rate of action potential clusters active at baseline.
Repeated measurement ofMo2in small aquatic organisms: a manual intermittent flow respirometer using off-the-shelf components
Authors: Baker Daniel W. , Hudson Michael E. , Frost Emily J. , Sewell Mary A.
Published: December 2017

Measurement of rates of oxygen consumption ( Mo2) in small aquatic embryos or larvae (<1 mm) in response to altered environmental conditions has traditionally been challenging. Here, using modifications of a commercially available fluorescent optode flow-through cell (FTC; PreSens FTC-PSt3) and routine laboratory supplies (syringes, stopcocks, tubing), we have constructed a manual intermittent flow respirometer (MIFR) that allows measurement of Mo2in small numbers of individuals when sequentially exposed to different environmental conditions (e.g., changes in seawater pH) through a gravity-driven media replacement perfusion system. We first show that the FTC can be used in “static” mode while incubating small numbers of embryos/larvae contained within the planar oxygen sensor (POS) chamber with Nitex filters. We then demonstrate the use of the MIFR by exposing larval echinoderms ( Fellaster zelandiae, Evechinus chloroticus, and Centrostephanus rodgersii) to seawater equilibrated with elevated CO2and measured Mo2during acute and chronic exposure to hypercapnia. This MIFR method will allow investigators to address questions regarding the respiratory physiology of small aquatic animals, such as the thresholds for metabolic depression in embryonic and larval forms.

NEW & NOTEWORTHY A manual intermittent flow respirometer (MIFR), allowing media exchange in a flow-through cell containing small aquatic organisms, permits repeated measurement of Mo2of individuals not only in a single medium (e.g., technical replication), but also in different media (here, high CO2-equilibrated seawater), enabling measurement of acute physiological responses to changed conditions. This versatile technique has wide-ranging implications for the study of the Mo2response of aquatic organisms in the face of climate change.
Distributed force feedback in the spinal cord and the regulation of limb mechanics
Authors: Nichols T. Richard
Published: December 2017

This review is an update on the role of force feedback from Golgi tendon organs in the regulation of limb mechanics during voluntary movement. Current ideas about the role of force feedback are based on modular circuits linking idealized systems of agonists, synergists, and antagonistic muscles. In contrast, force feedback is widely distributed across the muscles of a limb and cannot be understood based on these circuit motifs. Similarly, muscle architecture cannot be understood in terms of idealized systems, since muscles cross multiple joints and axes of rotation and further influence remote joints through inertial coupling. It is hypothesized that distributed force feedback better represents the complex mechanical interactions of muscles, including the stresses in the musculoskeletal network born by muscle articulations, myofascial force transmission, and inertial coupling. Together with the strains of muscle fascicles measured by length feedback from muscle spindle receptors, this integrated proprioceptive feedback represents the mechanical state of the musculoskeletal system. Within the spinal cord, force feedback has excitatory and inhibitory components that coexist in various combinations based on motor task and integrated with length feedback at the premotoneuronal and motoneuronal levels. It is concluded that, in agreement with other investigators, autogenic, excitatory force feedback contributes to propulsion and weight support. It is further concluded that coexistent inhibitory force feedback, together with length feedback, functions to manage interjoint coordination and the mechanical properties of the limb in the face of destabilizing inertial forces and positive force feedback, as required by the accelerations and changing directions of both predator and prey.
Altered synaptic transmission and maturation of hippocampal CA1 neurons in a mouse model of human chr16p11.2 microdeletion
Authors: Lu Hung-Chi , Mills Alea A. , Tian Di
Published: December 2017

The pathophysiology of neurodevelopmental disorders is often observed early in infancy and toddlerhood. Mouse models of syndromic disorders have provided insight regarding mechanisms of action, but most studies have focused on characterization in juveniles and adults. Insight into developmental trajectories, particularly those related to circuit and synaptic function, will likely yield important information regarding disorder pathogenesis that leads to symptom progression. Chromosome 16p11.2 microdeletion is one of the most common copy number variations associated with a spectrum of neurodevelopmental disorders. Yet, how haploinsufficiency of chr16p11.2 affects early synaptic maturation and function is unknown. To address this knowledge gap, the present study focused on three key components of circuit formation and function, basal synaptic transmission, local circuit function, and maturation of glutamatergic synapses, in developing hippocampal CA1 neurons in a chr16p11.2 microdeletion mouse model. The data demonstrate increased excitability, imbalance in excitation and inhibition, and accelerated maturation of glutamatergic synapses in heterozygous deletion mutant CA1 neurons. Given the critical role of early synaptic development in shaping neuronal connectivity and circuitry formation, these newly identified synaptic abnormalities in chr16p11.2 microdeletion mice may contribute to altered developmental trajectory and function of the developing brain.

NEW & NOTEWORTHY The synaptic pathophysiology underlying neurodevelopmental disorders often emerges during infancy and toddlerhood. Therefore, identifying initial changes in synaptic function is crucial for gaining a mechanistic understanding of the pathophysiology, which ultimately will facilitate the design of early interventions. Here, we investigated synaptic and local circuit properties of hippocampal CA1 neurons in a human chr16p11.2 microdeletion mouse model during early postnatal development (preweaning). The data demonstrate increased neuronal excitability, excitatory/inhibitory imbalance, and accelerated maturation of glutamatergic synapses. These perturbations in early hippocampal circuit function may underlie the early pathogenesis of the heterozygous chr16p11.2 microdeletion, which is often associated with epilepsy and intellectual disability.
Rhythmic arm cycling training improves walking and neurophysiological integrity in chronic stroke: the arms can give legs a helping hand in rehabilitation
Authors: Kaupp Chelsea , Pearcey Gregory E. P. , Klarner Taryn , Sun Yao , Cullen Hilary , Barss Trevor S. , Zehr E. Paul
Published: December 2017

Training locomotor central pattern-generating networks (CPGs) through arm and leg cycling improves walking in chronic stroke. These outcomes are presumed to result from enhanced interlimb connectivity and CPG function. The extent to which rhythmic arm training activates interlimb CPG networks for locomotion remains unclear and was assessed by studying chronic stroke participants before and after 5 wk of arm cycling training. Strength was assessed bilaterally via maximal voluntary isometric contractions in the legs and hands. Muscle activation during arm cycling and transfer to treadmill walking were assessed in the more affected (MA) and less affected (LA) sides via surface electromyography. Changes to interlimb coupling during rhythmic movement were evaluated using modulation of cutaneous reflexes elicited by electrical stimulation of the superficial radial nerve at the wrist. Bilateral soleus stretch reflexes were elicited at rest and during 1-Hz arm cycling. Clinical function tests assessed walking, balance, and motor function. Results show significant changes in function and neurophysiological integrity. Training increased bilateral grip strength, force during MA plantarflexion, and muscle activation. “Normalization” of cutaneous reflex modulation was found during arm cycling. There was enhanced activity in the dorsiflexor muscles on the MA side during the swing phase of walking. Enhanced interlimb coupling was shown by increased modulation of MA soleus stretch reflex amplitudes during arm cycling after training. Clinical evaluations showed enhanced walking ability and balance. These results are consistent with training-induced changes in CPG function and interlimb connectivity and underscore the need for arm training in the functional rehabilitation of walking after neurotrauma.

NEW & NOTEWORTHY It has been suggested but not tested that training the arms may influence rehabilitation of walking due to activation of interneuronal patterning networks after stroke. We show that arm cycling training improves strength, clinical function, coordination of muscle activity during walking, and neurological connectivity between the arms and the legs. The arms can, in fact, give the legs a helping hand in rehabilitation of walking after stroke.
Reward activations and face fields in monkey cingulate motor areas
Authors: Cléry Justine , Amiez Céline , Guipponi Olivier , Wardak Claire , Procyk Emmanuel , Ben Hamed Suliann
Published: December 2017

Several premotor areas have been identified within primate cingulate cortex; however their function is yet to be uncovered. Recent brain imaging work in humans revealed a topographic anatomofunctional overlap between feedback processing during exploratory behaviors and the corresponding body fields in the rostral cingulate motor area (RCZa), suggesting an embodied representation of feedback. In particular, a face field in RCZa processes juice feedback. Here we tested an extension of the embodied principle in which unexpected or relevant information obtained through the eye or the face would be processed by face fields in cingulate motor areas, and whether this applied to monkey cingulate cortex. We show that activations for juice reward, eye movement, eye blink, and tactile stimulation on the face overlap over two subfields within the cingulate sulcus likely corresponding to the rostral and caudal cingulate motor areas. This suggests that in monkeys as is the case in humans, behaviorally relevant information is processed through multiple cingulate body/effector maps.

NEW & NOTEWORTHY What is the role of cingulate motor areas? In this study we observed in monkeys that, as in humans, neural responses to face-related events, juice reward, eye movement, eye blink, and tactile stimulations, clustered redundantly in two separate cingulate subfields. This suggests that behaviorally relevant information is processed by multiple cingulate effector maps. Importantly, this overlap supports the principle that the cingulate cortex processes feedback based on where it is experienced on the body.
Done in 100 ms: path-dependent visuomotor transformation in the human upper limb
Authors: Gu Chao , Pruszynski J. Andrew , Gribble Paul L. , Corneil Brian D.
Published: December 2017

A core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. In this study we show that increases in task complexity alter the magnitude, rather than the latency, of the output for a circuit that rapidly transforms visual information into motor actions. We quantified visual stimulus-locked responses (SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency ~100 ms after novel visual stimulus onset. First, we studied the underlying reference frame of the SLR by dissociating the initial eye and hand position. Despite its quick latency, we found that the SLR was expressed in a hand-centric reference frame, suggesting that the circuit mediating the SLR integrated retinotopic visual information with body configuration. Next, we studied the influence of planned movement trajectory, requiring participants to prepare and generate either curved or straight reaches in the presence of obstacles to attain the same visual stimulus location. We found that SLR magnitude was influenced by the planned movement trajectory to the same visual stimulus. On the basis of these results, we suggest that the circuit mediating the SLR lies in parallel to other well-studied corticospinal pathways. Although the fixed latency of the SLR precludes extensive cortical processing, inputs conveying information relating to task complexity, such as body configuration and planned movement trajectory, can preset nodes within the circuit underlying the SLR to modulate its magnitude.

NEW & NOTEWORTHY We studied stimulus-locked responses (SLRs), which are changes in human upper limb muscle recruitment that evolve at a fixed latency ~100 ms after novel visual stimulus onset. We showed that despite its quick latency, the circuitry mediating the SLR transformed a retinotopic visual signal into a hand-centric motor command that is modulated by the planned movement trajectory. We suggest that the circuit generating the SLR is mediated through a tectoreticulospinal, rather than a corticospinal, pathway.
Comparative Physiology of Nociception and Pain
Authors: Sneddon Lynne U.
Published: December 2017

The study of diverse animal groups allows us to discern the evolution of the neurobiology of nociception. Nociception functions as an important alarm system alerting the individual to potential and actual tissue damage. All animals possess nociceptors, and, in some animal groups, it has been demonstrated that there are consistent physiological mechanisms underpinning the nociceptive system. This review considers the comparative biology of nociception and pain from an evolutionary perspective.
Stem Cell Differentiation is Regulated by Extracellular Matrix Mechanics
Authors: Smith Lucas R. , Cho Sangkyun , Discher Dennis E.
Published: December 2017

Stem cells mechanosense the stiffness of their microenvironment, which impacts differentiation. Although tissue hydration anti-correlates with stiffness, extracellular matrix (ECM) stiffness is clearly transduced into gene expression via adhesion and cytoskeleton proteins that tune fates. Cytoskeletal reorganization of ECM can create heterogeneity and influence fates, with fibrosis being one extreme.
HIV and Cardiovascular Disease: Role of Immunometabolic Perturbations
Authors: Teer Eman , Essop M. Faadiel
Published: December 2017

The successful rollout of anti-retroviral therapy ensured that HIV is increasingly managed as a chronic condition. HIV-positive persons are therefore exhibiting increased cardiovascular complications. This review focuses on the emerging role of ”immunometabolism” within the context of HIV-related immune dysregulation and cardiovascular disease onset. Here, persistent immune activation contributes to pathophysiological perturbations during early infection, resulting in immune cell metabolic reprogramming and the activation of coagulation pathways in HIV-positive individuals.
Bypassing Border Control: Nuclear Envelope Rupture in Disease
Authors: Houthaeve Gaëlle , Robijns Joke , Braeckmans Kevin , De Vos Winnok H.
Published: December 2017

Recent observations in laminopathy patient cells and cancer cells have revealed that the nuclear envelope (NE) can transiently rupture during interphase. NE rupture leads to an uncoordinated exchange of nuclear and cytoplasmic material, thereby deregulating cellular homeostasis. Moreover, concurrently inflicted DNA damage could prime rupture-prone cells for genome instability. Thus, NE rupture may represent a novel pathogenic mechanism that has far-reaching consequences for cell and organism physiology.
Associations of Del 301-303 alpha2B-adrenoceptor gene polymorphism with central hemodynamic parameters in the northern Russian population
Authors: Melnikov Vladimir N. , Baranov Victor I. , Suvorova Irina Yu. , Krivoschekov Sergey G.
Published: December 2017

The ADRA2B gene 301–303 I/D polymorphism is associated with various cardiovascular phenotypes. However, an association of genotypes with the timing structure of cardiac cycle remains unclear. The central hemodynamic parameters were assessed by pulse wave analysis in 63 residents of the Kola Peninsula (68 N) aged 27–65 yr. The genotypes were determined by PCR. The paired comparisons revealed that II genotype carriers had higher values of augmentation index ( P = 0.014), ejection duration ( P = 0.045), and lower SEVR ( P = 0.035) than DD homozygotes. Multiple regression analysis adjusted for age, body mass index, heart rate, and blood pressure confirmed these results. Further sex stratified analysis showed that the associations existed only in men ( n = 33) whereas in women ( n = 30) the differences were suggestive ( P < 0.1). It is concluded that in a northern Russian population men carrying I allele have stiffer arteries, shorter diastole duration, and impaired coronary perfusion and seem to be at higher risk for cardiovascular diseases than DD carriers.
Attempted replication of SNPs in RANKL and OPG with musculoskeletal adverse events during aromatase inhibitor treatment for breast cancer
Authors: Dempsey Jacqueline M. , Xi Jingyue , Henry N. Lynn , Rae James M. , Hertz Daniel L.
Published: December 2017

Aromatase inhibitor (AI) therapy is highly efficacious in the treatment of estrogen receptor-positive breast cancer; however, in a subset of patients AI use is discontinued due to drug-induced musculoskeletal adverse events (MS-AE). Several studies have investigated the role of germline single nucleotide polymorphisms (SNPs) on patients’ risk of MS-AEs; however, no associations have yet to be validated for translation into clinical practice. This study attempted to replicate SNPs in RANKL ( rs7984870 ) and OPG ( rs2073618 ) on the risk of AI-induced MS-AEs and screen for secondary associations with MS-AE-related treatment discontinuation and serum and urine markers of bone health. Previously reported associations were not replicated with our primary hypothesis, change in MS-AE from baseline to 3 mo; however, patients homozygous for the G allele of rs7984870 in RANKL had lower risk of MS-AE-associated treatment discontinuation in analyses of secondary phenotypes without statistical correction.
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Authors: Rorsman Patrik , Ashcroft Frances M.
Published: December 2017

The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM.
Left Paraduodenal Hernia: A Rare Complication following Laparoscopic Appendectomy
Authors: Kozman Mathew A. , Fisher Oliver M.
Published: December 2017

Paraduodenal hernias are rare congenital internal hernias accounting for <2% of intestinal obstruction. Left paraduodenal hernias (LPDHs) into the fossa of Landzert are the more common type and result from abnormal rotation of the midgut and failure of peritoneal fusion. Sequelae of these hernias usually occur spontaneously in the 4th or 5th decade of life and are more common in males and have a significant risk of incarceration and subsequent strangulation. We describe a case of a 15-year-old female who develops a LPDH following laparoscopic appendectomy, resulting in jejunal incarceration and subsequent small intestinal obstruction. The patient discussed is from an atypical demographic, being young and female. In addition, the precipitating event prompting incarceration of the hernia appears to be the application of pneumoperitoneum, placement in the Trendelenburg position, and manipulation of small intestine for the purpose of facilitating laparoscopic appendectomy. To our knowledge, this is the first reported case of LPDH exacerbated by laparoscopic procedure.
Difference between Burley Tobacco and Flue-Cured Tobacco in Nitrate Accumulation and Chemical Regulation of Nitrate and TSNA Contents
Authors: Li Yafei , Shi Hongzhi , Yang Huijuan , Zhou Jun , Wang Jing , Bai Ruoshi , Xu Dongya
Published: December 2017

Tobacco-specific nitrosamines (TSNAs) are harmful carcinogens, with nitrate as a precursor of their formation. Nitrate content is considerably higher in burley tobacco than in flue-cured tobacco, but little has been reported on the differences between types of nitrate accumulation during development. We explored nitrate accumulation prior to harvest and examined the effects of regulatory substances aimed at decreasing nitrate and TSNA accumulation. In growth experiments, nitrate accumulation in burley and flue-cured tobacco initially increased but then declined with the highest nitrate content observed during a fast-growth period. When treating tobacco crops with molybdenum (Mo) during fast growth, nitrate reductase activity in burley tobacco increased significantly, but the NO3-N content decreased. These treatments also yielded significant reductions in NO3-N and TSNA contents. Therefore, we suggest that treatment with Mo during the fast-growth period and a Mo-Gfo (Mo-glufosinate) combination at the maturity stage is an effective strategy for decreasing nitrate and TSNAs during cultivation.
Normalized Structured Compressed Sensing Based Signal Detection in Spatial Modulation 3D-MIMO Systems
Authors: Ren Wei , Gui Guan , Li Fei
Published: December 2017

Signal detection is one of the fundamental problems in three-dimensional multiple-input multiple-output (3D-MIMO) wireless communication systems. This paper addresses a signal detection problem in 3D-MIMO system, in which spatial modulation (SM) transmission scheme is considered due to its advantages of low complexity and high-energy efficiency. SM based signal transmission typically results in the block-sparse structure in received signals. Hence, structured compressed sensing (SCS) based signal detection is proposed to exploit the inherent block sparsity information in the received signal for the uplink (UL). Moreover, normalization preprocessing is considered before iteration process with the purpose of preventing the noise from being overamplified by the column vector with inadequately large elements. Simulation results are provided to show the stable and reliable performance of the proposed algorithm under both Gaussian and non-Gaussian noise, in comparison with methods such as compressed sensing based detectors, minimum mean square error (MMSE), and zero forcing (ZF).
Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in theHFEGene
Authors: Luszczyk Marcin , Kaczorowska-Hac Barbara , Milosz Ewa , Adamkiewicz-Drozynska Elzbieta , Ziemann Ewa , Laskowski Radoslaw , Flis Damian , Rokicka-Hebel Magdalena , Antosiewicz Jedrzej
Published: December 2017

Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene(HFE)mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in theHFEgene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing theHFEmutation compared to the control group. Moreover, theHFEmutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated thatHFEmutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.
Impacts of Bush Encroachment on Wildlife Species Diversity, Composition, and Habitat Preference in Ol Pejeta Conservancy, Laikipia, Kenya
Authors: Kavwele Cyrus M. , Kimanzi Johnstone K. , Kinyanjui Mwangi J.
Published: December 2017

Savannah ecosystems are currently facing a biome shift that changes grasslands to woody dominated landscapes, attributable to habitat degradation. In Ol Pejeta Conservancy (OPC), Euclea divinorum, an unpalatable and invasive woody species, is expanding to former savannah ecosystems with potential effects on herbivores key resources, wildlife species diversity, composition, and habitat use. We investigated wildlife species diversity, composition, and habitat preference or avoidance by wildlife in the conservancy. Infrared camera traps were deployed at the centroids of 2 km by 2 km, 50 cm above ground surface for 14 days and nights with 9 camera traps in each habitat type. Shannon wiener index revealed that wildlife species diversity was highest in E. divinorum dominated habitats and lowest in open grassland. Hierarchical Cluster Analysis revealed level of similarity in wildlife species composition between E. divinorum and mixed bushland. Jacobs index revealed that E. divinorum and mixed bushland were avoided by all guilds; however E. divinorum was significantly avoided while A. drepanolobium and open grassland were both preferred by all guilds. However, A. drepanolobium dominated habitats were significantly preferred compared to open grasslands. The findings are useful in management of sustainable ecosystems.
Frequency of c.35delG Mutation in GJB2 Gene (Connexin 26) in Syrian Patients with Nonsyndromic Hearing Impairment
Authors: Kaheel Hazem , Breß Andreas , Hassan Mohamed A. , Shah Aftab Ali , Amin Mutaz , Bakhit Yousuf H. Y. , Kniper Marlies
Published: December 2017

Background. Hearing impairments (HI) are the most common birth defect worldwide. Very large numbers of genes have been identified but the most profound is GJB2. The clinical interest regarding this gene is very pronounced due to its high carrier frequency (0.5–5.4%) across different ethnic groups. This study aimed to determine the prevalence of common GJB2 mutations in Syrian patients with profound sensorineural HI. Methods. We carried out PCR, restriction enzyme based screening, and sequencing of 132 Syrian patients diagnosed clinically with hereditary deafness for different GJB2 mutations. Results. The result revealed that, in GJB2 gene, c.35delG is the most prevalent among affected studied subjects (13.64%), followed by c.457G>A (2.4%). Conclusion. The benefit of this study on the one hand is its first report of prelingual deafness causative gene mutations identified by sequencing technology in the Syrian families. It is obvious from the results that the deployment in biomedical research is highly effective and has a great impact on the ability to uncover the cause of genetic variation in different genetic diseases.
Bandwidth-Enhanced Low-Profile Antenna with Parasitic Patches
Authors: Ta Son Xuat , Kedze Kam Eucharist , Chien Dao Ngoc , Park Ikmo
Published: December 2017

This paper presents low-profile broadband antennas, which are composed of four parasitic patches placed between planar radiators and a perfect electric conductor ground plane. Two types of planar radiators, a conventional dipole and a crossed dipole, are employed to produce linearly polarized (LP) and circularly polarized (CP) radiations, respectively. The radiator and parasitic patches are realized on thin substrates to lower the cost. Owing to the presence of parasitic patches, the antenna performance improves in terms of profile reduction, resonant frequency decrease, and bandwidth enhancement. These improvements are discussed and confirmed computationally and experimentally. The LP design with the overall dimensions of 120 mm × 120 mm × 16.3 mm (0.64λ0 × 0.64λ0 × 0.087λ0 at 1.6 GHz) has a |S11| < −10 dB bandwidth of 1.465–1.740 GHz (17.2%), a broadside gain of 8.5–8.8 dBi, and a radiation efficiency > 96%. The CP design, which has the same physical size as the LP case, has a |S11| < −10 dB bandwidth of 1.388–1.754 GHz (23.3%), a 3 dB AR (axial ratio) bandwidth of 1.450–1.685 GHz (15.0%), a right-hand CP broadside gain of 7.8–8.7 dBic, and a radiation efficiency > 90%.
Robot-Assisted Hybrid Esophagectomy Is Associated with a Shorter Length of Stay Compared to Conventional Transthoracic Esophagectomy: A Retrospective Study
Authors: Rolff Hans C. , Ambrus Rikard B. , Belmouhand Mohammed , Achiam Michael P. , Wegmann Marianne , Siemsen Mette , Kofoed Steen C. , Svendsen Lars B.
Published: December 2017

Aim. To compare the peri- and postoperative data between a hybrid minimally invasive esophagectomy (HMIE) and the conventional Ivor Lewis esophagectomy. Methods. Retrospective comparison of perioperative characteristics, postoperative complications, and survival between HMIE and Ivor Lewis esophagectomy. Results. 216 patients were included, with 160 procedures performed with the conventional and 56 with the HMIE approach. Lower perioperative blood loss was found in the HMIE group (600 ml versus 200 ml, p<0.001). Also, a higher median number of lymph nodes were harvested in the HMIE group (median 28) than in the conventional group (median 23) (p=0.002). The median length of stay was longer in the conventional group compared to the HMIE group (11.5 days versus 10.0 days, p=0.03). Patients in the HMIE group experienced fewer grade 2 or higher complications than the conventional group (39% versus 57%, p=0.03). The rate of all pulmonary (51% versus 43%, p=0.32) and severe pulmonary complications (38% versus 18%, p = 0.23) was not statistically different between the groups. Conclusions. The HMIE was associated with lower intraoperative blood loss, a higher lymph node harvest, and a shorter hospital stay. However, the inborn limitations with the retrospective design stress a need for prospective randomized studies. Registration number is DRKS00013023.
Inferring Molecular Processes Heterogeneity from Transcriptional Data
Authors: Gogolewski Krzysztof , Wronowska Weronika , Lech Agnieszka , Lesyng Bogdan , Gambin Anna
Published: December 2017

RNA microarrays and RNA-seq are nowadays standard technologies to study the transcriptional activity of cells. Most studies focus on tracking transcriptional changes caused by specific experimental conditions. Information referring to genes up- and downregulation is evaluated analyzing the behaviour of relatively large population of cells by averaging its properties. However, even assuming perfect sample homogeneity, different subpopulations of cells can exhibit diverse transcriptomic profiles, as they may follow different regulatory/signaling pathways. The purpose of this study is to provide a novel methodological scheme to account for possible internal, functional heterogeneity in homogeneous cell lines, including cancer ones. We propose a novel computational method to infer the proportion between subpopulations of cells that manifest various functional behaviour in a given sample. Our method was validated using two datasets from RNA microarray experiments. Both experiments aimed to examine cell viability in specific experimental conditions. The presented methodology can be easily extended to RNA-seq data as well as other molecular processes. Moreover, it complements standard tools to indicate most important networks from transcriptomic data and in particular could be useful in the analysis of cancer cell lines affected by biologically active compounds or drugs.