bluuebunny/crossref_metadata_2025 huggingface dataset:
Sub-Level Stoping in an Underground Limestone Quarry: An Analysis of the State of Stress in an Evolutionary Scenario
Authors: Cardu Marilena , Dipietromaria Sergio , Oreste Pierpaolo
Published: May 2016

The aim of this study was to evaluate the state of stress of a „voids-pillar“ structure excavated by means of the sub-level stoping method in an underground limestone quarry near Bergamo (Italy). Both the current structure of the quarry (i.e. the rooms exploited till now) and a possible future scenario were analysed using the (FDM) FLAC 2D code. The quarry has been in operation since 1927; at present, exploitation is carried out underground via the sub-level stoping method. Exploitation involves two levels, with 5 rooms on the upper level and 9 rooms on the lower level.

After analysing data obtained from laboratory and in situ tests carried out on rock samples and natural discontinuities, the geomechanical properties of the medium, knowledge of which is essential in order to establish the parameters that must be included in the numerical model, were evaluated.

The implementation of three numerical models made it possible to study both the present conditions of quarry exploitation and the evolution of the exploited rooms, as well as a possible expansion involving a third level of rooms. Using the results obtained regarding the stress-strain present in the pillars, a potential change in room geometry was proposed aimed at reducing the stress state inside the pillars, decreasing plasticity and increasing overall quarry safety.
Manifestations of Slovak and Rusyn Identity in Vasil Stefan Koban’s The Sorrows of Marienka and Excerpt from Michal
Authors: Židová Diana
Published: May 2016

Vasil Stefan Koban (1918-2007) was an American writer of Slovak origin. His cultural identity is, however, somewhere between Rusyn and Slovak, but all his writings were published in Slovak journals such as Slovakia, or Almanac run by National Slovak Society. The Slovak translation of his only novel, The Sorrows of Marienka, was published in 2006 with the subtitle Púť Slovákov za lepším životom do Ameriky. The book is about the life of his mother Marienka who after marriage to Ivan Kinda emigrates from Jarabina to Conemaugh, an American coal mine town. Excerpt from Michal: Biography of a Galician Coal Miner, 1906-1933 is a revised version of the story in which Michal, Koban’s father and Marienka’s second husband, loses his leg in an accident and he must stay in a hospital for a year. In both stories Koban uses lots of Slovak words, but on the other hand, he mentions that Michal helped to build the Russian Orthodox Church of St. John the Baptist in Conemaugh with other Galicians, his natives, since he was born in Habowa. Although he considered himself to be of Slovak origin, Koban is enlisted under Carpatho-Rusyn Literature in The Greenwood Encyclopedia of Multiethnic American Literature. The article focuses on manifestations of Slovak and Rusyn identity in Koban’s two most notable literary works.
Weighted Sobolev spaces on metric measure spaces
Authors: Ambrosio Luigi , Pinamonti Andrea , Speight Gareth
Published: May 2016

We investigate weighted Sobolev spaces on metric measure spaces

(
X
,
d
,
𝔪
)

{(X,\mathrm{d},\mathfrak{m})}

. Denoting by ρ the weight function,
we compare the space

W

1
,
p

⁢

(
X
,
d
,

ρ
⁢
𝔪

)

{W^{1,p}(X,\mathrm{d},\rho\mathfrak{m})}

(which always coincides with the closure

H

1
,
p

⁢

(
X
,
d
,

ρ
⁢
𝔪

)

{H^{1,p}(X,\mathrm{d},\rho\mathfrak{m})}

of Lipschitz functions)
with the weighted Sobolev spaces

W
ρ

1
,
p

⁢

(
X
,
d
,
𝔪
)

{W^{1,p}_{\rho}(X,\mathrm{d},\mathfrak{m})}

and

H
ρ

1
,
p

⁢

(
X
,
d
,
𝔪
)

{H^{1,p}_{\rho}(X,\mathrm{d},\mathfrak{m})}

defined as in the Euclidean theory of weighted Sobolev spaces.
Under mild assumptions on the metric measure structure and on the weight we show that

W

1
,
p

⁢

(
X
,
d
,

ρ
⁢
𝔪

)

=

H
ρ

1
,
p

⁢

(
X
,
d
,
𝔪
)

{W^{1,p}(X,\mathrm{d},\rho\mathfrak{m})=H^{1,p}_{\rho}(X,\mathrm{d},\mathfrak{%
m})}

. We also adapt the results in [23] and in the recent paper [27]
to the metric measure setting, considering appropriate conditions on ρ that ensure the equality

W
ρ

1
,
p

⁢

(
X
,
d
,
𝔪
)

=

H
ρ

1
,
p

⁢

(
X
,
d
,
𝔪
)

{W^{1,p}_{\rho}(X,\mathrm{d},\mathfrak{m})=H^{1,p}_{\rho}(X,\mathrm{d},%
\mathfrak{m})}

.
Effect of hypoxia on the expression of genes encoding insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function
Authors: Minchenko Dmytro O. , Kharkova A. P. , Halkin O. V. , Karbovskyi L. L. , Minchenko O. H.
Published: May 2016

Objective. The aim of the present study was to investigate the effect of hypoxia on the expression of genes encoding insulin-like growth factors (IGF1 and IGF2), their receptor (IGF1R), binding protein-4 (IGFBP4), and stanniocalcin 2 (STC2) in U87 glioma cells in relation to inhibition of endoplasmic reticulum stress signaling mediated by IRE1 (inositol requiring enzyme 1) for evaluation of their possible significance in the control of tumor growth.

Methods. The expression of IGF1, IGF2, IGF1R, IGFBP4, and STC2 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia was studied by qPCR.

Results. The expression of IGF1 and IGF2 genes is down-regulated in glioma cells without IRE1 signaling enzyme function in comparison with the control cells. At the same time, the expression of IGF1R, IGFBP4, and STC2 genes was up-regulated in glioma cells upon inhibition of IRE1, with more significant changes for IGFBP4 and STC2 genes. We also showed that hypoxia does not change significantly the expression of IGF1, IGF2, and IGF1R genes but up-regulated IGFBP4 and STC2 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells does not change significantly the effect of hypoxia on the expression of IGF1, IGF1R, and IGFBP4 genes but introduces sensitivity of IGF2 gene to hypoxic condition. Thus, the expression of IGF2 gene is resistant to hypoxia only in control glioma cells and significantly down-regulated in cells without functional activity of IRE1 signaling enzyme, which is central mediator of the unfolded protein response and an important component of the tumor growth as well as metabolic diseases.

Conclusions. Results of this study demonstrate that the expression of IGF1 and IGF1R genes is resistant to hypoxic condition both in control U87 glioma cells and cells without IRE1 signaling enzyme function. However, hypoxia significantly up-regulates the expression of IGFBP4 gene independently on the inhibition of IRE1 enzyme. These data show that proteins encoded by these genes are resistant to hypoxia except IGFBP4 and participate in the regulation of metabolic and proliferative processes through IRE1 signaling.
Mechanisms involved in the regulation of neuropeptide-mediated neurite outgrowth: a minireview
Authors: Lestanova Z. , Bacova Z. , Bakos Jan
Published: May 2016

The present knowledge, regarding the neuronal growth and neurite extension, includes neuropeptide action in the central nervous system. Research reports have brought much information about the multiple intracellular signaling pathways of neuropeptides. However, regardless of the differences in the local responses elicited by neuropeptides, there exist certain functional similarities in the effects of neuropeptides, mediated by their receptors. In the present review, data of the relevant studies, focused on G protein-coupled receptors activated by neuropeptides, are summarized. Particularly, receptors that activate phosphatidylinositol-calcium system and protein kinase C pathways, resulting in the reorganization of the neuronal cytoskeleton and changes in the neuronal morphology, are discussed. Based on our data received, we are showing that oxytocin increases the gene expression of GTPase cell division cycle protein 42 (Cdc42), implicated in many aspects of the neuronal growth and morphology. We are also paying a special attention to neurite extension and retraction in the context of neuropeptide regulation.
Micro RNAs: an arguable appraisal in medicine
Authors: Voglova K. , Bezakova J. , Herichova Iveta
Published: May 2016

Micro RNAs (miRNAs) represent a newly discovered class of regulatory molecules in the human body. miRNA is a short double stranded RNA sequence interfering with mRNA, causing in most cases, inhibition of translation. Synthesis of miRNAs shows an increasing developmental pattern and postnatally miRNAs are synthesized in all cells possessing transcriptional machinery. miRNAs usually target several mRNAs and therefore conclusive evidences proving their functions are not always ease to be acquired. In spite of this difficulty, functions of miRNAs were firmly established in the development, the cardiovascular and neural diseases, and cancer. Many miRNAs have been reported to be associated with physiological state of cells and/or tissues. This finding becomes fundamental, especially when consider that these miRNAs can be released from cell into intracellular space or circulation. Correlation between miRNA production in tissues and its contribution to multisource miRNA pool in the circulation is in a focus of biomarker-oriented researchers. Recently, circulating miRNAs have been suggested to be applicable as biomarkers in several types of cancer, cardiovascular injury, and diabetes. Role of miRNAs in the organism intercellular signaling is still under the broad investigation. Several miRNA mimics, intended for treatment of disease, are being currently tested in the clinical trials.
Post-harvest longevity of ornamental grasses conditioned in gibberellic acid and 8-hydroxyquinoline sulphate
Authors: Henschke Monika , Pers Katarzyna , Opalińska Sylwia
Published: May 2016

Florists’ greens are becoming increasingly important in contemporary floristry. Numerous studies conducted on cut flowers have led to the development of technologies for their post-harvest handling; however, in the case of florists’ greens they are still insufficient. Moreover, the extensive range of florists’ greens lacks leaves and the leafy culms of grasses. The aim of this study was to determine the post-harvest longevity of the leaves and leafy culms of ornamental grasses conditioned in water solutions of gibberellic acid and 8-hydroxyquinoline sulphate. The post-harvest longevity of leaves was examined in cultivars of the following species: Glyceria maxima Hartm. ‘Variegata’, Miscanthus sinensis Thunb. ‘Zebrinus’ and Spartina pectinata Link. ‘Aureomarginata’. The post-harvest longevity of leafy culms was investigated in Alopecurus pratensis L. ‘Aureovariegatus’, Chasmanthium latifolium Michx., Miscanthus sinensis Thunb. ‘Silberspinne’, Pennisetum alopecuroides L. and Phalaris arundinacea L. ‘Picta’. Conditioning in gibberellic acid had a positive effect on the post-harvest longevity and fresh weight loss and the index of leaf greenness of leaves in the case of Miscanthus sinensis ‘Zebrinus’, while conditioning in 8-hydroxyquinoline sulphate improved fresh weight loss and the index of leaf greenness of the leafy culms of Miscanthus sinensis ‘Zebrinus’, Pennisetum alopecuroides and the leaves of Glyceria maxima ‘Variegata’.
Factors Contributing to SMEs Failure in Meeting Supplier Performance Standards
Authors: van Scheers Louise
Published: May 2016

This study sought to determine the factors that contribute to the failure of small and medium enterprises (SMEs) in meeting supplier performance standards. Suppliers are faced with the challenge of SMEs failing to meet supplier performance standards because they rely on these providers of products and services, mainly SMEs, for their operations and to ultimately achieve their mandate. The researchers were able to establish the main factors contributing to SME failure in meeting supplier performance standards. These are as follows: unclear specifications and terms of references from suppliers; insufficient information provided to SME suppliers to ensure understanding of requirements; insufficient feedback and support; no support of SME suppliers based on their Black Economic Empowerment (BEE) status; limited or no use of business support programs by SME suppliers; and external factors such as access to finance, changes in the economy, and location.
New Factors Inducing Changes in the Retail Banking Customer Relationship Management (CRM) and Their Exploration by the Fintech Industry
Authors: Kotarba Marcin
Published: May 2016

Growing levels of regulation force financial institutions to change their business models toward lower risk levels, higher capital adequacy, service quality, and more stable revenue pools. In parallel with the regulatory changes, the banks are subject to pressure from accelerated technology development and social changes. These two factors influence the behavior of customers and induce changes in the customer relationship management (CRM). Taking the example of retail banking, the factors and their impacts are explained. Additionally, a view on the FinTech industry is presented, highlighting areas where traditional financial institutions are losing market share to technology-savvy and socially oriented new ventures with exceptional CRM capabilities. The conclusion contains proposed strategic actions that need to be undertaken in order to prepare the financial services industry for managing customer relationships in the increasingly technosocial environment.
The Management of Staphylococcal Toxic Shock Syndrome. A Case Report
Authors: Bîrluţiu Victoria , Criştiu Ofelia , Baicu Marius , Bîrluţiu Rareş Mircea
Published: May 2016

Staphylococcal toxic shock syndrome (TSS) is most frequently produced by TSS toxin-1 (TSST-1) and Staphylococcal enterotoxin B (SEB), and only rarely by enterotoxins A, C, D, E, and H. Various clinical pictures can occur depending on severity, patient age and immune status of the host. Severe forms, complicated by sepsis, are associated with a death rate of 50-60%. The case of a Caucasian female infant, aged seven weeks, hospitalized with a diffuse skin rash, characterized as allergodermia, who initially developed TSS with axillary intertrigo, is reported.

TSS was confirmed according to 2011 CDC criteria, and blood cultures positive for Methicillin-sensitive Staphylococcus aureus (MSSA). Severe development occurred initial, including acidosis, consumption coagulopathy, multiple organ failures (MOF), including impaired liver and kidney function. Central nervous system damage was manifest by seizures. Clinical management included medical supervision by a multidisciplinary team of infectious diseases specialist and intensive care specialist, as well as the initiation of a complex treatment plan to correct hydro electrolytic imbalances and acidosis. This treatment included antibiotic and antifungal therapy, diuretic therapy, immunoglobulins, and local treatment similar to a patient with burns to prevent superinfection of skin and mucous membranes lesions. There was a favourable response to the treatment with resolution of the illness.
The Pitfalls of Febrile Jaundice. A Case Report
Authors: Obreja Maria , Teodor Andra , Leca Daniela , Ceasovschih Alexandr , Miftode Egidia
Published: May 2016

Jaundice in sepsis is usually caused by cholestasis, and its onset can precede other manifestations of the infection. Inflammation-induced cholestasis is a common complication in patients with an extrahepatic infection or those with inflammatory processes. We describe the case of a 47 years old female who presented with low back pain and paravertebral muscular contracture. She subsequently developed a cholestatic syndrome with clinical manifestations such as jaundice, followed by fever and sepsis with multiple organ dysfunction. Initially labeled as biliary sepsis, the diagnosis was crucially reoriented as the blood cultures were positive for Streptococcus pyogenes and the magnetic resonance imaging (MRI) findings suggested spondylodiscitis as well as a paravertebral abscess.
Influence of Ventilation Parameters on Intraabdominal Pressure
Authors: Puiac Claudiu , Szederjesi Janos , Lazar Alexandra , Almasy Emoke , Rad Paul , Puscasiu Lucian
Published: May 2016

Introduction: Intraabdominal pressure monitoring is not routinely performed because the procedure assumes some invasiveness and, like other invasive procedures, it needs to have a clear indication to be performed. The causes of IAH are various. Mechanically ventilated patients have numerous parameters set in order to be optimally ventilated and it is important to identify the ones with the biggest interference in abdominal pressure. Although it was stated that mechanical ventilation is a potential factor of high intraabdominal pressure the set parameters which may lead to this diagnostic are not clearly named.

Objectives: To evaluate the relation between intraabdominal pressure and ventilator parameters in patients with mechanical ventilation and to determine the correlation between intraabdominal pressure and body mass index. Material and method: This is an observational study which enrolled 16 invasive ventilated patients from which we obtained 61 record sheets. The following parameters were recorded twice daily: ventilator parameters, intraabdominal pressure, SpO2, Partial Oxygen pressure of arterial blood. We calculated the Body Mass Index (BMI) for each patient and the volume tidal/body weight ratio for every recorded data point.

Results: We observed a significant correlation between intraabdominal pressure (IAP) and the value of PEEP (p=0.0006). A significant statistical correlation was noted regarding the tidal volumes used for patient ventilation. The mean tidal volume was 5.18 ml/kg. Another significant correlation was noted between IAP and tidal volume per kilogram (p=0.0022). A positive correlation was found between BMI and IAP (p=0.0049), and another one related to the age of the enrolled patients. (p=0.0045).

Conclusions: The use of positive end-expiratory pressures and high tidal volumes during mechanical ventilation may lead to the elevation of intraabdominal pressure, a possible way of reducing this risk would be using low values of PEEP and also low volumes for the setting of ventilation parameters. There is a close positive correlation between the intraabdominal pressure levels and body mass index.
Analysis of time-fractional hunter-saxton equation: a model of neumatic liquid crystal
Authors: Atangana Abdon , Baleanu Dumitru , Alsaedi Ahmed
Published: May 2016

In this work, a theoretical study of diffusion of neumatic liquid crystals was done using the concept of fractional order derivative. This version of fractional derivative is very easy to handle and obey to almost all the properties satisfied by the conventional Newtonian concept of derivative. The mathematical equation underpinning this physical phenomenon was solved analytically via the so-called homotopy decomposition method. In order to show the accuracy of this iteration method, we constructed a Hilbert space in which we proved its stability for the time-fractional Hunder-Saxton equation.
Oscillation criteria for nonlinear fractional differential equation with damping term
Authors: Bayram Mustafa , Adiguzel Hakan , Secer Aydin
Published: May 2016

In this paper, we study the oscillation of solutions to a non-linear fractional differential equation with damping term. The fractional derivative is defined in the sense of the modified Riemann-Liouville derivative. By using a variable transformation, a generalized Riccati transformation, inequalities, and integration average techniquewe establish new oscillation criteria for the fractional differential equation. Several illustrative examples are also given.
Electromyographical Comparison of Pike Variations Performed With and Without Instability Devices
Authors: Snarr Ronald L. , Hallmark Ashleigh V. , Nickerson Brett S. , Esco Michael R.
Published: May 2016

Snarr, RL, Hallmark, AV, Nickerson, BS, and Esco, MR. Electromyographical comparison of pike variations performed with and without instability devices. J Strength Cond Res 30(12): 3436–3442, 2016—Instability devices are primarily used with the intent of increasing the intensity of traditional exercises by providing further muscular demands of the abdominal wall by decreasing stability. Although there are multiple studies examining these devices, most often they only compare one such device to a stable movement and overlook the comparison among multiple devices. The purpose of this investigation was to compare the electromyographical differences of the rectus abdominis (RA), external oblique (EO), erector spinae (LSES), and rectus femoris (RF) during pike variations performed on various surfaces. Twenty men and women volunteered for this study. All subjects performed 5 variations of a pike on varying surfaces (i.e., stable ground [PK], Swiss ball [SB], suspension training device [ST], BOSU ball [BOSU], and Core Coaster [CC]). Normalized (%MVC) values were recorded for each muscle during 5 repetitions of each pike variations. For the RA, EO, LSES, and RF, the PK elicited significantly lower values compared with the instability devices. In terms of the EO, the ST was significantly higher than the BOSU, SB, and CC. Results of this investigation demonstrated significant differences between the instability devices and the stable pike. These results indicate that with more freely moving instability devices (e.g., suspension device, Swiss ball, etc.), core musculature may require greater muscular demands. Practitioners should take note that traditional stable pikes may not offer a core musculature challenge to resistance-trained individuals.
Effects of 16 Weeks of Concurrent Training on Resting Heart Rate Variability and Cardiorespiratory Fitness in People Living With HIV/AIDS Using Antiretroviral Therapy: A Randomized Clinical Trial
Authors: Pedro Rafael E. , Guariglia Débora A. , Okuno Nilo M. , Deminice Rafael , Peres Sidney B. , Moraes Solange M.F.
Published: May 2016

Pedro, RE, Guariglia, DA, Okuno, NM, Deminice, R, Peres, SB, and Moraes, SMF. Effects of 16 weeks of concurrent training on resting heart rate variability and cardiorespiratory fitness in people living with HIV/AIDS using antiretroviral therapy: a randomized clinical trial. J Strength Cond Res 30(12): 3494–3502, 2016—The study evaluated the effects of concurrent training on resting heart rate variability (HRVrest) and cardiorespiratory fitness in people living with HIV/AIDS undergoing antiretroviral therapy (ART). Fifty-eight participants were randomized into 2 groups (control and training group); however, only 33 were analyzed. The variables studied were HRVrest indices, submaximal values of oxygen uptake (V̇o
2sub) and heart rate (HR5min), peak speed (Vpeak), and peak oxygen uptake (V̇o
2peak). The training group performed concurrent training (15–20 minutes of aerobic exercise plus 40 minutes of resistance exercise), 3 times per week, for 16 weeks. Posttraining V̇o
2peak and Vpeak increased, and HR5min decreased. Resting heart rate variability indices did not present statistical differences posttraining; however, the magnitude-based inferences demonstrated a “possibly positive effect” for high frequency (HF) and low frequency (LF) plus high frequency (LF + HF) and a “likely positive effect” for R-Rmean posttraining. In conclusion, concurrent training was effective at improving cardiorespiratory fitness and endurance performance. Moreover, it led to probably a positive effect on HF and a likely positive effect on R-Rmean in people living with HIV/AIDS undergoing ART.
Maximal Aerobic Frequency of Ball Hitting: A New Training Load Parameter in Tennis
Authors: Baiget Ernest , Iglesias Xavier , Rodríguez Ferran A.
Published: May 2016

Baiget, E, Iglesias, X, and Rodríguez, FA. Maximal aerobic frequency of ball hitting: a new training load parameter in tennis. J Strength Cond Res 31(1): 106–114, 2017—This study aimed (a) to evaluate a new training load parameter in tennis based on the ball-hitting frequency (Ballf) at V̇o
2max occurs (maximal aerobic frequency of ball hitting, MAF) and (b) to assess the accuracy of a specific endurance tennis test (SET-Test) for predicting MAF. Thirty-five male competitive tennis players performed the SET-Test and selected physiological and performance parameters at maximal workload (MAX), and last completed stage (LS) and MAF were compared. Performance parameters (Ballf, time, stage, and hits per test) at LS were higher than at MAF (20.2 ± 1.7 vs. 18.1 ± 1.5 shots·min−1, 6.6 ± 0.8 vs. 5.6 ± 0.8 stages, and 189 ± 33 vs. 147 ± 27 hits; p < 0.001), and highly correlated (r = 0.72−0.77; p < 0.001). The mean difference between Ballf and stage at MAF and LS were 2.1 ± 1.1 shots·min−1 and 1.1 ± 0.6 stages, respectively. The main physiological parameters (heart rate, V̇o
2, and V̇c
o
2 at LS) were higher than at MAF (191 ± 9 vs. 186 ± 8 beats·min−1, 55.5 ± 5.9 vs. 55.0 ± 6.0 ml·kg−1·min−1 and 4,724 ± 880 vs. 4,253 ± 739 ml·min−1; p < 0.005), and were very strongly correlated (r = 0.93−0.99; p < 0.001). We conclude that MAF can be used as a practical performance parameter to prescribe tennis-specific training, and that the SET-Test is a valid method for assessing MAF. Gas exchange measurements not being available, as a rule of thumb, most players reach their MAF at ∼1 stage (95% confidence interval: 0.9−1.2) and ∼2 shots·min−1 (95% confidence interval: 1.7−2.5) less than their completed LS. A model for specific on-court training protocols for optimizing aerobic fitness in competitive tennis player is proposed.
Effect of Time-of-Day on Biochemical Markers in Response to Physical Exercise
Authors: Ammar Achraf , Chtourou Hamdi , Souissi Nizar
Published: May 2016

Ammar, A, Chtourou, H, and Souissi, N. Effect of time-of-day on biochemical markers in response to physical exercise. J Strength Cond Res 31(1): 272–282, 2017—It is well established that many physiological functions are time-of-day (TOD) dependent, and their circadian rhythms are well documented in healthy populations at resting state. In fact, greater rate of oxidative stress, white blood cell, homocysteine, and muscle damage markers were shown in the early evening (≈18:00 hours), and more efficient antioxidant activity was observed in the early morning (≈06:00 hours). During physical tasks, the majority of the above-mentioned physiological functions increase from pre to post physical exercise with different rates of increases from morning to evening. These different rates of increases are suggested to alter the physiological resting diurnal variation. In this context, given the possible significant interaction “TOD × physical exercise,” circadian rhythms of the physiological responses during physical activity are still not well established in trained subjects. Otherwise, it was suggested that the diurnal variation of these biochemical parameters could, in part, explain the typical diurnal fluctuation of physical performance. Therefore, the aim of this review was to summarize the currently available studies investigating the circadian rhythms of physiological functions at rest and after physical exercise and to establish their possible effect on the diurnal variation of sport performance. Although studies in this field are limited, the available information shows that compared with sedentary subjects, trained population maintained similar diurnal variations of hematological parameters, homocysteine, and some biochemical markers at rest and even after physical exercise. However, after strength exercises, the circadian rhythms for the majority of oxidative stress and muscle damage markers were altered because of the higher rate of increased pre-post exercises registered in the morning compared with the afternoon and evening. The available studies reveal that the significant circadian variation observed for sport performances could be more likely explained by the alteration of ionic movement and the diurnal fluctuation of homocysteine, lactate, muscle damage, and antioxidant markers.
Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2
Authors: Huang Teng-Wei , Kochukov Mikhail Y. , Ward Christopher S. , Merritt Jonathan , Thomas Kaitlin , Nguyen Tiffani , Arenkiel Benjamin R. , Neul Jeffrey L.
Published: May 2016

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations inMethyl-CpG-binding protein 2(MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings fromin vitrobrainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration.

SIGNIFICANCE STATEMENTBreathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of MeCP2, the protein encoded by the gene mutated in Rett syndrome, within the hindbrain are critical for control of normal breathing. Here we show that MeCP2 function plays distinct roles in specific brainstem regions in the genesis of various aspects of abnormal breathing. This provides insight into the pathogenesis of these breathing abnormalities in Rett syndrome, which could be used to target treatments to improve these symptoms. Furthermore, it provides further knowledge about the fundamental neural circuits that control breathing.
Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95
Authors: Antonelli Roberta , De Filippo Roberto , Middei Silvia , Stancheva Stefka , Pastore Beatrice , Ammassari-Teule Martine , Barberis Andrea , Cherubini Enrico , Zacchi Paola
Published: May 2016

Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolylcis-/transisomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/−mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/−or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB.

Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.

SIGNIFICANCE STATEMENTPSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein at excitatory postsynaptic densities and a potent regulator of synaptic strength and plasticity. The activity of PSD-95 is tightly controlled by several post-translational mechanisms including proline-directed phosphorylation. This signaling cascade regulates the fate of its targets through postphosphorylation conformational modifications catalyzed by the peptidyl-prolylcis-/transisomerase Pin1. Here, we uncover a new role of Pin1 in glutamatergic signaling. By interacting with PSD-95, Pin1 dampens PSD-95 ability to complex with NMDARs, thus negatively affecting NMDAR signaling and spine morphology. Our findings further emphasize the emerging role of Pin1 as a key modulator of synaptic transmission.
Identification of a Circadian Clock in the Inferior Colliculus and Its Dysregulation by Noise Exposure
Authors: Park Jung-sub , Cederroth Christopher R. , Basinou Vasiliki , Meltser Inna , Lundkvist Gabriella , Canlon Barbara
Published: May 2016

Circadian rhythms regulate bodily functions within 24 h and long-term disruptions in these rhythms can cause various diseases. Recently, the peripheral auditory organ, the cochlea, has been shown to contain a self-sustained circadian clock that regulates differential sensitivity to noise exposure throughout the day. Animals exposed to noise during the night are more vulnerable than when exposed during the day. However, whether other structures throughout the auditory pathway also possess a circadian clock remains unknown. Here, we focus on the inferior colliculus (IC), which plays an important role in noise-induced pathologies such as tinnitus, hyperacusis, and audiogenic seizures. Using PER2::LUC transgenic mice and real-time bioluminescence recordings, we revealed circadian oscillations of Period 2 protein in IC explants for up to 1 week. Clock genes (Cry1,Bmal1,Per1,Per2,Rev-erbα, andDbp) displayed circadian molecular oscillations in the IC. Averaged expression levels of early-induced genes and clock genes during 24 h revealed differential responses to day or night noise exposure.Rev-erbα andDbpgenes were affected only by day noise exposure, whereasPer1andPer2were affected only by night noise exposure. However, the expression ofBdnfwas affected by both day and night noise exposure, suggesting that plastic changes are unlikely to be involved in the differences in day or night noise sensitivity in the IC. These novel findings highlight the importance of circadian responses in the IC and emphasize the importance of circadian mechanisms for understanding central auditory function and disorders.

SIGNIFICANCE STATEMENTRecent findings identified the presence of a circadian clock in the inner ear. Here, we present novel findings that neurons in the inferior colliculus (IC), a central auditory relay structure involved in sound processing, express a circadian clock as evidenced at both the mRNA and protein levels. Using a reporter mouse that expresses a luciferase protein coupled to the core clock protein PERIOD2 (PER2::LUC), we could observe spontaneous circadian oscillations in culture. Furthermore, we reveal that the mRNA profile of clock-related genes in the IC is altered differentially by day or night noise exposure. The identification of a clock in the IC is relevant for understanding the mechanisms underlying dysfunctions of the IC such as tinnitus, hyperacusis, or audiogenic seizures.
Bcl-xL Is Essential for the Survival and Function of Differentiated Neurons in the Cortex That Control Complex Behaviors
Authors: Nakamura Ayumi , Swahari Vijay , Plestant Charlotte , Smith Ikuko , McCoy Eric , Smith Spencer , Moy Sheryl S. , Anton E. S. , Deshmukh Mohanish
Published: May 2016

Apoptosis plays an essential role during brain development, yet the precise mechanism by which this pathway is regulated in the brain remains unknown. In particular, mammalian cells are known to express multiple anti-apoptotic Bcl-2 family proteins. However, the cells of the developing brain could also exist in a primed state in which the loss of a single anti-apoptotic Bcl-2 family protein is sufficient to trigger apoptosis. Here, we examined the critical role of Bcl-xL, an anti-apoptotic protein, during brain development. Using conditional knock-out mice in which Bcl-xL is deleted in neural progenitor cells (Bcl-xLEmx1–Cre), we show that the loss of Bcl-xL is not sufficient to trigger apoptosis in these proliferating progenitors. In contrast, specific populations of postmitotic neurons derived from these progenitors, including upper layer cortical neurons and the CA1–CA3 regions of the hippocampus, were acutely dependent on Bcl-xL. Consistent with this finding, deletion of Bcl-xL selectively in the postmitotic neurons in the brain (Bcl-xLNex–Cre) also resulted in similar patterns of apoptosis. This Bcl-xL deficiency-induced neuronal death was a consequence of activation of the apoptotic pathway, because the cell death was rescued with codeletion of the proapoptotic proteins Bax and Bak. Importantly, the loss of these Bcl-xL-dependent neurons led to severe neurobehavioral abnormalities, including deficits in motor learning, hyperactivity, and increased risk-taking and self-injurious behaviors. Together, our results identify a population of neurons in the developing brain that are acutely dependent on Bcl-xL during the peak period of synaptic connectivity that are important for the establishment of higher-order complex behaviors.

SIGNIFICANCE STATEMENTAlthough Bcl-xL is known to inhibit apoptosis, exactly which cells in the brain are dependent on Bcl-xL has remained unclear because of the embryonic lethality of mice globally deleted for Bcl-xL. Here, we conditionally deleted Bcl-xL in the brain and found that this did not result in widespread apoptosis in the proliferating progenitors. Instead, Bcl-xL deficiency induced apoptosis in a select population of differentiated neurons predominantly in the early postnatal stages. Importantly, these Bcl-xL-dependent neurons are not essential for survival of the organism but instead regulate complex behaviors. Our results show that the selective loss of these Bcl-xL-dependent neurons results in mice exhibiting severe neurobehavioral abnormalities, including self-injurious and risk-taking behaviors, hyperactivity, and learning and memory defects.
Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System
Authors: Kim Byung-Wook , Jeong Kyoung Hoon , Kim Jae-Hong , Jin Myungwon , Kim Jong-Heon , Lee Maan-Gee , Choi Dong-Kug , Won So-Yoon , McLean Catriona , Jeon Min-Tae , Lee Ho-Won , Kim Sang Ryong , Suk Kyoungho
Published: May 2016

Lipocalin-2 (LCN2) is a member of the highly heterogeneous secretory protein family of lipocalins and increases in its levels can contribute to neurodegeneration in the adult brain. However, there are no reports on the role of LCN2 in Parkinson's disease (PD). Here, we report for the first time that LCN2 expression is increased in the substantia nigra (SN) of patients with PD. In mouse brains, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment for a neurotoxin model of PD significantly upregulated LCN2 expression, mainly in reactive astrocytes in both the SN and striatum. The increased LCN2 levels contributed to neurotoxicity and neuroinflammation, resulting in disruption of the nigrostriatal dopaminergic (DA) projection and abnormal locomotor behaviors, which were ameliorated in LCN2-deficient mice. Similar to the effects of MPTP treatment, LCN2-induced neurotoxicity was also observed in the 6-hydroxydopamine (6-OHDA)-treated animal model of PD. Moreover, treatment with the iron donor ferric citrate (FC) and the iron chelator deferoxamine mesylate (DFO) increased and decreased, respectively, the LCN2-induced neurotoxicityin vivo. In addition to thein vivoresults, 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in cocultures of mesencephalic neurons and astrocytes was reduced by LCN2 gene deficiency in the astrocytes and conditioned media derived from MPP+-treated SH-SY5Y neuronal enhanced glial expression of LCN2in vitro. Therefore, our results demonstrate that astrocytic LCN2 upregulation in the lesioned DA system may play a role as a potential pathogenic factor in PD and suggest that inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal DA system in the adult brain.

SIGNIFICANCE STATEMENTLipocalin-2 (LCN2), a member of the highly heterogeneous secretory protein family of lipocalins, may contribute to neuroinflammation and neurotoxicity in the brain. However, LCN2 expression and its role in Parkinson's disease (PD) are largely unknown. Here, we report that LCN2 is upregulated in the substantia nigra of patients with PD and neurotoxin-treated animal models of PD. Our results suggest that LCN2 upregulation might be a potential pathogenic mechanism of PD, which would result in disruption of the nigrostriatal dopaminergic system through neurotoxic iron accumulation and neuroinflammation. Therefore, inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in PD.
Multimodal Feature Integration in the Angular Gyrus during Episodic and Semantic Retrieval
Authors: Bonnici Heidi M. , Richter Franziska R. , Yazar Yasemin , Simons Jon S.
Published: May 2016

Much evidence from distinct lines of investigation indicates the involvement of angular gyrus (AnG) in the retrieval of both episodic and semantic information, but the region's precise function and whether that function differs across episodic and semantic retrieval have yet to be determined. We used univariate and multivariate fMRI analysis methods to examine the role of AnG in multimodal feature integration during episodic and semantic retrieval. Human participants completed episodic and semantic memory tasks involving unimodal (auditory or visual) and multimodal (audio-visual) stimuli. Univariate analyses revealed the recruitment of functionally distinct AnG subregions during the retrieval of episodic and semantic information. Consistent with a role in multimodal feature integration during episodic retrieval, significantly greater AnG activity was observed during retrieval of integrated multimodal episodic memories compared with unimodal episodic memories. Multivariate classification analyses revealed that individual multimodal episodic memories could be differentiated in AnG, with classification accuracy tracking the vividness of participants' reported recollections, whereas distinct unimodal memories were represented in sensory association areas only. In contrast to episodic retrieval, AnG was engaged to a statistically equivalent degree during retrieval of unimodal and multimodal semantic memories, suggesting a distinct role for AnG during semantic retrieval. Modality-specific sensory association areas exhibited corresponding activity during both episodic and semantic retrieval, which mirrored the functional specialization of these regions during perception. The results offer new insights into the integrative processes subserved by AnG and its contribution to our subjective experience of remembering.

SIGNIFICANCE STATEMENTUsing univariate and multivariate fMRI analyses, we provide evidence that functionally distinct subregions of angular gyrus (AnG) contribute to the retrieval of episodic and semantic memories. Our multivariate pattern classifier could distinguish episodic memory representations in AnG according to whether they were multimodal (audio-visual) or unimodal (auditory or visual) in nature, whereas statistically equivalent AnG activity was observed during retrieval of unimodal and multimodal semantic memories. Classification accuracy during episodic retrieval scaled with the trial-by-trial vividness with which participants experienced their recollections. Therefore, the findings offer new insights into the integrative processes subserved by AnG and how its function may contribute to our subjective experience of remembering.
Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography–tandem mass spectrometry
Authors: Belli S , Santi D , Leoni E , Dall’Olio E , Fanelli F , Mezzullo M , Pelusi C , Roli L , Tagliavini S , Trenti T , Granata A R , Pagotto U , Pasquali R , Rochira V , Carani C , Simoni M
Published: May 2016

Background

Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS.

Objective

To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men.

Design

A prospective, longitudinal, case–control, clinical trial.

Methods

Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG.

Results

Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001).

Conclusion

This study demonstrates for the first time using LC–MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.