O trabalho tem o objetivo de estudar a tutela inibitória no processo do trabalho, especialmente no sentido da prevenção do assédio moral no ambiente de trabalho. A abordagem parte da perspectiva da proteção dos direitos fundamentais dos trabalhadores, principalmente em face do poder diretivo do empregador. Analisa a vinculação dos particulares às normas de direitos fundamentais e ressalta a importância da vinculação direta ou imediata do empregador às normas de direitos fundamentais, no âmbito da relação de emprego. Põe em relevo a função do processo do trabalho na perspectiva da tutela dos direitos fundamentais. Analisa as características do assédio moral praticado no ambiente de trabalho, sua classificação e suas consequências. Trata das modificações sociais que impuseram novas necessidades ao direito processual, especialmente ao direito processual do trabalho. Aborda a natureza e as características da tutela inibitória, como tutela judicial preventiva da conduta ilícita. Trata dos meios concretos de operar a tutela inibitória no processo do trabalho, com o objetivo de prevenir o assédio moral. Cuida de aspectos controversos da legitimidade para a ação inibitória, bem como de peculiaridades da causa de pedir e da prova. Analisa os requisitos da sentença e da coisa julgada na ação inibitória. Conclama à assunção da lógica da prevenção no direito processual. Realça a necessidade de uma atuação mais criativa e livre dos juízes trabalhistas. / The work aims to study the inhibitory injunction in the labor process, especially towards the prevention of bullying in the workplace. The approach starts from the perspective of protecting the fundamental rights of workers, particularly against the directive power of the employer. Analyzes linking the particular standards of fundamental rights and emphasizes the importance of direct or immediate employer to binding rules relating to fundamental rights within the employment relationship. It highlights the role of the procedural labor law from the perspective of the protection of fundamental rights. It analyzes the characteristics of bullying practiced in the workplace, their classification and environmental consequences. It analyzes the social changes that have imposed new requirements of procedural law, especially procedural labor law. It approaches the nature and characteristics of inhibitory injunction, like a judicial protection as a preventive of unlawful conduct. It analyzes the specific means to operate the inhibitory injunction in the labor process, with the goal of preventing bullying. It takes care of controversial aspects of legitimacy to the inhibitory action, as well as peculiarities of the cause of action and proofs. It analyzes the requirements of the sentence and the inhibitory action on res judicata. It urges the assumption of prevention logic in procedural law. It stresses the need for a more creative and free activity of labor judges.

Vancomycin is an antibiotic used for the treatment of systemic infections. It is given intravenously usually every twelve or twenty-four hours. This particular drug has a medium level of boundedness, with approximately fty percent of the drug being free and thus physiologically eective. A physiologically-based pharmacokinetic (PBPK) model was used to better understand the absorption, distribution, and elimination of the drug. Using optimal parameters, the model could be used in the future to test how various factors, such as BMI or excretion levels, might aect the concentration of the antibiotic.

Levofloxacin is in a class of antibiotics known as fluoroquinolones, which treat infections by killing the bacteria that cause them. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of Levofloxacin after a single dose. PBPK modeling uses parameters such as body weight, blood flow rates, partition coefficients, organ volumes, and several other parameters in order to model the distribution of a particular drug throughout the body. Levofloxacin is only moderately bound in human blood plasma, and, thus, for the purposes of this paper, linear bonding is incorporated into the model because the free or unbound portion of the drug is the only portion that is considered to be medicinally effective. Parameter estimation is then used to estimate the two unknown parameters given clinical data from literature on the total concentration of Levofloxacin in the blood over time. Once an adequate model is generated, the effects of varying Body Mass Index are tested for the absorption and distribution of Levofloxacin throughout the body.

This study examined the effect of an 8-week, progressive exercise intervention on neural responses, specifically N2 amplitude as a measure of inhibitory control, to pictures of food. Healthy women ages 18-44 years were randomized to a morning (AM) exercise group or evening (PM) exercise group. The AM group did moderate-to-vigorous intensity exercise on 4 days per week between 6:30 and 9:30 a.m. while the PM group had the identical volume of exercise between 6:30 and 9:30 p.m. Neural responses, eating behaviors, cardiovascular fitness outcomes, and body weight/composition were measured at baseline and after the 8-week intervention. The N2 amplitude in response to pictures of high- and low-calorie foods was assessed using electroencephalography during a go/no-go task. Dietary restraint, emotional eating, and external eating were assessed using the Dutch Eating Behavior Questionnaire. VO2peak, HRmax, and time to completion were measured during a maximal treadmill test. Body weight was measured on a digital scale, and body composition was measured using dual-energy x-ray absorptiometry. There was not a significant task (go, no-go) × group (AM, PM) × period (baseline, 8 weeks) interaction (F = 0.18; p = 0.677), but there was a main effect of exercise over 8 weeks (F = 6.26; p = 0.017) with increased N2 amplitude following the intervention. There was not a significant interaction as a function of picture type (high-calorie, low-calorie), task, group, and period (F = 0.52; p = 0.478). Changes in body weight and neural outcomes were not significantly associated with changes in eating behaviors for either group (ps < 0.05). There was a significant group × period interaction for body weight (F = 4.90; p = 0.032). Body weight increased by 0.79 ± 1.16 kg in the AM group and decreased by 0.21 ± 1.46 kg in the PM group (effect size = 0.77; CI = 0.15-1.35). There was not a significant group × period interaction for body fat percentage, total body fat or fat-free mass (ps < 0.05). When examining the main effect of exercise on cardiovascular fitness outcomes, VO2peak was not different (F = 1.80; p = 0.187), time-to-completion on treadmill increased (F = 6.51; p = 0.014), and HRmax during the treadmill test was significantly lower (F = 5.49; p = 0.025). This study suggests that 8 weeks of exercise training may increase the inhibitory response to pictures of both high- and low-calorie foods. However, time of day of exercise did not influence this response. Eight weeks of exercise training did not change self-reported dietary restraint, external eating, or emotional eating, and there was no correlation between these eating behaviors and inhibitory control. However, evening exercise was more beneficial for body weight than morning exercise. Given the novelty of this study and its results, additional studies on the influence of time of day of exercise on weight management are needed.

Tauopathy, which results from the oligomerization of misfolded tau protein in neurons, is a feature present in a number of neurodegenerative diseases and a hallmark of Alzheimer’s Disease (AD). Tau is an important phosphoprotein that regulates the assembly of microtubules, but tauopathy can occur when tau becomes hyperphosphorylated. Phosphorylation prevents tau from binding to tubulin, which results in cytosolic accumulation of tau and eventual oligomerization. This abnormal accumulation of tau leads to the spreading of hyperphosphorylated tau to downstream synaptically connected neurons through an unknown mechanism. In AD, the hippocampus is one of the first brain structures to be affected by tauopathy in humans. According to previous research, tauopathy occurs primarily between principal cells in the hippocampus. The involvement of local inhibitory interneurons in tauopathy and their potential role in AD is more controversial. Previous research suggests that tau pathogenesis primarily affects principal cells; however, given the importance, diversity, and function of interneurons in the hippocampus, it is important to gain a better understanding of the interneuron subtypes that may be impacted by the spread of trans-synaptic tau into the hippocampus. Understanding the involvement of interneurons in trans-synaptic tau transmission is important to understanding neurodegeneration in AD and other neurodegenerative disorders. To investigate this, both male and female genetically-modified mice underwent surgery to examine the trans-synaptic spread of pathogenic tau (EGFP-Tau P301L) from the entorhinal cortex to hippocampal neurons. Histology and imaging analysis of brain sections were performed to examine the hippocampal cells impacted by trans-synaptic spread of tau. Results show that pathogenic tau can trans-synaptically spread from presynaptic neurons in the entorhinal cortex into downstream hippocampal interneurons and also that hippocampal interneurons are capable of trans-synaptically spreading tau. Future studies examining the specific subtypes of hippocampal interneurons vulnerable to trans-synaptic spread of tau will be important for a better understanding of disease progression, which could lead to uncovering new therapeutic targets for neurodegenerative diseases, like AD, which are associated with tauopathy.

Hokkaido University (北海道大学) / 博士 / 医学

<p>ABSTRACT</p><p>A defect implantation process is the major reason for unexplained infertility. Estrogen andprogesterone are steroid hormones preparing the endometrium for implantation. They mediatetheir effect through their receptors: estrogen receptor alpha and beta and progesteronereceptor A and B, respectively. Leukemia inhibitory factor (LIF), which is also important forimplantation, mediates its effect through LIF receptor and the coreceptor, gp130, and is downregulated by suppressors of cytokine signaling 1. The aim of the study was to compare thelevels of the steroid hormone receptors and LIF related factors in the endometrium of twogroups of women with the diagnosis unexplained infertility: one that became pregnant afterassisted reproduction and one that did not become pregnant. Before treatment of thesewomen, endometrial mRNA was collected during the window of implantation in themenstrual cycle. The levels of specific mRNAs were measured with real-time PCR. Womenwho had become pregnant had a significantly higher level of steroid hormone receptors. Thus,these proteins seem to be important for a pregnancy and may be suitable as receptivitymarkers.</p>

The purpose of this dissertation is threefold: to determine the differences in apparent prevalence and the antimicrobial susceptibility of Campylobacter spp. between antimicrobial-free and conventional swine farms; secondly, to introduce an appropriate statistical model to compare the minimum inhibitory concentration distributions of Escherichia coli and Campylobacter spp. isolated from both farm types; and thirdly, to examine the potential herd level risk factors that may be associated with antimicrobial resistance of Campylobacter spp. and E. coli isolates from finishers on antimicrobial-free and conventional farming systems. In addition, a critical review of studies that have compared the levels and patterns of antimicrobial resistance among animals from antimicrobial-free and conventional farming practices was performed. Fecal samples from 15 pigs were collected from each of 35 antimicrobial-free and 60 conventional farms in the Midwestern U.S. Campylobacter spp. was isolated from 464 of 1,422 fecal samples, and each isolate was tested for susceptibility to 6 antimicrobials. The apparent prevalence of Campylobacter spp. isolates was approximately 33 percent on both conventional and antimicrobial-free farms. The proportion of antimicrobial resistance among Campylobacter was higher for three antimicrobials within conventional compared to antimicrobial-free farms. The susceptibilities of populations of bacteria to antimicrobial drugs were summarized as minimum inhibitory concentration (MIC) frequency distributions. The use of MIC values removed the subjectivity associated with the choice of breakpoints which define an isolate as susceptible or resistant. A discrete-time survival analysis model was introduced as the recommended statistical model when MICs are the outcome. A questionnaire was completed by each farm manager on biosecurity, preventive medication, vaccines, disease history, and production management. Multivariable population-averaged statistical models were used to determine the relationships among antimicrobial susceptibility patterns and potential herd-level risk factors. Controlling for herd type (antimicrobial-free versus conventional), each antimicrobial-bacterial species combination yielded unique combinations of risk factors; however, housing type, history of rhinitis, farm ventilation, and history of swine flu were significant in more than one model. A variety of herd-level practices were associated with the prevalence of antimicrobial resistance on swine farms. Further studies are encouraged when considering interventions for antimicrobial resistance on both antimicrobial-free and conventional farms.

Oligodendrocytes (OL)s are the dominant cell type in the white matter and are integral for synaptic transmission essential for proper neuronal communication between brain areas. Previous studies have shown that intravenous administration of the mononuclear fraction of human umbilical cord blood (HUCB) cells in rat models of stroke reduced white matter injury, gray matter injury and behavioral deficits. Yet the mechanisms used by HUCB cells remain unknown in ischemic injury. These studies will investigate both in vitro and in vivo approaches to elucidate this mechanism in OLs. When mature primary OLs were coincubated with HUCB cells, HUCB cells secreted soluble factors that reduced cell death in OLs exposed to OGD. Microarray analysis revealed that HUCB cell treatment induced OL gene changes. These changes included genes involved in cell proliferation, signaling, anti-oxidant activity, and myelination. To extend these findings, the middle cerebral artery occlusion (MCAO) model was used to assess the expression profile of protein products of gene changes observed in vitro. The in vivo data mirrored in vitro data in that metallothionein 3 (Mt3), peroxiredoxin 4 (Prdx4), myelin oligodendrocyte glycoprotein (Mog), U2AF homology kinase 1(Uhmk1), and insulin induce gene 1(Insig1) were upregulated in OLs of the white matter tract adjacent to the infarct. Furthermore, double immunofluorescence staining determined that OLs expressed these proteins. Other reports have shown that HUCB cells secrete soluble factors related to cellular protection, including interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10). Other factors are known for their proliferative actions, such as vascular endothelial growth factor (VEGF), BDNF, platelet derived growth factor B (PDGF-B), leukemia inhibitory factor (LIF), and granulocyte colony stimulating factor (GCSF) all of which converge on the Akt survival pathway. Given these findings we hypothesize that Akt activation is integral to HUCB cell mediated OL protection. In models of excitotoxicity, the addition of Akt inhibitor IV blocked HUCB cell mediated protection in OL cultures exposed to 24 hrs OGD. In vivo, HUCB cell treatment increased Akt activation, antioxidant protein expression and decreased caspase 3 cleavage in the external capsule in a time dependent manner. The next series of experiments determine whether the soluble factors secreted by HUCB cells could replace HUCB cells as treatment. LIF expression is increased in HUCB cells as compared to peripheral blood and as previously mentioned, LIF is secreted by HUCB cells. Additionally, LIF rescued OLs from spinal cord and experimental autoimmune encephalomyelitis injury. Thus LIF was investigated. LIF protected OL subjected to 24 hr OGD, increased antioxidant Prdx4 gene expression and reduced reactive oxygen species production. Additionally the inclusion of Akt inhibitor IV blocked LIF induced OL protection. Similar results were obtained when GCSF was evaluated. All these findings indicate that HUCB cell mediated OL/white matter protection is due to the soluble factors secreted by the mononuclear population of these cells. These soluble factors including LIF activate cellular machinery leading to enhanced cellular survival. Here we found a specific survival pathway activated by soluble factors released from HUCB cells, leading to Akt activation. Akt activation arrests stroke induced apoptosis and reduced the expansion of the infarct, promoting functional recovery from acute ischemic injury.

β-lactam antibiotics have long been a reliable course of treatment for bacterial infections. However, with recent increases in resistance and rising populations of immunocompromised patients new β-lactams have been synthesized and tested. The Turos laboratory has recently discovered novel β-lactams that have a mode of action distinct from penicillin and other β-lactam antibiotics as cell lysis is not observed. In the current investigations, these compounds are shown to also have antifungal properties. The rising incidence and prevalence of invasive fungal infections has become an increasing concern. The most common fungal pathogens involved in these infections are species in the genus Candida. In this study antifungal activity is observed for a wide range of N-methylthio β-lactams against C. albicans, C. tropicalis, C. keyfr, C. glabrata, C. lusitinae, C. utilis, and C. parapsilosis. The structure-activity relationship based on studies of β−lactam derivatives leaving different substituents at various positions on the lactam ring are investigated, and the minimum inhibitory concentration values determined using standard methods. In studies towards understanding the mode of action, the products of the interaction between the drug and fungal cells in a suspension were investigated using nuclear magnetic resonance spectroscopy and transmission electron microscopy. The mode of action of these new lactams seems to be similar to that observed in bacteria, involving transfer of the methylthio group to a cellular thiol.