Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Runx2 in Microtubule Acetylation in Bone Metastatic Breast Cancer Cells

Simple Summary Breast cancer is the most commonly diagnosed cancer type, making up a quarter of all cases among women. While modern-day research has shown tremendous progress in the development of treatment options, complications related to bone metastasis remain an obstacle that demands further attention. Cancer cells that migrate into the bone microenvironment show significant alterations in their metabolism and gene expression profiles. In this study, we set out to better understand the changes induced by Runx2 in bone-derived breast cancer cells. We identified key changes in the stability of the microtubule cytoskeleton of bone-derived cells expressing Runx2. These changes have implications on a variety of processes related to metabolism, cellular stress response, and response to common chemotherapies. These studies help to shed light on the changes that take place as a tumor begins to metastasize and to better predict which therapies will benefit patients with bone metastasis. Abstract Bone metastasis of breast cancer results in severe bone loss, fractures, and death. Crosstalk between breast cancer cells and bone resident cells promotes osteoclast activity and the release of growth factors from the bone matrix resulting in aggressive tumor growth and bone loss. We and others have shown that Runt-related transcription factor-2 (Runx2) promotes metastatic tumor growth-associated bone loss. Breast cancer cells also induce autophagy to survive metabolic stress at the metastatic site. Recently, we reported a Runx2-dependent increase in autophagy. In this study, to examine the underlying mechanisms of metastasis and tumor resistance to stress, we used a bone metastatic isogenic variant of breast cancer MDA-MB-231 cells isolated from a xenograft tumor mouse model of metastasis. Our results with immunofluorescence and biochemical approaches revealed that Runx2 promotes microtubule (MT) stability to facilitate autophagy. Stable MTs are critical for autophagosome trafficking and display increased acetylation at Lysine 40 of α-tubulin. Runx2 silencing decreases acetylated α-tubulin levels. The expression levels of HDAC6 and αTAT1, which serve to regulate the acetylation of α-tubulin, were not altered with Runx2 silencing. We found that HDAC6 interaction with α-tubulin is inhibited by Runt-related factor-2 (Runx2). We show that the expression of wild-type Runx2 can restore the acetylated polymer of MTs in Runx2 knockdown cells, while the C-terminal deletion mutant fails to rescue the polymer of MTs. Importantly, cellular stress, such as glucose starvation also increases the acetylation of α-tubulin. We found that the loss of Runx2 increases the sensitivity of breast cancer cells to MT-targeting agents. Overall, our results indicate a novel regulatory mechanism of microtubule acetylation and suggest that Runx2 and acetylated microtubules may serve as therapeutic targets for bone metastatic tumors.
Thiogenistein—Antioxidant Chemistry, Antitumor Activity, and Structure Elucidation of New Oxidation Products

Isoflavonoids such as genistein (GE) are well known antioxidants. The predictive biological activity of structurally new compounds such as thiogenistein (TGE)–a new analogue of GE–becomes an interesting way to design new drug candidates with promising properties. Two oxidation strategies were used to characterize TGE oxidation products: the first in solution and the second on the 2D surface of the Au electrode as a self-assembling TGE monolayer. The structure elucidation of products generated by different oxidation strategies was performed. The electrospray ionization mass spectrometry (ESI-MS) was used for identifying the product of electrochemical and hydrogen peroxide oxidation in the solution. Fourier transform infrared spectroscopy (FT-IR) with the ATR mode was used to identify a product after hydrogen peroxide treatment of TGE on the 2D surface. The density functional theory was used to support the experimental results for the estimation of antioxidant activity of TGE as well as for the molecular modeling of oxidation products. The biological studies were performed simultaneously to assess the suitability of TGE for antioxidant and antitumor properties. It was found that TGE was characterized by a high cytotoxic activity toward human breast cancer cells. The research was also carried out on mice macrophages, disclosing that TGE neutralized the production of the LPS-induced reactive oxygen species (ROS) and exhibits ABTS (2,2′-azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid) radical scavenging ability. In the presented study, we identified the main oxidation products of TGE generated under different environmental conditions. The electroactive centers of TGE were identified and its oxidation mechanisms were proposed. TGE redox properties can be related to its various pharmacological activities. Our new thiolated analogue of genistein neutralizes the LPS-induced ROS production better than GE. Additionally, TGE shows a high cytotoxic activity against human breast cancer cells. The viability of MCF-7 (estrogen-positive cells) drops two times after a 72-h incubation with 12.5 μM TGE (viability 53.86%) compared to genistein (viability 94.46%).
Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by the recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin-releasing factor (CRF)-CRF1 receptor and Gamma-Aminobutyric Acid (GABA)-ergic signaling dysregulation occurring in alcohol-dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch-clamp electrophysiology to examine the effects of alcohol dependence on the CRF modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared to males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had fewer CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike in males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.
Combination Therapies for Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.
A Grounded Theory Study on the Intention to Work While Ill among Workers with Musculoskeletal Disorders: An In-Depth Understanding of Workers’ Experiences

Background: Frequent short-term sickness absence is prevalent among workers with musculoskeletal disorders (MSDs). This in return leads to poor productivity in organizations and decreased ability to work among workers. Nevertheless, some workers with MSDs still continue to work despite pain and are able to maintain their productivity. Existing literature on attending work while ill is very limited. Understanding the factors influencing workers’ attendance to work while having symptoms is crucial to help workers live with their MSD productively and healthily. According to literature on behavior theories, the proximal determinant of behavior is one’s intention to engage in that behavior. Thus, this study was conducted to explore the factors that influence the intention to work while ill among workers with MSD. Methods: Twenty-one in-depth interviews were conducted using a semi-structured guide according to a grounded theory approach. Workers with MSD were recruited via a purposive and snowballing sampling until data saturation was attained. Data were analyzed by means of thematic analysis using computer software, ATLAS.ti. Results: Nine major significant themes of factors influencing the intention to work while ill were identified after transcription. From these, a total of six themes were associated with attendance incentives driving workers to attend work while ill (work commitment, work satisfaction, support from colleagues, workplace arrangements, ability to recover at home and ability to manage pain at work) and three themes were linked to attendance requirements (consequences to self, consequences to others and poor acceptance of one’s illness for sickness absence by supervisor and colleagues) faced by workers to attend work while ill. Conclusions: This study underlines the importance of both positive and negative motivators in influencing the intention to work while ill among workers with MSD. Future research suggests comparing both motivators in terms of work performance to aid more workers to work while ill.
Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins

Excitable cells of the nervous and cardiovascular systems depend on an assortment of plasmalemmal potassium channels to control diverse cellular functions. Voltage-gated potassium (Kv) channels are central to the feedback control of membrane excitability in these processes due to their activation by depolarized membrane potentials permitting K+ efflux. Accordingly, Kv currents are differentially controlled not only by numerous cellular signaling paradigms that influence channel abundance and shape voltage sensitivity, but also by heteromeric configurations of channel complexes. In this context, we discuss the current knowledge related to how intracellular Kvβ proteins interacting with pore complexes of Shaker-related Kv1 channels may establish a modifiable link between excitability and metabolic state. Past studies in heterologous systems have indicated roles for Kvβ proteins in regulating channel stability, trafficking, subcellular targeting, and gating. More recent works identifying potential in vivo physiologic roles are considered in light of these earlier studies and key gaps in knowledge to be addressed by future research are described.
Resilience Improves the Quality of Life and Subjective Happiness of Physiotherapists during the COVID-19 Pandemic

Resilience is an individual characteristic that protects mental health. However, its impact on the lives of Brazilian physiotherapists during COVID-19 is not known. This study aimed to analyze whether resilience modulates the perceived quality of life (QoL) and subjective happiness (SH) of physiotherapists who work with COVID-19 patients, compared with those who do not. A cross-sectional study was conducted between 22 August and 22 October 2020. Physiotherapists working in critical and non-critical hospital sectors were invited to participate in the study. The participants completed sociodemographic questionnaires and were graded on the 14-item Resilience Scale, 36-item Short-Form Health Survey (SF-36), and the Subjective Happiness Scale. In total, 519 physiotherapists were enrolled in the study. Physiotherapists with low resilience who worked with COVID-19 patients reported lower scores on the SF-36 subscales (except for social functioning) and the Subjective Happiness Scale, compared with those with high resilience who did not work with COVID-19 patients. These responses were modulated by age, sex, absence from work, receipt of personal protective equipment, host leadership, and practice and maintenance of regular physical activity. In conclusion, physiotherapists with low resilience who worked with COVID-19 patients presented lower perceptions of QoL and SH, compared with the other study participants.
Development in Decolonization: Walter Rodney, Third World Developmentalism, and “Decolonizing Political Theory”

Developmentalism is the idea that progress entails the temporal movement of societies along a universal trajectory. Prevailing accounts conceptualize Eurocentric developmental discourses as ideological weapons of imperial domination, specifically because they defer colonial claims to popular self-rule. Rejecting the idea that these historical entanglements exhaust the meanings of developmental thought, this article sheds light on anticolonial debates over developmentalism. Turning to Guyanese scholar-activist Walter Rodney, it reconstructs what I call “popular anticolonial developmentalism,” as a way of construing popular legitimation in actual contexts of anticolonial and postcolonial politics. From the premise that capitalist-imperialism “deflected” the historical motion of colonized societies, popular anticolonial developmentalism places the agencies of progressive transformation with democratically empowered popular subjects. Shifting the lens of “decolonizing political theory” from epistemic critique to worldly anticolonialism shows how developmentalism became a primary idiom for contesting and reimagining anticolonial futures. In turn, anticolonial practices reshaped developmentalism’s very conceptual parameters.
What kind of science for dual diagnosis? A pragmatic examination of the enactive approach to psychiatry

The recommended treatment for dual diagnosis - the co-occurrence of substance use and another mental disorder - requires seamless integration of the involved disciplines and services. However, no integrative framework exists for communicating about dual diagnosis cases across disciplinary or sectoral boundaries. We examine if Enactive Psychiatry may bridge this theoretical gap. We evaluate the enactive approach through a two-step pragmatic lens: Firstly, by taking a historical perspective to describe more accurately how the theoretical gap within the field of dual diagnosis initially developed. Secondly, by applying the Enactive Psychiatry approach to data from a longitudinal study on the trajectory of cannabis use in psychosis disorders. By applying the theory rather than simply presenting it, we position ourselves better to evaluate whether it may assist the purpose of achieving a more expedient pragmatic “grip” on the field of dual diagnosis. In our discussion, we suggest that this may very well be the case. Finally, we consider the enactive approach as one of a small handful of new theories of mental disorders that draw on systems thinking and ecological psychology, and discuss whether they have the potential for a wider progressive problemshift within psychiatry. The case in favor of such potential, we argue, is less strong unless the role of complexity, similar to that seen within the dual diagnosis field, may be demonstrated for other fields of clinical practice.
Demographic estimates to assess the translocation of a threatened New Zealand amphibian

ABSTRACT Context: Leiopelma archeyi is a threatened New Zealand amphibian species translocated for conservation purposes. A disease outbreak triggered the translocation of 70 frogs to Pureora Forest in 2006 to establish a new wild population of L. archeyi. Ten years after, 60 more frogs were translocated to this site to enhance the genetic and demographic profile of L. archeyi in Pureora Forest. Here, we analysed 14 years of capture–recapture monitoring data collected for this translocated population. Aims: Our aim was to estimate population demographic parameters that allow us to assess the demographic performance of this translocated population. Methods: We used spatially explicit capture–recapture (SECR; also called spatial capture–recapture) multi strata/session models to estimate population density and derive its rate of change over time. Key results: Here we show that the density of translocated Leiopelma archeyi in Pureora (central North Island, New Zealand) remains stable for most of the study period. After the release of 70 frogs in 2006, density varied from 0.02 frogs/m2 in April 2007 to 0.06 frogs/m2 in December 2014. After the second release of 60 frogs in 2016, density in Pureora of L. archeyi varied from 0.21 frogs/m2 in November 2016 to 0.63 frogs/m2 in November 2018. Conclusions: The study species is a long-lived k-selected species, therefore long-term monitoring (>20 years) is required to corroborate demographic indicators. Nevertheless, as the current density estimates are higher than the density estimated for this population after each release (April 2007 and November 2016), we suggest progress towards the establishment of a new wild population of L. archeyi in Pureora Forest. Implications: Translocations are a useful conservation tool for many threatened species and post-release monitoring data are the main source of information needed to empirically prove their success.
A literature review

Public-private partnerships (PPP) is used to advance health service access and quality. PPP implementation in hospitals is vital to shorten the service and quality gap. Hospitals are the most significant health budget spender, and this study aimed to identify the PPP effect on hospital performance indicators and its implementation challenges. Thirty-three inclusive articles were filtered and collected from Pubmed, ScienceDirect, Medline, and Sage Publication databases. Results showed that various articles succeeded in implementing PPP and improving the access and quality of health services. Several hospital performance indicators such as diagnosis, therapy, service waiting time, length of stay, referral rate, mortality rate, and patient satisfaction were reported to show better results. However, there was insufficient evidence to say the same on related financial indicators. Policy, resource, communication and trust, risk, and evaluation monitoring were considered challenges in PPP implementation. Its success was not only influenced by major factors such as governance model, finance, politics, and social but also was influenced by the medical practice model applied within the organization. This study contributed to whether PPP affects the hospital performance indicators.
Motivation and Limiting Factors for Adherence to Weight Loss Interventions among Patients with Obesity in Primary Care

The cornerstones of obesity management are diet, physical activity and behavioral change. However, there is considerable scientific evidence that lifestyle interventions to treat obesity are rarely implemented in primary care. The aim of this study is to analyze motivation to lose weight among patients with obesity, the resources implemented by primary care centers to promote behavioral change and the limiting factors reported by the patients themselves when attempting to lose weight. A total of 209 patients diagnosed with obesity were interviewed. The variables were obtained from both electronic clinical records (sex, age, BMI, diagnosis of metabolic syndrome and records of activities prescribed to promote behavioral change) and a self-administered personal questionnaire. A total of 67.5% of the respondents reported not having sufficient motivation to adhere to a weight loss program. Records of behavioral change activities were identified in only 3% of the clinical records reviewed. The barriers to adherence to diet and exercise plans most frequently mentioned by patients were not having a prescribed diet (27.8%), joint pain (17.7%), getting tired or bored of dieting (14.8%) and laziness (11.5%). Both the high percentage of patients reporting insufficient motivation to lose weight and the barriers to weight loss identified suggest that patients feel the need to improve their motivation, which should be promoted through primary care.
DSCAM-AS1 Long Non-Coding RNA Exerts Oncogenic Functions in Endometrial Adenocarcinoma via Activation of a Tumor-Promoting Transcriptome Profile

Accumulating evidence suggests that lncRNA DSCAM-AS1 acts tumor-promoting in various cancer entities. In breast cancer, DSCAM-AS1 was shown to be the lncRNA being most responsive to induction by estrogen receptor α (ERα). In this study, we examined the function of DSCAM-AS1 in endometrial adenocarcinoma using in silico and different in vitro approaches. Initial analysis of open-source data revealed DSCAM-AS1 overexpression in endometrial cancer (EC) (p < 0.01) and a significant association with shorter overall survival of EC patients (HR = 1.78, p < 0.01). In EC, DSCAM-AS1 was associated with endometrial tumor promotor gene PRL and with expression of ERα and its target genes TFF1 and PGR. Silencing of this lncRNA by RNAi in two EC cell lines was more efficient in ERα-negative HEC-1B cells and reduced their growth and the expression of proliferation activators like NOTCH1, PTK2 and EGR1. DSCAM-AS1 knockdown triggered an anti-tumoral transcriptome response as revealed by Affymetrix microarray analysis, emerging from down-regulation of tumor-promoting genes and induction of tumor-suppressive networks. Finally, several genes regulated upon DSCAM-AS1 silencing in vitro were found to be inversely correlated with this lncRNA in EC tissues. This study clearly suggests an oncogenic function of DSCAM-AS1 in endometrial adenocarcinoma via activation of a tumor-promoting transcriptome profile.
In Vitro Growth-Inhibitory Synergistic Effect of Zinc Pyrithione in Combination with Gentamicin against Bacterial Skin Pathogens of Livestock

Bacterial skin diseases of livestock could be a serious global threat, especially in association with overcoming bacterial resistance. Combinatory action of antimicrobial agents proves to be an effective strategy to overcome the problem of increasing antibiotic resistance of microorganisms. In this study, the in vitro combined effect of zinc pyrithione with gentamicin against bacterial skin pathogens of livestock (Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus dysgalactiae) was evaluated according to the sum of fractional inhibitory concentration indices (FICI) obtained by checkerboard method. The results showed that a combination of zinc pyrithione with gentamicin produced a strong synergistic effect (p < 0.001) against all tested streptococcal strains (with FICI values ranging from 0.20 to 0.42). Compared to that, only three out of eight S. aureus strains were highly susceptible to the combination of antimicrobial agents at single concentration (0.25 µg/mL) of zinc pyrithione with range of FICI 0.35–0.43. These findings suggest that interference between agents tested in this study can be used for the development of future veterinary pharmaceutical preparations for the treatment of bacterial skin infections of livestock.