Miracle-dz/UniFAR-FTUs huggingface dataset:
Positive and Negative Regulation of Vertebrate Separase by Cdk1-Cyclin B1 May Explain Why Securin Is Dispensable*

Background: Separase, the trigger protease of eukaryotic anaphase, remains regulated in the absence of its inhibitor, securin. Results: Cdk1-cyclin B1 triggers precipitation of separase by phosphorylation but stabilizes it by inhibitory binding. Conclusion: Only separase that is first complexed by Cdk1-cyclin B1 can later be activated by cyclin B1 degradation. Significance: These minimal requirements of separase regulation could explain the faithful execution of anaphase in the absence of securin. Sister chromatid cohesion is established during replication by entrapment of both dsDNAs within the cohesin ring complex. It is dissolved in anaphase when separase, a giant cysteine endopeptidase, cleaves the Scc1/Rad21 subunit of cohesin, thereby triggering chromosome segregation. Separase is held inactive by association with securin until this anaphase inhibitor is destroyed at the metaphase-to-anaphase transition by ubiquitin-dependent degradation. The relevant ubiquitin ligase, the anaphase-promoting complex/cyclosome, also targets cyclin B1, thereby causing inactivation of Cdk1 and mitotic exit. Although separase is essential, securin knock-out mice are surprisingly viable and fertile. Capitalizing on our previous finding that Cdk1-cyclin B1 can also bind and inhibit separase, we investigated whether this kinase might be suitable to maintain faithful timing and execution of anaphase in the absence of securin. We found that, similar to securin, Cdk1-cyclin B1 regulates separase in both a positive and negative manner. Although securin associates with nascent separase to co-translationally assist proper folding, Cdk1-cyclin B1 acts on native state separase. Upon entry into mitosis, Cdk1-cyclin B1-dependent phosphorylation of Ser-1126 renders separase prone to inactivation by aggregation/precipitation. Stable association of Cdk1-cyclin B1 with phosphorylated separase counteracts this tendency and stabilizes separase in an inhibited yet activatable state. These opposing effects are suited to prevent premature cleavage of cohesin in early mitosis while ensuring timely activation of separase by anaphase-promoting complex/cyclosome-dependent degradation of cyclin B1. Coupling sister chromatid separation with subsequent exit from mitosis by this simplified mode might have been the common scheme of mitotic control prior to the evolution of securin.
The Role of Interleukin-6/GP130 Signaling in Prostate Cancer Progression and its Contribution to Bone Metastasis Morbidity

Abstract : Prostate cancer (PrCa) is the leading cause of male cancer death in Western civilization. Interleukin-6 (IL-6) is a cytokine implicated in primary PrCa growth and survival post-androgen withdrawal. Moreover, IL-6 is strongly associated with bone metastasis, a major cause of morbidity in PrCa patients. This project aims to investigate the IL-6 axis in a novel in vivo PrCa xenograft model (BM18) of androgen-dependent growth (McCulloch et al., 2005) and osteosclerotic bone metastasis. The IL- 6/gp130 signaling pathway was also investigated using PrCa bone metastases from human patient biopsies. Pursuit of the aims outlined herein will greatly improve our understanding of the role of IL- 6/gp130 signaling in prostate cancer growth, regression, survival post-androgen withdrawal and bone metastasis. This study provides a unique opportunity to examine the role of IL-6/gp130 signaling in a model that closely mimics human PrCa growth, progression and regression as well as osteosclerotic bone remodeling. Disease recurrence and osteosclerotic metastases are poorly understood processes that cause immense suffering, culminating in a painful demise. Understanding the role of IL-6/gp130 signaling molecules in this disease may lead to identification of novel targets and therapeutic strategies to improve and extend the quality of life for PrCa patients.
'If we can't do more, let's do it differently!': using appreciative inquiry to promote innovative ideas for better health care work environments.

AIM To examine the use of appreciative inquiry to promote the emergence of innovative ideas regarding the reorganization of health care services. BACKGROUND With persistent employee dissatisfaction with work environments, experts are calling for radical changes in health care organizations. Appreciative inquiry is a transformational change process based on the premise that nurses and health care workers are accumulators and producers of knowledge who are agents of change. METHODS A multiple embedded case study was conducted in two interdisciplinary groups in outpatient cancer care to better understand the emergence and implementation of innovative ideas. RESULTS The appreciative inquiry process and the diversity of the group promoted the emergence and adoption of innovative ideas. Nurses mostly proposed new ideas about work reorganization. Both groups adopted ideas related to interdisciplinary networks and collaboration. A forum was created to examine health care quality and efficiency issues in the delivery of cancer care. CONCLUSION This study makes a contribution to the literature that examines micro systems change processes and how ideas evolve in an interdisciplinary context. IMPLICATIONS FOR NURSING MANAGEMENT The appreciative inquiry process created an opportunity for team members to meet and share their successes while proposing innovative ideas about care delivery. Managers need to support the implementation of the proposed ideas to sustain the momentum engendered by the appreciative inquiry process.
One-year prospective study on the effect of workplace bullying on long-term sickness absence.

AIMS To examine the effect of workplace bullying on long-term sickness absence using a prospective design. BACKGROUND Although bullying has been identified as a serious problem in the health care sector, little attention has been given to the possible effect of workplace bullying on long-term sickness absence and its implications. METHODS The sample consisted of 9949 employees (78.1% response rate) working in the elderly-care sector in 36 Danish municipalities. Long-term sickness absence was measured by linking a survey on work and health to the national register on social transfer payments. RESULTS Among the 1171 employees that were bullied at work in the past 12 months, 1.8% were frequently bullied and 7.3% were occasionally bullied. The risk of long-term sickness absence was higher for those frequently bullied even after adjusting for psychosocial work characteristics [rate ratio (RR) = 1.92, confidence interval (CI): 1.29-2.84; P < 0.05]. CONCLUSION This is the first prospective study that explored the effect of both frequent and occasional bullying on long-term sickness absence among health care employees. The effect of frequent bullying on long-term sickness absence was independent of the psychosocial work characteristics. IMPLICATIONS FOR NURSING MANAGEMENT Workplace bullying might impact negatively the quality of care and patients safety.
TRWG developmental pathway for biospecimen-based assessment modalities

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of NCI's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of biospecimen-based assays that utilize biomarkers for the detection, diagnosis, prognosis, and assessment of response to cancer treatment. The biospecimen-based assessment modality (BM) pathway was conceived not as comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper introduces the pathway in the context of prior work and discusses key challenges associated with the biomarker development process in light of the pathway.
Implications for nurse managers arising from immigrant women's experience of midwifery care in a hospital.

AIM This paper focuses on implications for nurse managers to support midwives in delivering nursing care to immigrant mothers in some government hospitals in Gauteng, South Africa. BACKGROUND Immigration and poverty in Africa has led to midwives providing nursing care to immigrant mothers in a culturally sensitive environment. This necessitates an environment in which nurse managers should support midwives in caring for these mothers as unique individuals. METHOD An exploratory, descriptive phenomenological design was followed. The target population included nine immigrant mothers living in the inner centre of Johannesburg who, for the first time, attended, had antenatal clinics, laboured and gave birth at a Government Hospital in the Gauteng province of South Africa. After purposive sampling, phenomenological interviews were conducted until data saturation occurred. RESULTS The findings indicate that nurse managers should ensure that midwifery care of immigrant mothers comply with the ethical-legal context of the South African constitution. Actions should be taken in combating issues related to impaired maternal-midwife relationship, lack of cultural sensitivity and psychological distress. CONCLUSION The delivery of maternity care to immigrant mothers is below the standard expected in the South African context. IMPLICATIONS FOR NURSING MANAGEMENT The nurse manager should support midwives to ensure an environment to care for immigrant mothers in maternity wards.
Combining State and Voluntary Provision: Using Volunteers in Home-Based Child Protection - Preliminary Indications for the Mental Wellbeing of Family Members

Background: In the UK there is a policy initiative to encourage volunteering to promote community participation and engagement in society. ‘Volunteers in Child Protection’ is a scheme promoting volunteers to work alongside statutory child care workers in complex child protection cases. Trained volunteers offer practical and emotional support to families. This project evaluated the experience of the scheme from the perspective of the families, the statutory workers and the mental health outcomes for the family.Methods: This is a small scale mixed methods study of families subject to child protection procedures, who are very hard to engage in research. The study examines the impact of volunteers using standardized, repeat measures of mental wellbeing, plus semi-structured interviews with parents, volunteers and stakeholders.Results: Family experience – families value their volunteers involvement and report increased confidence in their parenting capacity. Volunteer experience – volunteers feel they are performing a worthwhile service and report improvement in the families. Mental wellbeing outcomes - on referral two thirds of the families are dysfunctional, children have emotional and behavioral disturbance and some mothers have clinical levels of depression. Repeat measures indicate improvements during the volunteer intervention.Conclusions: Volunteers can work effectively with complex families, working alongside statutory professional involvement. The volunteers are highly valued by the service users who report improved confidence in their parenting skills and improvements in their own mental wellbeing. Repeat measures support the service user’s reports of improvement in children’s emotional and behavioral wellbeing, family functioning and mother’s mental wellbeing.
Eosinophil-associated Ribonuclease 11 Is a Macrophage Chemoattractant*

Background: The RNase A ribonucleases are enzymatically active secretory proteins that can promote innate immunity. Results: Mouse eosinophil-associated RNase (mEar) 11 is expressed in response to IL-33 and promotes TLR2-independent macrophage activation. Conclusion: Mouse Ear 11 is an RNase A ribonuclease with unique expression, targets, and functions. Significance: This work elucidates the versatility of RNase A ribonucleases in promoting innate immunity. RNase A is the prototype of an extensive family of divergent proteins whose members share a unique disulfide-bonded tertiary structure, conserved catalytic motifs, and the ability to hydrolyze polymeric RNA. Several members of this family maintain independent roles as ribonucleases and modulators of innate immunity. Here we characterize mouse eosinophil-associated RNase (Ear) 11, a divergent member of the eosinophil ribonuclease cluster, and the only known RNase A ribonuclease expressed specifically in response to Th2 cytokine stimulation. Mouse Ear 11 is differentially expressed in somatic tissues at baseline (brain ≪ liver < lung < spleen); systemic stimulation with IL-33 results in 10–5000-fold increased expression in lung and spleen, respectively. Ear 11 is also expressed in response to protective priming of the respiratory mucosa with Lactobacillus plantarum; transcripts are detected both locally in lung as well as systemically in bone marrow and spleen. Mouse Ear 11 is enzymatically active, although substantially less so than mEar 1 and mEar 2; the relative catalytic efficiency (kcat/Km) of mEar 11 is diminished ∼1000–1500-fold. However, in contrast to RNase 2/EDN and mEar 2, which have been characterized as selective chemoattractants for CD11c+ dendritic cells, mEar 11 has prominent chemoattractant activity for F4/80+CD11c− tissue macrophages. Chemoattractant activity is not dependent on full enzymatic activity, and requires no interaction with the pattern recognition receptor, Toll-like receptor 2 (TLR2). Taken together, this work characterizes a divergent RNase A ribonuclease with a unique expression pattern and function, and highlights the versatility of this family in promoting innate immunity.
Communication between the N and C Termini Is Required for Copper-stimulated Ser/Thr Phosphorylation of Cu(I)-ATPase (ATP7B)*

Background: Copper levels stimulate trafficking and hyperphosphorylation of the copper transporter ATP7B. Results: Hyperphosphorylation can occur prior to exit from the TGN and requires intact N and C terminus but is not required for apically directed trafficking. Conclusion: Copper-stimulated hyperphosphorylation of ATP7B occurs on the C terminus. Significance: Hyperphosphorylation and apically directed trafficking are independent events. The Wilson disease protein ATP7B exhibits copper-dependent trafficking. In high copper, ATP7B exits the trans-Golgi network and moves to the apical domain of hepatocytes where it facilitates elimination of excess copper through the bile. Copper levels also affect ATP7B phosphorylation. ATP7B is basally phosphorylated in low copper and becomes more phosphorylated (“hyperphosphorylated”) in elevated copper. The functional significance of hyperphosphorylation remains unclear. We showed that hyperphosphorylation occurs even when ATP7B is restricted to the trans-Golgi network. We performed comprehensive phosphoproteomics of ATP7B in low versus high copper, which revealed that 24 Ser/Thr residues in ATP7B could be phosphorylated, and only four of these were copper-responsive. Most of the phosphorylated sites were found in the N- and C-terminal cytoplasmic domains. Using truncation and mutagenesis, we showed that inactivation or elimination of all six N-terminal metal binding domains did not block copper-dependent, reversible, apical trafficking but did block hyperphosphorylation in hepatic cells. We showed that nine of 15 Ser/Thr residues in the C-terminal domain were phosphorylated. Inactivation of 13 C-terminal phosphorylation sites reduced basal phosphorylation and eliminated hyperphosphorylation, suggesting that copper binding at the N terminus propagates to the ATP7B C-terminal region. C-terminal mutants with either inactivating or phosphomimetic substitutions showed little effect upon copper-stimulated trafficking, indicating that trafficking does not depend on phosphorylation at these sites. Thus, our studies revealed that copper-dependent conformational changes in the N-terminal region lead to hyperphosphorylation at C-terminal sites, which seem not to affect trafficking and may instead fine-tune copper sequestration.
Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment*

Background: Amyloidogenic human lung surfactant protein C (SP-C) is a transmembrane peptide generated from pro-SP-C, containing a luminal BRICHOS domain. Results: BRICHOS inserts partly in ER membranes, binds unfolded SP-C, and prevents misfolding. Conclusion: Disease-associated pro-SP-C mutations result in loss of membrane insertion and binding to SP-C. Significance: Co-translational folding of transmembrane pro-SP-C is inefficient and membrane insertion of BRICHOS promotes correct folding. Surfactant protein C (SP-C) is a novel amyloid protein found in the lung tissue of patients suffering from interstitial lung disease (ILD) due to mutations in the gene of the precursor protein pro-SP-C. SP-C is a small α-helical hydrophobic protein with an unusually high content of valine residues. SP-C is prone to convert into β-sheet aggregates, forming amyloid fibrils. Nature's way of solving this folding problem is to include a BRICHOS domain in pro-SP-C, which functions as a chaperone for SP-C during biosynthesis. Mutations in the pro-SP-C BRICHOS domain or linker region lead to amyloid formation of the SP-C protein and ILD. In this study, we used an in vitro transcription/translation system to study translocon-mediated folding of the WT pro-SP-C poly-Val and a designed poly-Leu transmembrane (TM) segment in the endoplasmic reticulum (ER) membrane. Furthermore, to understand how the pro-SP-C BRICHOS domain present in the ER lumen can interact with the TM segment of pro-SP-C, we studied the membrane insertion properties of the recombinant form of the pro-SP-C BRICHOS domain and two ILD-associated mutants. The results show that the co-translational folding of the WT pro-SP-C TM segment is inefficient, that the BRICHOS domain inserts into superficial parts of fluid membranes, and that BRICHOS membrane insertion is promoted by poly-Val peptides present in the membrane. In contrast, one BRICHOS and one non-BRICHOS ILD-associated mutant could not insert into membranes. These findings support a chaperone function of the BRICHOS domain, possibly together with the linker region, during pro-SP-C biosynthesis in the ER.
How to perform a small animal post mortem in practice

This article provides a detailed protocol for performing a thorough post-mortem examination in small animal practice, together with details of the equipment required and information on collecting the best samples for further tests such as histopathology, microbiology and toxicology. It also discusses some of the reasons for performing a post mortem, and areas to consider carefully before embarking on the process itself — obtaining the relevant history, health and safety considerations and note-taking. Remember that not all post-mortem examinations will result in a definitive diagnosis, and in many cases further tests such as histopathology will still be required; owners should be made aware of this.
The N-terminal Set-β Protein Isoform Induces Neuronal Death*

Background: Set-β protein can suppress or promote neuronal recovery. We investigated Set-β isoforms to understand its different roles in neurons. Results: Neurons express several Set-β transcripts, Set-β proteins localize to different compartments, and the N-terminal Set-β induces neuronal death. Conclusion: N-terminal Set-β induces neuronal death. Other isoforms could play different roles. Significance: Different Set-β isoforms could underlie its diverse roles in neurons. Set-β protein plays different roles in neurons, but the diversity of Set-β neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-β are altered in Alzheimer disease, cleavage of Set-β leads to neuronal death after stroke, and the full-length Set-β regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-β isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-β-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-β transcript lacking the nuclear localization signal and demonstrated that the full-length (∼39-kDa) Set-β is localized predominantly in the nucleus, whereas a shorter (∼25-kDa) Set-β isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-β cleavage product can induce neuronal death.
HCO3−-independent pH Regulation in Astrocytes in Situ Is Dominated by V-ATPase* ♦

Background: Astrocyte pH regulation is essential for brain function. Results: Bicarbonate-independent acid load recovery in whole-mount astrocytes was achieved primarily via V-ATPase, which also held astrocytes at a basic resting pH. Conclusion: V-ATPase is the major bicarbonate-independent H+ extruder in a whole-mount astrocyte population. Significance: High levels of V-ATPase expression will isolate astrocyte pH regulation from cytoplasm changes in other ion species. The mechanisms of HCO3−-independent intracellular pH (pHi) regulation were examined in fibrous astrocytes within isolated neonatal rat optic nerve (RON) and in cultured cortical astrocytes. In agreement with previous studies, resting pHi in cultured astrocytes was 6.82 ± 0.06 and inhibition of the V-ATPase H+ pump by Cl− removal or via the selective inhibitor bafilomycin had only a small effect upon resting pHi and recovery following an acid load. In contrast, resting pHi in RON astrocytes was 7.10 ± 0.04, significantly less acidic than that in cultured cells (p < 0.001), and responded to inhibition of V-ATPase with profound acidification to the 6.3–6.5 range. Fluorescent immuno-staining and immuno-gold labeling confirmed the presence V-ATPase in the cell membrane of RON astrocyte processes and somata. Using ammonia pulse recovery, pHi recovery in RON astrocyte was achieved largely via V-ATPase with sodium-proton exchange (NHE) playing a minor role. The findings indicate that astrocytes in a whole-mount preparation such as the optic nerve rely to a greater degree upon V-ATPase for HCO3−-independent pHi regulation than do cultured astrocytes, with important functional consequences for the regulation of pH in the CNS.
C-type cytochromes wire electricity-producing bacteria to electrodes.

Fil: Busalmen, Juan Pablo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnologia de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingenieria. Instituto de Investigaciones en Ciencia y Tecnologia de Materiales; Argentina