The protein import apparatus of chloroplasts

Routing of cytosolically synthesized precursor proteins into chloroplasts is a specific process which involves a multitude of soluble and membrane components. In this review we wil1 focus on early events of the translocation pathway of nuclear coded plastidic precursor proteins and compare import routes for polypeptide of the outer chloroplast envelope to that of internal chloroplast compartments. A number of proteins housed in the chloroplast envelopes have been implied to be involved in the translocation process, but so far a certain function has not been assigned to any of these proteins. The only exception could be an envelope localized hsc 70 homologue which could retain the import competence of a precursor protein in transit into the organelle

COVID-19 impact on social work admissions and education in seven international universities

Inter-country Social Work admissions and educational comparisons are difficult due to variance in policy and practices between Social Work educational providers, even within the same country. However, this paper aims to provide an examination of different levels of impact that COVID-19 ‘lockdown’ had on ‘admissions to social work’ processes and on education, using examples from universities in Australia, England, Finland, Northern Ireland, Norway, Ireland and Sweden. Already we know that across these examples, admissions processes differ significantly. Variances are between selection and entry methodologies with some institutions using academic entry criteria and personal statements and interviews, while others use academic entry criteria and relevant experience or academic entry only. We also know that practicum duration is variable across providers, lasting between seventy-five and two hundred days. Despite all differences, a distinct adjustment to lockdown required a shift to virtual teaching methods for each institution. This paper seeks to explore the range of approaches adopted to lockdown in relation to practice learning placements in each example. We consider the underpinning values and principles that guided responses to these change processes in the various institutions and longer-term implications emerging from the required rapid change processes are discussed

Mild Idiopathic Infantile Hypercalcemia—Part 1: Biochemical and Genetic Findings

Context: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. Objective: This work aims to characterize the genetic associations and biochemical profile of mild IIH. Methods: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. Results: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. Conclusion: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants. Keywords: CYP24A1; genetic; hypercalcemia; nephrocalcinosis; nephrolithiasis; vitamin

Topological wave functions and heat equations

It is generally known that the holomorphic anomaly equations in topological string theory reflect the quantum mechanical nature of the topological string partition function. We present two new results which make this assertion more precise: (i) we give a new, purely holomorphic version of the holomorphic anomaly equations, clarifying their relation to the heat equation satisfied by the Jacobi theta series; (ii) in cases where the moduli space is a Hermitian symmetric tube domain $G/K$, we show that the general solution of the anomaly equations is a matrix element \IP{\Psi | g | \Omega} of the Schr\"odinger-Weil representation of a Heisenberg extension of $G$, between an arbitrary state $\bra{\Psi}$ and a particular vacuum state $\ket{\Omega}$. Based on these results, we speculate on the existence of a one-parameter generalization of the usual topological amplitude, which in symmetric cases transforms in the smallest unitary representation of the duality group $G'$ in three dimensions, and on its relations to hypermultiplet couplings, nonabelian Donaldson-Thomas theory and black hole degeneracies.Comment: 50 pages; v2: small typos fixed, references added; v3: cosmetic changes, published version; v4: typos fixed, small clarification adde

Effect of Lactobacillus acidophilus supernatants on body weight and leptin expression in rats

<p>Abstract</p> <p>Background</p> <p><it>Lactobacillus </it>extracts and supernatants have been used as probiotics in human and veterinary medicine for their ability to enhance wound healing and immunity. Previous data from our laboratory demonstrated that <it>Lactobacillus </it>supernatant (LS) stimulated wound healing, angiogenesis and proliferation of embryonic cells after topical application. This current study shows that LS after its administration into the cerebral ventricles of male rats exerts systemic effects.</p> <p>Methods</p> <p>The right lateral cerebral ventricle of young male rats was accessed through intracerebroventricular cannulation (ICV) under anesthesia and aseptic conditions. One group of control rats received saline solution, a second control group received 0.8 M lactic acid solution (to control for acidity of LS), and a third group received LS. The animals were sacrificed 12, 24, 48, 96 and 120 hours after the injection. Selected tissues were collected, fixed in 10% buffered formalin and used for immunohistochemistry and <it>in situ </it>hybridization. Other tissues were frozen and extracted for immunoblotting</p> <p>Results</p> <p>LS-injected animals had a slight decrease in body weight when compared to their initial weight and to both control groups. Using immunohistochemistry and <it>in situ </it>hybridization leptin expression was studied in multiple brain sections and peripheral adipose tissue of control and LS-injected rats. Strong cytoplasmic stain was observed by both techniques in neurons of the cerebral cortex, thalamus, hypothalamus, hippocampus and, to lesser degree, in the cells of the choroid plexus in the LS-injected rats. Control animals demonstrated much less intense staining in neurons located in the same regions using immunohistochemistry and almost no staining with <it>in situ </it>hybridization technique. Adipose tissue exhibited slight presence of leptin in LS-treated animals. In contrast no immunohistochemical staining for GM-CSF and TNFα was observed in brains from control and treated rats. Western blotting showed mild increase in leptin and leptin receptors in intestines and retroperitoneal adipose tissues of LS-injected rats.</p> <p>Conclusion</p> <p>This study demonstrates that direct administration of LS into rat CNS leads to a decrease in body weight of rats and an increase in the expression of leptin in specific areas of the brain and retroperitoneal adipose tissue.</p

Learning from Conect4children: A Collaborative Approach towards Standardization of Disease-Specific Paediatric Research Data

The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognized that there are not enough medicines tested in all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post-hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop the cross-cutting data resources that build on existing CDISC standards, in an effort to standardize paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and to analyse their use for standardizing disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardization. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were: National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardizing disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions– FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organization of further workshops and educational materials

Phocid Seal Leptin: Tertiary Structure and Hydrophobic Receptor Binding Site Preservation during Distinct Leptin Gene Evolution

The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids) have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR) binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re-inflation upon surfacing, while maintaining patent airways. We suggest that this additional surfactant requirement is met by the leptin pulmonary surfactant production pathway which normally appears only to function in the mammalian foetus

Tryptophan degradation in women with breast cancer: a pilot study

<p>Abstract</p> <p>Background</p> <p>Altered tryptophan metabolism and indoleamine 2,3-dioxygenase activity are linked to cancer development and progression. In addition, these biological factors have been associated with the development and severity of neuropsychiatric syndromes, including major depressive disorder. However, this biological mechanism associated with both poor disease outcomes and adverse neuropsychiatric symptoms has received little attention in women with breast cancer. Therefore, a pilot study was undertaken to compare levels of tryptophan and other proteins involved in tryptophan degradation in women with breast cancer to women without cancer, and secondarily, to examine levels in women with breast caner over the course of chemotherapy.</p> <p>Findings</p> <p>Blood samples were collected from women with a recent diagnosis of breast cancer (<it>n </it>= 33) before their first cycle of chemotherapy and after their last cycle of chemotherapy. The comparison group (<it>n </it>= 24) provided a blood sample prior to breast biopsy. Plasma concentrations of tryptophan, kynurenine, and tyrosine were determined. The kynurenine to tryptophan ratio (KYN/TRP) was used to estimate indoleamine 2,3-dioxygenase activity. On average, the women with breast cancer had lower levels of tryptophan, elevated levels of kynurenine and tyrosine and an increased KYN/TRP ratio compared to women without breast cancer. There was a statistically significant difference between the two groups in the KYN/TRP ratio (<it>p </it>= 0.036), which remained elevated in women with breast cancer throughout the treatment trajectory.</p> <p>Conclusions</p> <p>The findings of this pilot study suggest that increased tryptophan degradation may occur in women with early-stage breast cancer. Given the multifactorial consequences of increased tryptophan degradation in cancer outcomes and neuropsychiatric symptom manifestation, this biological mechanism deserves broader attention in women with breast cancer.</p