Vascular Endothelial Growth Factor In Cortical Development

One of the characteristics unique to mammalian evolution is the development of the neocortex. The neocortex is a highly ordered six-layered structure, the development of which is tightly regulated. The formation of the cortex is concomitantly dependent upon an outward expansion of the neuroepithelium, a tissue from which all of the neuronal subtypes and glia are born and differentiated, and the investment of blood vessels from the outer pial surface. Orchestration of neurogenesis and blood vessel investment, or angiogenesis, in the cortex is critical for development; however, these processes are often studied independent of one another. While independent investigation of neurogenesis can simplify a study, by removing the potentially confounding variable of angiogenesis, this reductionist approach ignores the fact that the two processes, neurogenesis and angiogenesis, are dependent upon each other and intimately linked. Many growth factors and transcription factors have roles in both angiogenesis and neurogenesis. Members of both the Notch and Inhibitor of DNA binding (Id) family of proteins have been shown to guide differentiation in neural stem cells, as well as to direct the migration of newly sprouting vessels. Another growth factor that has been linked to both angiogenesis and neurogenesis is Vascular endothelial growth factor A (Vegf). Vegf is a pleiotrophic factor linked to a broad range of effects in neurovascular systems including proliferation, migration and differentiation. Vegf and its receptors (VegfR1, VegfR2, Nrp1, and Nrp2) are expressed in many of the cell types critical for neurogenesis and angiogenesis. The Vegf gene is expressed as three main isoforms in the mouse brain, and these isoforms have distinct biochemical properties based on the presence or absence of a heparin sulfate proteoglycan (HSPG) binding domain. Vegf isoforms with the full HSPG-binding domain are not diffusible in the microenvironment (Vegf188) without proteolytic cleavage, those with a partial HSPG-binding domain are partially diffusible (Vegf164), and those lacking the domain entirely are freely diffusible (Vegf120). The different biochemical properties of the Vegf isoforms allow gradients of Vegf to form in the microenvironment. We hypothesize that it is through these differing gradients of Vegf isoforms, that Vegf can orchestrate neurogenesis and angiogenesis in the cortex. To investigate this, we took advantage of a transgenic mouse model in which mice express single Vegf isoforms (Vegf120 or Vegf188), or combinations of Vegf isoforms (Vegf120/188), and lack the Vegf164 isoform. These mice represent a loss of function model (no Vegf164) as well as misexpression models through which we can test the role of Vegf in cortical neurogenesis and angiogenesis

Emotionally-focused therapy and couples from collectivistic cultures: Impact on relationship satisfaction

This study aims to explore the efficacy of EFT in increasing marital satisfaction in couples of a non-Western, collectivist origin. Our treatment group, consisting of 30 couples of a non-Western, collectivist origin will participate in 14 sessions of EFT in which their marital satisfaction will be measured pretreatment, posttreatment, and at 6 and 12 month follow-ups. Utilizing a control group consisting of 30 couples of a Western, non-collectivist origin receiving the same treatment, we seek to explore how cultural factors such as a collectivist mindset and the de-emphasis of individual’s feelings and emotions might affect the efficacy of EFT in one or more directions

Searching for Novel Biomarkers Using a Mouse Model of CLN3-Batten Disease

CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten disease. Interestingly, we found that significant differences between Batten and non-disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten disease can influence potential biomarkers of the disease

Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of \u3ci\u3eFOXP1\u3c/i\u3e

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G\u3eA (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization

Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum

Procollagen requires COPII coat proteins for export from the endoplasmic reticulum (ER). SEC24 is the major component of the COPII proteins that selects cargo during COPII vesicle assembly. There are four paralogs (A to D) of SEC24 in mammals, which are classified into two subgroups. Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans and sec24d mutant fish also recapitulate this phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. To explore this possibility, we generated Sec24d knockout (KO) mice. Homozygous KO mice died prior to bone development. When we analyzed embryonic and extraembryonic tissues of mutant animals, we observed tissue-dependent defects of procollagen processing and ER export. The spacial patterns of these defects mirrored with SEC24B deficiency. By systematically knocking down the expression of Sec24 paralogs, we determined that, in addition to SEC24C and SEC24D, SEC24A and SEC24B also contribute to collagen secretion. In contrast, fibronectin 1 preferred either SEC24C or SEC24D. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A

Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries (Nature, (2022), 611, 7934, (115-123), 10.1038/s41586-022-05165-3)

In the version of this article initially published, the name of the PRECISE4Q Consortium was misspelled as “PRECISEQ” and has now been amended in the HTML and PDF versions of the article. Further, data in the first column of Supplementary Table 55 were mistakenly shifted and have been corrected in the file accompanying the HTML version of the article

Large Methane Emission Fluxes Observed From Tropical Wetlands in Zambia

Methane (CH4) is a potent greenhouse gas with a warming potential 84 times that of carbon dioxide (CO2) over a 20-year period. Atmospheric CH4 concentrations have been rising since the nineteenth century but the cause of large increases post-2007 is disputed. Tropical wetlands are thought to account for ∼20% of global CH4 emissions, but African tropical wetlands are understudied and their contribution is uncertain. In this work, we use the first airborne measurements of CH4 sampled over three wetland areas in Zambia to derive emission fluxes. Three independent approaches to flux quantification from airborne measurements were used: Airborne mass balance, airborne eddy-covariance, and an atmospheric inversion. Measured emissions (ranging from 5 to 28 mg m−2 hr−1) were found to be an order of magnitude greater than those simulated by land surface models (ranging from 0.6 to 3.9 mg m−2 hr−1), suggesting much greater emissions from tropical wetlands than currently accounted for. The prevalence of such underestimated CH4 sources may necessitate additional reductions in anthropogenic greenhouse gas emissions to keep global warming below a threshold of 2°C above preindustrial levels

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients