Cell birth and death in the mouse retinal ganglion cell layer

Here we describe quantitatively the birth and death of the two separate populations of neurons, ganglion cells and displaced amacrine cells, in the mouse retinal ganglion cell layer (GCL). The two cell types, which are roughly equally numerous, were distinguished pre- and postnatally by labeling the ganglion cells retrogradely with fluorescent dye. Embryos were labeled cumulatively with bromodeoxyuridine (BrdU) delivered by an osmotic minipump implanted in the mother; cell birth dates were established as having occurred before or after pump implantation. Early cohorts (GCL cells born before embryonic day [E] 11.8 and E12.8) were 98 ± 1.1% and 99 ± 0.2% ganglion cells (mean ± SEM), respectively, and a late cohort (born after E15.8) was 97 ± 1.2% displaced amacrines. Thus birth date was a strong predictor of a GCL cell's ultimate identity. Cell death in each cohort was estimated by counting cells at different time points (soon after the cohort was produced and later) and subtracting the later from the earlier number. This method avoids the problem of simultaneous birth and death that has plagued many of the earlier attempts to assess cell death. Negligible numbers died during the first week after a cell's birthday. The amount of cell death differed in the two cohorts; 48.5 ± 15% and 29.0 ± 12.4% in early and late, respectively, and most of it was postnatal. These findings disagree sharply with an earlier conclusion that ganglion cells die within 5 days of their birthdays or not at all. J. Comp. Neurol. 489:120–134, 2005. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48679/1/20615_ftp.pd

Gene duplication and functional divergence of the zebrafish insulin‐like growth factor 1 receptors

Insulin‐like growth factor (IGF) 1 receptor (IGF1R)‐mediated signaling plays key roles in growth, development, and physiology. Recent studies have shown that there are two distinct igf1r genes in zebrafish, termed igf1ra and igf1rb. In this study, we tested the hypothesis that zebrafish igf1ra and igf1rb resulted from a gene duplication event at the igf1r locus and that this has led to their functional divergence. The genomic structures of zebrafish igf1ra and igf1rb were determined and their loci mapped. While zebrafish igf1ra has 21 exons and is located on linkage group (LG) 18, zebrafish igf1rb has 22 exons and mapped to LG 7. There is a strong syntenic relationship between the two zebrafish genes and the human IGF1R gene. Using a MO‐based loss‐of‐function approach, we show that both Igf1ra and Igf1rb are required for zebrafish embryo viability and proper growth and development. Although Igf1ra and Igf1rb demonstrated a large degree of functional overlap with regard to cell differentiation in the developing eye, inner ear, heart, and muscle, they also exhibited functional distinction involving a greater requirement for Igf1rb in spontaneous muscle contractility. These findings suggest that the duplicated zebrafish igf1r genes play largely overlapping but not identical functional roles in early development and provide novel insight into the functional evolution of the IGF1R/insulin receptor gene family.— Schlueter, P. J., Royer, T., Mohamed, H. F., Laser, B., Chan, S. J., Steiner, D. F., Duan, C. Gene duplication and functional divergence of the zebrafish insulin‐like growth factor 1 receptors. FASEB J. 20, E462–E471 (2006)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154460/1/fsb2fj053882fje.pd

Importance of radiative transfer processes in urban climate models: A study based on the PALM 6.0 model system

Including radiative transfer processes within the urban canopy layer into microscale urban climate models (UCMs) is essential to obtain realistic model results. These processes include the interaction of buildings and vegetation with shortwave and longwave radiation, thermal emission, and radiation reflections. They contribute differently to the radiation budget of urban surfaces. Each process requires different computational resources and physical data for the urban elements. This study investigates how much detail modellers should include to parameterize radiative transfer in microscale building-resolving UCMs. To that end, we introduce a stepwise parameterization method to the Parallelized Large-eddy Simulation Model (PALM) system 6.0 to quantify individually the effects of the main radiative transfer processes on the radiation budget and on the flow field. We quantify numerical simulations of both simple and realistic urban configurations to identify the major and the minor effects of radiative transfer processes on the radiation budget. The study shows that processes such as surface and vegetation interaction with shortwave and longwave radiation will have major effects, while a process such as multiple reflections will have minor effects. The study also shows that radiative transfer processes within the canopy layer implicitly affect the incoming radiation since the radiative transfer model is coupled to the radiation model. The flow field changes considerably in response to the radiative transfer processes included in the model. The study identified those processes which are essentially needed to assure acceptable quality of the flow field. These processes are receiving radiation from atmosphere based on the sky-view factors, interaction of urban vegetation with radiation, radiative transfer among urban surfaces, and considering at least single reflection of radiation. Omitting any of these processes may lead to high uncertainties in the model results.publishedVersio

Causes of anterior cruciate ligament reconstruction failure: A meta-analysis

Anterior cruciate ligament (ACL) injury is one of the most common knee injuries among athletes and during sports activities for which ligament reconstruction is the optimal therapeutic procedure. Functional instability of the knee because of ACL injury is prone to relapse. Relapse is commonly reported following surgery due to various reasons. Knowing the possible causes are major key in the management of patients with an ACL tear after reconstruction. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, Cochrane library, and Google Scholar were searched for eligible articles from January 1, 2010, to December 31, 2020. The articles were selected on inclusion and exclusion criteria mentioned in the study protocol. Following the screening of all the articles, the short-listed articles were subjected to full-text review by two independent reviewers. The overall search process gave us 1571 articles in total, from which 13 were selected for meta-analysis. A total of 891 patients were included in the 13 studies evaluated with respect to the factors responsible for failure of the primary ACL reconstructive procedure. Tunnel placement error and traumatic reinjury were the most reported associated factors responsible for primary ACL reconstruction failure. However, the overall summary estimate for the two major etiologies was not significant. The P-value for overall effect was 0.76, along with a Z score of 0.30 and an I2 test value of 91%, indicating high study variability. The odd’s ratio was calculated using the Mantel-Haenszel random effects model for ACL reconstruction failure, which was 0.88. Understanding the cause of primary ACL failure and developing strategies to minimize or avoid it completely will help in reducing the incidence of ACL reconstructive failure and improve patient outcomes

Neuroethical issues in pharmacological cognitive enhancement.

This is the published manuscript. It is available online from the Wiley in Wiley Interdisciplinary Reviews: Cognitive Science here: http://onlinelibrary.wiley.com/doi/10.1002/wcs.1306/abstract;jsessionid=05002026F7F8502EFC9A9553EC8CE45C.f03t02.UNLABELLED: Neuroethics is an emerging field that in general deals with the ethics of neuroscience and the neuroscience of ethics. In particular, it is concerned with the ethical issues in the translation of neuroscience to clinical practice and in the public domain. Numerous ethical issues arise when healthy individuals use pharmacological substances known as pharmacological cognitive enhancers (PCEs) for non-medical purposes in order to boost higher-order cognitive processes such as memory, attention, and executive functions. However, information regarding their actual use, benefits, and harms to healthy individuals is currently lacking. Neuroethical issues that arise from their use include the unknown side effects that are associated with these drugs, concerns about the modification of authenticity and personhood, and as a result of inequality of access to these drugs, the lack of distributive justice and competitive fairness that they may cause in society. Healthy individuals might be coerced by social institutions that force them to take these drugs to function better. These drugs might enable or hinder healthy individuals to gain better moral and self-understanding and autonomy. However, how these drugs might achieve this still remains speculative and unknown. Hence, before concrete policy decisions are made, the cognitive effects of these drugs should be determined. The initiation of accurate surveys to determine the actual usage of these drugs by healthy individuals from different sections of the society is proposed. In addition, robust empirical research need to be conducted to delineate not only whether or not these drugs modify complex higher-order cognitive processes but also how they might alter important human virtues such as empathy, moral reasoning, creativity, and motivation in healthy individuals. WIREs Cogn Sci 2014, 5:533-549. doi: 10.1002/wcs.1306 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction

Hypermethylation of the DLC1 CpG island does not alter gene expression in canine lymphoma

<p>Abstract</p> <p>Background</p> <p>This study is a comparative epigenetic evaluation of the methylation status of the <it>DLC1 </it>tumor suppressor gene in naturally-occurring canine lymphoma. Canine non-Hodgkin's lymphoma (NHL) has been proposed to be a relevant preclinical model that occurs spontaneously and may share causative factors with human NHL due to a shared home environment. The canine <it>DLC1 </it>mRNA sequence was derived from normal tissue. Using lymphoid samples from 21 dogs with NHL and 7 normal dogs, the methylation status of the promoter CpG island of the gene was defined for each sample using combined bisulfite restriction analysis (COBRA), methylation-specific PCR (MSP), and bisulfite sequencing methods. Relative gene expression was determined using real-time PCR.</p> <p>Results</p> <p>The mRNA sequence of canine <it>DLC1 </it>is highly similar to the human orthologue and contains all protein functional groups, with 97% or greater similarity in functional regions. Hypermethylation of the 5' and 3' flanking regions of the promoter was statistically significantly associated with the NHL phenotype, but was not associated with silencing of expression or differences in survival.</p> <p>Conclusion</p> <p>The canine <it>DLC1 </it>is constructed highly similarly to the human gene, which has been shown to be an important tumor suppressor in many forms of cancer. As in human NHL, the promoter CpG island of <it>DLC1 </it>in canine NHL samples is abnormally hypermethylated, relative to normal lymphoid tissue. This study confirms that hypermethylation occurs in canine cancers, further supporting the use of companion dogs as comparative models of disease for evaluation of carcinogenesis, biomarker diagnosis, and therapy.</p