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Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems.Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. check details Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic cell transplant (HCT) for AML. Accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity and GVL. A retrospective study of 2359 donor-recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML was performed. KIR-KIRL combinations were determined and associations with clinical outcomes examined. Relapse risk was reduced in DRP with both higher inhibitory KIR-KIRL (iKIR) and missing KIRL (mKIR) scores, with HR 0.86 (P = 0.01) & HR 0.84 (P = 0.02) respectively. The iKIR and mKIR score components were summed to give a maximal inhibitory KIR ligand (IM-KIR) score for each donor, which if it was 5, as opposed to less then 5, was also associated with a lower relapse risk, SHR 0.8 (P = 0.004). All IM = 5 donors possess KIR Haplotype B/x. Transplant-related mortality was increased among those with IM-KIR = 5, HR, 1.32 (P = 0.01). In a subset analysis of those transplanted with 8/8 HLA-matched DRP, anti-thymocyte globulin recipients with IM-KIR = 5, had a lower relapse rate HR, 0.61 (p = 0.001). This study demonstrates that HLA-matched unrelated donors with the highest inhibitory KIR content confer relapse protection, albeit with increased TRM. These donors all have KIR haplotype B. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT in recipients with AML to optimize clinical outcomes.Amblyopia is a cause of significant ocular morbidity in pediatric population and may lead to visual impairment in future life. It is caused due to formed visual deprivation or abnormal binocular interactions. Several risk factors in pediatric age group may lead to this disease. Author groups have tried managing different types of amblyopia, like anisometropic amblyopia, strabismic amblyopia and combined mechanism amblyopia, with optical correction, occlusion therapy, penalization, binocular therapy and surgery. We review historical and current management strategies of different types of amblyopia affecting children and outcomes in terms of visual acuity, binocularity and ocular deviation, highlighting evidence from recent studies. Literature searches were performed through Pubmed. Risk factors for amblyopia need to be identified in pediatric population as early in life as possible and managed accordingly, as visual outcomes in amblyopia are best if treated at the earliest. Although, monocular therapies like occlusion or penalization have been shown to be quite beneficial over the years, newer concepts related to binocular vision therapy are still evolving.
To develop and test a patient-reported outcome measure for assessing health-related quality of life (HRQOL) in surgically amenable epiphora.

Questionnaire development and validation study.

201 patients with a cause of epiphora amenable to surgical intervention, recruited across three independent centres.

The watery eye quality of life (WEQOL) questionnaire was developed and refined according to defined psychometric standards. Both surgical and non-surgical participants completed WEQOL at baseline and follow-up (>3 months), along with the Lacrimal Symptom Questionnaire (Lac-Q), RAND Short Form Health Survey (SF-36) and Glasgow Benefit Inventory (GBI). Convergent validity of WEQOL was evaluated according to correlation (R > 0.40) with each of these additional tests. Responsiveness of WEQOL to intervention was evaluated according to patient-reported success. Test-retest reliability was assessed by the Bland-Altman method and intraclass correlation (ICC) in a subset of 64 participants at baseline.

naire has been developed systematically according to modern psychometric standards and has been designed to evaluate the quality of life in patients with epiphora that is of a surgically amenable cause. In this study, it has demonstrated appropriate test-retest reliability, responsiveness and construct validity.
To evaluate retinal thickness fluctuations in patients with diabetic macular oedema (DMO) treated with anti-vascular endothelial growth factor (anti-VEGF) injections.

Visual acuity (VA) and central subfield thickness (CST) were collected at baseline, 3, 6, 9 and 12months. Retinal thickness fluctuation was quantified by standard deviation (SD) of CST across 12 months. A mixed effects regression model evaluated the relationship between CST SD and VA at 12 months. Multiple linear regression analysis was performed to investigate predictors of CST SD.

Mean baseline and 12-month VAs were 63.5 ± 15.7 and 69.0 ± 13.8 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (change = +5.1 ± 16.1 letters, p < 0.001). Mean baseline and 12-month CSTs were 396.9 ± 109.7 and 337.7 ± 100.7 μm(change = -59.2 ± 114.8 μm, p < 0.001). Retinal thickness variability across the first 12 months was 59.4 ± 43.6 μm. Stratification of patient eyes by CST SD demonstrated 9.7letters difference in 12-month VA between first and fourth quartiles. Significant predictors of CST SD include baseline CST, injection type, laser treatment, and DR stage.

Larger retinal thickness fluctuations are associated with poorer visual outcomes in eyes with DMO treated with anti-VEGF injections. Retinal thickness variability may be an important prognostic biomarker for DMO patients.
Larger retinal thickness fluctuations are associated with poorer visual outcomes in eyes with DMO treated with anti-VEGF injections. Retinal thickness variability may be an important prognostic biomarker for DMO patients.The inherited retinal diseases (IRDs) have traditionally been described phenotypically with the description evolving to incorporate more sophisticated structural and functional assessments. In the last 25 years there has been considerable advances in the understanding of underlying genetic aetiologies. The role of the ophthalmologist is now to work in a multi-disciplinary team to identify the disease-causing genotype, which might be amenable to gene-directed intervention. Visual electrophysiology is an important tool to assist the ophthalmologist in guiding the clinical geneticist to reach a final molecular diagnosis. This review outlines the physiological basis for the ISCEV standard electrophysiology tests, the role of electrophysiology in localising the functional deficit, correlation with structural findings to guide diagnosis and finally management of IRDs in the era of genomics with emphasis on the outer retina.Hypotheses and beliefs guide credit assignment - the process of determining which previous events or actions caused an outcome. Adaptive hypothesis formation and testing are crucial in uncertain and changing environments in which associations and meanings are volatile. Despite primates' abilities to form and test hypotheses, establishing what is causally responsible for the occurrence of particular outcomes remains a fundamental challenge for credit assignment and learning. Hypotheses about what surprises are due to stochasticity inherent in an environment as opposed to real, systematic changes are necessary for identifying the environment's predictive features, but are often hard to test. We review evidence that two highly interconnected frontal cortical regions, anterior cingulate cortex and ventrolateral prefrontal area 47/12o, provide a biological substrate for linking two crucial components of hypothesis-formation and testing the control of information seeking and credit assignment. Neuroimaging, targeted disruptions, and neurophysiological studies link an anterior cingulate - 47/12o circuit to generation of exploratory behaviour, non-instrumental information seeking, and interpretation of subsequent feedback in the service of credit assignment. Our observations support the idea that information seeking and credit assignment are linked at the level of neural circuits and explain why this circuit is important for ensuring behaviour is flexible and adaptive.A novel angucyclinone, 6,9-dihydroxytetrangulol, was isolated from Streptomyces lividans TK23 transformed with a kinanthraquinone biosynthetic gene cluster in which the kiqO gene was disrupted. The chemical structure was elucidated by spectroscopic analyses. It showed significant antibacterial activities with an IC50 value of 1.9 μM against Staphylococcus aureus and moderate anticancer activities against HL-60 cells.The superbug infection caused by metallo-β-lactamases (MβLs) carrying drug-resistant bacteria, specifically, New Delhi metallo-β-lactamase (NDM-1) has become an emerging threat. In an effort to develop novel inhibitors of NDM-1, thirteen thiosemicarbazones (1a-1m) were synthesized and assayed. The obtained molecules specifically inhibited NDM-1, with an IC50 in the range of 0.88-20.2 µM, and 1a and 1f were found to be the potent inhibitors (IC50 = 1.79 and 0.88 μM) using cefazolin as substrate. ITC and kinetic assays indicated that 1a irreversibly and non-competitively inhibited NDM-1 in vitro. Importantly, MIC assays revealed that these molecules by themselves can sterilize NDM-producing clinical isolates EC01 and EC08, exhibited 78-312-fold stronger activities than the cefazolin. MIC assays suggest that 1a (16 μg ml-1) has synergistic antimicrobial effect with ampicillin, cefazolin and meropenem on E. coli producing NDM-1, resulting in MICs of 4-32-, 4-32-, and 4-8-fold decrease, respectively. These studies indicate that the thiosemicarbazide is a valuable scaffold for the development of inhibitors of NDM-1 and NDM-1 carrying drug-resistant bacteria.
Website: https://www.selleckchem.com/products/gusacitinib.html
     
 
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