Development of Midbrain Dopaminergic Neurons and the Advantage of Using hiPSCs as a Model System to Study Parkinson's Disease.

Midbrain dopaminergic (mDA) neurons are significantly impaired in patients inflicted with Parkinson's disease (PD), subsequently affecting a variety of motor functions. There are four pathways through which dopamine elicits its function, namely, nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular dopamine pathways. SHH and Wnt signalling pathways in association with favourable expression of a variety of genes, promotes the development and differentiation of mDA neurons in the brain. However, there is a knowledge gap regarding the complex signalling pathways involved in development of mDA neurons. hiPSC models have been acclaimed to be effective in generating complex disease phenotypes. These models mimic the microenvironment found in vivo thus ensuring maximum reliability. Further, a variety of therapeutic compounds can be screened using hiPSCs since they can be used to generate neurons that could carry an array of mutations associated with both familial and sporadic PD. Thus, culturing hiPSCs to study gene expression and dysregulation of cellular processes associated with PD can be useful in developing targeted therapies that will be a step towards halting disease progression.

Prospects of microRNAs as therapeutic biomarkers in non-small cell lung cancer.

Lung Cancer, the second most common cancer worldwide, remains the leading cause of cancer-related deaths, contemporarily. More than 85% of identified lung cancer cases are comprised of non-small-cell lung carcinoma (NSCLC). Despite the best advancements in the realm of NSCLC therapy, the five-year survival period of NSCLC patients remains unchanged. Underlying complex molecular heterogeneity, delay in early detection resulting in progression of the disease to its advanced stage and acquired resistance of NSCLC cells during therapy have posed additional challenges for circumventing the discrepancies in treatment strategy. microRNAs (miRNAs) are a class of non-coding RNAs, identified as molecules playing an indispensable role in tumorigenesis & progression and metastasis of several cancers, including NSCLC, either by possessing tumor suppressor or by oncogenic functions. As observed across several studies, miRNA dysregulation has been recognised as a causative mechanism behind NSCLC tumorigenesis. In this review, we discuss the role of miRNAs in NSCLC tumor progression caused by their dysregulation, thereby stating their potential therapeutic application in NSCLC as therapeutic biomarkers. We have also highlighted the recent findings of some of the most widely studied tumor suppressor (miR-486, miR-7 miR-34), and oncogene miRNAs (miR-21, miR-224, miR-135b) that can be further explored for its therapeutic potentialities in the management of NSCLC.

Learning From Video: A Meta-Analysis of the Video Deficit in Children Ages 0 to 6 Years.

Young children often learn less from video than face-to-face presentations. Meta-regression models were used to examine the average size of this difference (video deficit) and investigate moderators. An average deficit of about half of a standard deviation was reported across 122 independent effect sizes from 59 reports, involving children ages 0-6 years. Moderator analyses suggested (a) the deficit decreased with age, (b) object retrieval studies showed larger deficits than other domains, and (c) there was no difference between studies using live versus prerecorded video. Results are consistent with a multiple-mechanism explanation for the deficit. However, the analyses highlighted potential quality and publication bias issues that may have resulted in overestimation of the effect and should be addressed by future researchers.

Peroxisome compartmentalization of a toxic enzyme improves alkaloid production.

Eukaryotic cells compartmentalize metabolic pathways in organelles to achieve optimal reaction conditions and avoid crosstalk with cytosolic factors. We found that cytosolic expression of norcoclaurine synthase (NCS), the enzyme that catalyzes the first committed reaction in benzylisoquinoline alkaloid biosynthesis, is toxic in Saccharomyces cerevisiae and, consequently, restricts (S)-reticuline production. We developed a compartmentalization strategy that alleviates NCS toxicity while promoting increased (S)-reticuline titer. This strategy is achieved through efficient targeting of toxic NCS to the peroxisome while, crucially, taking advantage of the free flow of metabolite substrates and products across the peroxisome membrane. We demonstrate that expression of engineered transcription factors can mimic the oleate response for larger peroxisomes, further increasing benzylisoquinoline alkaloid titer without the requirement for peroxisome induction with fatty acids. This work specifically addresses the challenges associated with toxic NCS expression and, more broadly, highlights the potential for engineering organelles with desired characteristics for metabolic engineering.

Publisher Correction: Modular and tunable biological feedback control using a de novo protein switch.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Modular and tunable biological feedback control using a de novo protein switch.

De novo-designed proteins1-3 hold great promise as building blocks for synthetic circuits, and can complement the use of engineered variants of natural proteins4-7. One such designer protein-degronLOCKR, which is based on 'latching orthogonal cage-key proteins' (LOCKR) technology8-is a switch that degrades a protein of interest in vivo upon induction by a genetically encoded small peptide. Here we leverage the plug-and-play nature of degronLOCKR to implement feedback control of endogenous signalling pathways and synthetic gene circuits. We first generate synthetic negative and positive feedback in the yeast mating pathway by fusing degronLOCKR to endogenous signalling molecules, illustrating the ease with which this strategy can be used to rewire complex endogenous pathways. We next evaluate feedback control mediated by degronLOCKR on a synthetic gene circuit9, to quantify the feedback capabilities and operational range of the feedback control circuit. The designed nature of degronLOCKR proteins enables simple and rational modifications to tune feedback behaviour in both the synthetic circuit and the mating pathway. The ability to engineer feedback control into living cells represents an important milestone in achieving the full potential of synthetic biology10,11,12. More broadly, this work demonstrates the large and untapped potential of de novo design of proteins for generating tools that implement complex synthetic functionalities in cells for biotechnological and therapeutic applications.

De novo design of bioactive protein switches.

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix 'cage' with a single interface that can interact either intramolecularly with a terminal 'latch' helix or intermolecularly with a peptide 'key'. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cage-key systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering.

Young of the year bluefish (Pomatomus saltatrix) as a bioindicator of estuarine health: Establishing a new baseline for persistent organic pollutants after Hurricane Sandy for selected estuaries in New Jersey and New York.

Atlantic coastal bays of the US are essential habitat for young of year bluefish (Pomatomus saltatrix). Their residence in these estuaries during critical life stages, high lipid content, and piscivory make bluefish an ideal bioindicator species for evaluating estuarine health. Individual whole fish from four estuaries impacted by Hurricane Sandy were collected in August 2013, analyzed for a suite of persistent organic pollutants (POPs) including polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides and evaluated using health metrics. Concentrations in whole bluefish differed by estuary; however, concentrations for many POPs decreased or were similar to those observed prior to the hurricane. Prevalence of the ectoparasitic gill isopod (Lironeca ovalis) varied by estuary and no relationships between contaminants and lesions were observed. Bluefish should be considered for monitoring programs and, if sampled frequently, could be an effective bioindicator of incremental and episodic changes in contaminants within aquatic food webs.

Single-Session Alcohol Interventions for Heavy Drinking College Students: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to conduct a meta-analysis summarizing the effectiveness of brief, single-session interventions to reduce alcohol use among heavy drinking college students. METHOD: A comprehensive literature search identified 73 studies comparing the effects of single-session brief alcohol intervention with treatment-as-usual or no-treatment control conditions on alcohol use among heavy drinking college students. Random-effects meta-analyses with robust variance estimates were used to synthesize 662 effect sizes, estimating the average overall effect of the interventions and the variability in effects across a range of moderators. RESULTS: An overall mean effect size of g = 0.18, 95% CI [0.12, 0.24] indicated that, on average, single-session brief alcohol interventions significantly reduced alcohol use among heavy drinking college students relative to comparison conditions. There was minimal variability in effects associated with study method and quality, general study characteristics, participant demographics, or outcome measure type. However, studies using motivational enhancement therapy/motivational interviewing (MET/MI) modalities reported larger effects than those using psychoeducational therapy (PET) interventions. Further investigation revealed that studies using MET/ MI and feedback-only interventions, but not those using cognitive-behavioral therapy or PET modalities, reported average effect sizes that differed significantly from zero. There was also evidence that long-term effects were weaker than short-term effects. CONCLUSIONS: Single-session brief alcohol interventions show modest effects for reducing alcohol consumption among heavy drinking college students and may be particularly effective when they incorporate MET/MI principles. More research is needed to directly compare intervention modalities, to develop more potent interventions, and to explore the persistence of long-term effects.

Language-minority learners in special education: rates and predictors of identification for services.

Using data from the Early Childhood Longitudinal Study-Kindergarten Cohort, this study was designed to investigate proportional representation, identification rates, and predictors of language-minority (LM) learners in special education using a nationally representative sample of kindergarten, first graders, and third graders. The findings indicate that although LM learners were underrepresented in special education in kindergarten and first grade, they were overrepresented in third grade across all disability categories. LM status, teacher ratings of language and literacy skills, and reading proficiency level were significant predictors of placement in special education. Kindergarten teacher ratings of language and literacy skills were highly predictive of subsequent placement in special education. The implications for developing a model of early identification, the response-to-intervention model in particular, for LM learners at risk for academic difficulties are discussed.

Evaluating prey capture by larval mummichogs (Fundulus heteroclitus) as a potential biomarker for contaminants.

We evaluated larval prey capture as a "behavioral biomarker" of contamination by examining feeding behavior of larval mummichogs (Fundulus heteroclitus) from many different sites, including a severely contaminated "Superfund" site, moderately contaminated sites, and reference areas. Prey capture ability was related to sediment contaminant levels. The levels of contaminants at a site were highly correlated with each other, so that the impact of individual contaminants was confounded. The number of captures of brine shrimp by mummichog larvae from all sites was highly variable, but significant negative correlations of prey capture were seen with mercury, lead, zinc, cadmium, and PCBs. As observed previously with adults, polyaromatic hydrocarbons (PAHs) did not appear to impair prey capture ability. The only site in which prey capture rates of 8-day old larvae were severely affected was the most highly contaminated Superfund site, Berry's Creek, NJ. This implies that larval prey capture is not as sensitive a behavioral biomarker for contamination as adult behavior studied previously.