Access To Essential Maternal Health Interventions and Human Rights Violations among Vulnerable Communities in Eastern Burma

Luke Mullany and colleagues examine access to essential maternal health interventions and human rights violations within vulnerable communities in eastern Burma

Impact of Community-Based Maternal Health Workers on Coverage of Essential Maternal Health Interventions among Internally Displaced Communities in Eastern Burma: The MOM Project

Mullany and colleagues report outcomes from a project involving delivery of community-based maternal health services in eastern Burma, and report substantial increases in coverage of care

Feeding effect of selenium enriched rotifers on larval growth and development in red sea bream Pagrus major

Feeding trials were conducted to investigate the effect of selenium (Se)-enriched rotifers on growth and development of red sea bream Pagrus major larvae. Fish were reared from fertilized eggs (98% hatch rate) to 20. days post hatch (dph) at 19. °C with two different food sources; non-enriched S-type rotifers (0.0. μg. Se/g D.W., control diet) or Se-enriched rotifers (2.2. μg. Se/g D.W., Se-enriched diet) at 10. rotifers/mL, respectively. On the last day of larviculture, the Se-enriched diet accelerated growth and developmental stage of fish larvae. The larvae fed Se-enriched rotifers were advanced in the following parameters compared to those fed control diet: total length (6.06 vs 5.53. mm), standard length (5.74 vs 5.26. mm), head length (1.46 vs 1.28. mm), eye diameter (0.57 vs 0.50. mm), the number of caudal fin rays (5.8 vs 1.9), and the proportion of individuals undergoing notochord flexion (55 vs 3%). Fish larvae of 20. dph showed higher Se concentration (9.5 ± 0.2. μg/g DW) with the Se-enriched diet than with the control diet (1.3 ± 0.3. μg/g DW), but there were no significant differences in the composition of polyunsaturated fatty acids which significantly affect larval growth and development. Therefore, the feeding of Se enriched rotifers enhanced growth and development of the red sea bream P. major larvae

Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma

Transcription factor fusions (TFFs) are present in ∼30% of soft-tissue sarcomas. TFFs are not readily "druggable" in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer

Hybrid phenolic-inducible promoters towards construction of self-inducible systems for microbial lignin valorization

Abstract Background Engineering strategies to create promoters that are both higher strength and tunable in the presence of inexpensive compounds are of high importance to develop metabolic engineering technologies that can be commercialized. Lignocellulosic biomass stands out as the most abundant renewable feedstock for the production of biofuels and chemicals. However, lignin a major polymeric component of the biomass is made up of aromatic units and remains as an untapped resource. Novel synthetic biology tools for the expression of heterologous proteins are critical for the effective engineering of a microbe to valorize lignin. This study demonstrates the first successful attempt in the creation of engineered promoters that can be induced by aromatics present in lignocellulosic hydrolysates to increase heterologous protein production. Results A hybrid promoter engineering approach was utilized for the construction of phenolic-inducible promoters of higher strength. The hybrid promoters were constructed by replacing the spacer region of an endogenous promoter, P emrR present in E. coli that was naturally inducible by phenolics. In the presence of vanillin, the engineered promoters P vtac, P vtrc, and P vtic increased protein expression by 4.6-, 3.0-, and 1.5-fold, respectively, in comparison with a native promoter, P emrR. In the presence of vanillic acid, P vtac, P vtrc, and P vtic improved protein expression by 9.5-, 6.8-, and 2.1-fold, respectively, in comparison with P emrR. Among the cells induced with vanillin, the emergence of a sub-population constituting the healthy and dividing cells using flow cytometry was observed. The analysis also revealed this smaller sub-population to be the primary contributor for the increased expression that was observed with the engineered promoters. Conclusions This study demonstrates the first successful attempt in the creation of engineered promoters that can be induced by aromatics to increase heterologous protein production. Employing promoters inducible by phenolics will provide the following advantages: (1) develop substrate inducible systems; (2) lower operating costs by replacing expensive IPTG currently used for induction; (3) develop dynamic regulatory systems; and (4) provide flexibility in operating conditions. The flow cytometry findings strongly suggest the need for novel approaches to maintain a healthy cell population in the presence of phenolics to achieve increased heterologous protein expression and, thereby, valorize lignin efficiently

Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma

Significance Oncogenic transcription factors, such as the CIC-DUX4 fusion protein, constitute cancer-specific but highly challenging therapeutic targets. Consequently, pharmacologic targeting of transcription factor fusions has relied on identifying downstream actionable targets that relay fusion protein function. While informative, this approach has been limited by the divergent pleotropic effects of transcription factor fusion output. To overcome this, we have developed a mechanism-based strategy to directly degrade the CIC-DUX4 oncoprotein through ligand-dependent or pharmacologic MAPK activation. Using small-molecule drugs that block negative regulators of MAPK-ERK signaling, such as DUSP6, we reveal MAPK-mediated CIC-DUX4 degradation as an innovative therapeutic approach to targeting CIC-fused sarcoma.</jats:p