Control of Leaf Width by the APC/CTAD1-WL1-NAL1 Pathway in Rice

Leaf morphology is one of the most important features of the ideal plant architecture. However, the genetic and molecular mechanisms controlling leaf morphology in crops remain largely unknown, despite their central importance. Here we demonstrate that the APC/CTAD1-WL1-NAL1 pathway regulates leaf width in rice, and mutation of WL1 leads to width leaf variation. WL1 interacts with TAD1 and is degraded by APC/CTAD1, with the loss of TAD1 function resulting in narrow leaves. The WL1 protein directly binds to the regulatory region of NAL1 and recruits the corepressor TOPLESS-RELATED PROTEIN to inhibit NAL1 expression by down-regulating the level of histone acetylation of chromatin. Furthermore, biochemical and genetic analyses revealed that TAD1, WL1, and NAL1 function in a common pathway to control leaf width. Our study establishes an important framework for the APC/CTAD1-WL1-NAL1 pathway-mediated control of leaf width in rice and introduces novel perspectives for using this regulatory pathway for improving crop plant architecture.

Endoscopic Imaging Using a Multimode Optical Fibre Calibrated with Multiple Internal References

The interferometric acquisition of the transmission matrix (TM) of a multimode optical fibre (MMF), which is at the heart of multimode fibre-based endoscopic imaging methods, requires using a reference beam. Attempts to use an internal reference, that is to provide the reference in a common pathway geometry through the MMF itself, lead to a speckled reference intensity and consequential occurrence of “blind spots”—locations where insufficient optical power in the reference wave inflicts strong measurement errors. Here we show that combining a relatively small number of TMs, which are measured using different internal references, facilitates a complete elimination of blind spots, and thereby a significant enhancement of the imaging quality.

Development and application of a hybrid implementation research framework to understand success in reducing under-5 mortality in Rwanda

Background: We describe the development and testing of a hybrid implementation research (IR) framework to understand the pathways, successes, and challenges in addressing amenable under-5 mortality (U5M) – deaths preventable through health system-delivered evidence-based interventions (EBIs) – in low- and middle-income countries (LMICs). Methods: We reviewed existing IR frameworks to develop a hybrid framework designed to better understand U5M reduction in LMICs from identification of leading causes of amenable U5M, to EBI choice, identification, and testing of strategies, work to achieve sustainability at scale, and key contextual factors. We then conducted a mixed-methods case study of Rwanda using the framework to explore its utility in understanding the steps the country took in EBI-related decision-making and implementation between 2000-2015, key contextual factors which hindered or facilitated success, and to extract actionable knowledge for other countries working to reduce U5M. Results: While relevant frameworks were identified, none individually covered the scope needed to understand Rwanda’s actions and success. Building on these frameworks, we combined and adapted relevant frameworks to capture exploration, planning, implementation, contextual factors in LMICs such as Rwanda, and outcomes beyond effectiveness and coverage. Utilizing our hybrid framework in Rwanda, we studied multiple EBIs and identified a common pathway and cross-cutting strategies and contextual factors that supported the country’s success in reducing U5M through the health system EBIs. Using these findings, we identified transferable lessons for other countries working to accelerate reduction in U5M. Conclusions: We found that a hybrid framework building on and adapting existing frameworks was successful in guiding data collection and interpretation of results, emerging new insights into how and why Rwanda achieved equitable introduction and implementation of health system EBIs that contributed to the decline in U5M, and generated lessons for countries working to drop U5M.

RalA, PLD and mTORC1 Are Required for Kinase-Independent Pathways in DGKβ-Induced Neurite Outgrowth

Diacylglycerol kinase β (DGKβ) is an enzyme that converts diacylglycerol to phosphatidic acid and is mainly expressed in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain functions, including emotion and memory. To elucidate the mechanisms involved in neuronal development by DGKβ, we investigated the importance of DGKβ activity in the induction of neurite outgrowth using human neuroblastoma SH-SY5Y cells. Interestingly, both wild-type DGKβ and the kinase-negative (KN) mutant partially induced neurite outgrowth, and these functions shared a common pathway via the activation of mammalian target of rapamycin complex 1 (mTORC1). In addition, we found that DGKβ interacted with the small GTPase RalA and that siRNA against RalA and phospholipase D (PLD) inhibitor treatments abolished DGKβKN-induced neurite outgrowth. These results indicate that binding of RalA and activation of PLD and mTORC1 are involved in DGKβKN-induced neurite outgrowth. Taken together with our previous reports, mTORC1 is a key molecule in both kinase-dependent and kinase-independent pathways of DGKβ-mediated neurite outgrowth, which is important for higher brain functions.

Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity

Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life. While this phenotypic signature may be broadly similar by the time of presentation, it is likely that this is only the final common pathway with a number of possible preceding causative factors and disparate pathogenic mechanisms—i.e., aetiological heterogeneity. Certainly, there are distinguishable variants which suggest a higher degree of aetiological homogeneity such as the syndromic variants of biliary atresia splenic malformation or cat-eye syndrome, which implicate an early developmental mechanism. In others, the presence of synchronous viral infection also make this plausible as an aetiological agent though it is likely that disease onset is from the perinatal period. In the majority of cases, currently termed isolated BA, there are still too few clues as to aetiology or indeed pathogenesis.

Development and application of a hybrid implementation research framework to understand success in reducing under-5 mortality in Rwanda

Background: We describe the development and testing of a hybrid implementation research (IR) framework to understand the pathways, successes, and challenges in addressing amenable under-5 mortality (U5M) – deaths preventable through health system-delivered evidence-based interventions (EBIs) – in low- and middle-income countries (LMICs). Methods: We reviewed existing IR frameworks to develop a hybrid framework designed to better understand U5M reduction in LMICs from identification of leading causes of amenable U5M, to EBI choice, identification, and testing of strategies, work to achieve sustainability at scale, and key contextual factors. We then conducted a mixed-methods case study of Rwanda using the framework to explore its utility in understanding the steps the country took in EBI-related decision-making and implementation between 2000-2015, key contextual factors which hindered or facilitated success, and to extract actionable knowledge for other countries working to reduce U5M. Results: While relevant frameworks were identified, none individually covered the scope needed to understand Rwanda’s actions and success. Building on these frameworks, we combined and adapted relevant frameworks to capture exploration, planning, implementation, contextual factors in LMICs such as Rwanda, and outcomes beyond effectiveness and coverage. Utilizing our hybrid framework in Rwanda, we studied multiple EBIs and identified a common pathway and cross-cutting strategies and contextual factors that supported the country’s success in reducing U5M through the health system EBIs. Using these findings, we identified transferable lessons for other countries working to accelerate reduction in U5M. Conclusions: We found that a hybrid framework building on and adapting existing frameworks was successful in guiding data collection and interpretation of results, emerging new insights into how and why Rwanda achieved equitable introduction and implementation of health system EBIs that contributed to the decline in U5M, and generated lessons for countries working to drop U5M.

Murine AML12 hepatocytes allow Salmonella Typhimurium T3SS1-independent invasion and intracellular fate

Numerous studies have demonstrated the key role of the Salmonella Pathogenicity Island 1-encoded type III secretion system (T3SS1) apparatus as well as its associated effectors in the invasion and intracellular fate of Salmonella in the host cell. Several T3SS1 effectors work together to control cytoskeleton networks and induce massive membrane ruffles, allowing pathogen internalization. Salmonella resides in a vacuole whose maturation requires that the activity of T3SS1 subverts early stages of cell signaling. Recently, we identified five cell lines in which Salmonella Typhimurium enters without using its three known invasion factors: T3SS1, Rck and PagN. The present study investigated the intracellular fate of Salmonella Typhimurium in one of these models, the murine hepatocyte cell line AML12. We demonstrated that both wild-type Salmonella and T3SS1-invalidated Salmonella followed a common pathway leading to the formation of a Salmonella containing vacuole (SCV) without classical recruitment of Rho-GTPases. Maturation of the SCV continued through an acidified phase that led to Salmonella multiplication as well as the formation of a tubular network resembling Salmonella induced filaments (SIF). The fact that in the murine AML12 hepatocyte, the T3SS1 mutant induced an intracellular fate resembling to the wild-type strain highlights the fact that Salmonella Typhimurium invasion and intracellular survival can be completely independent of T3SS1.