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The history of Earth's carbon cycle reflects trends in atmospheric composition convolved with the evolution of photosynthesis. Fortunately, key parts of the carbon cycle have been recorded in the carbon isotope ratios of sedimentary rocks. The dominant model used to interpret this record as a proxy for ancient atmospheric CO2 is based on carbon isotope fractionations of modern photoautotrophs, and longstanding questions remain about how their evolution might have impacted the record. Therefore, we measured both biomass (εp) and enzymatic (εRubisco) carbon isotope fractionations of a cyanobacterial strain (Synechococcus elongatus PCC 7942) solely expressing a putative ancestral Form 1B rubisco dating to ≫1 Ga. This strain, nicknamed ANC, grows in ambient pCO2 and displays larger εp values than WT, despite having a much smaller εRubisco (17.23 ± 0.61‰ vs. 25.18 ± 0.31‰, respectively). Surprisingly, ANC εp exceeded ANC εRubisco in all conditions tested, contradicting prevailing models of cyanobacterial carbon isotope fractionation. Such models can be rectified by introducing additional isotopic fractionation associated with powered inorganic carbon uptake mechanisms present in Cyanobacteria, but this amendment hinders the ability to accurately estimate historical pCO2 from geological data. Understanding the evolution of rubisco and the CO2 concentrating mechanism is therefore critical for interpreting the carbon isotope record, and fluctuations in the record may reflect the evolving efficiency of carbon fixing metabolisms in addition to changes in atmospheric CO2.

Science education and research have the potential to drive profound change in low- and middle-income countries (LMICs) through encouraging innovation, attracting industry, and creating job opportunities. However, in LMICs, research capacity is often limited, and acquisition of funding and access to state-of-the-art technologies is challenging. The Alliance for Global Health and Science (the Alliance) was founded as a partnership between the University of California, Berkeley (USA) and Makerere University (Uganda), with the goal of strengthening Makerere University's capacity for bioscience research. The flagship program of the Alliance partnership is the MU/UCB Biosciences Training Program, an in-country, hands-on workshop model that trains a large number of students from Makerere University in infectious disease and molecular biology research. This approach nucleates training of larger and more diverse groups of students, development of mentoring and bi-directional research partnerships, and support of the local economy. Here, we describe the project, its conception, implementation, challenges, and outcomes of bioscience research workshops. We aim to provide a blueprint for workshop implementation, and create a valuable resource for bioscience research capacity strengthening in LMICs.

Schools in the United States support a large group of students requiring the assistance of augmentative and alternate communication (AAC). It is currently unknown what types of training and supports special education teachers require or are receiving to meet the needs of these students. A convenience sample of 3,200 teachers was surveyed about the following topics: (a) number and description of students who do not have a proficient way of communicating, (b) the efforts employed by teachers to support AAC adoption, and (c) the type and length of training the teachers had specific to supporting students who need communication supports. Researchers found a statistically significant association between the amounts of training the teacher received and the communication functionality of their students. In addition, teachers with more training tend to utilize a wider variety of support strategies and certain types of training may be more effective for specific modes of communication.

Prokaryotic nanocompartments, also known as encapsulins, are a recently discovered proteinaceous organelle-like compartment in prokaryotes that compartmentalize cargo enzymes. While initial studies have begun to elucidate the structure and physiological roles of encapsulins, bioinformatic evidence suggests that a great diversity of encapsulin nanocompartments remains unexplored. Here, we describe a novel encapsulin in the freshwater cyanobacterium Synechococcus elongatus PCC 7942. This nanocompartment is upregulated upon sulfate starvation and encapsulates a cysteine desulfurase enzyme via an N-terminal targeting sequence. Using cryo-electron microscopy, we have determined the structure of the nanocompartment complex to 2.2 Å resolution. Lastly, biochemical characterization of the complex demonstrated that the activity of the cysteine desulfurase is enhanced upon encapsulation. Taken together, our discovery, structural analysis, and enzymatic characterization of this prokaryotic nanocompartment provide a foundation for future studies seeking to understand the physiological role of this encapsulin in various bacteria.

Bacterial nanocompartments, also known as encapsulins, are an emerging class of protein-based 'organelles' found in bacteria and archaea. Encapsulins are virus-like icosahedral particles comprising a ~ 25-50 nm shell surrounding a specific cargo enzyme. Compartmentalization is thought to create a unique chemical environment to facilitate catalysis and isolate toxic intermediates. Many questions regarding nanocompartment structure-function remain unanswered, including how shell symmetry dictates cargo loading and to what extent the shell facilitates enzymatic activity. Here, we explore these questions using the model Thermotoga maritima nanocompartment known to encapsulate a redox-active ferritin-like protein. Biochemical analysis revealed the encapsulin shell to possess a flavin binding site located at the interface between capsomere subunits, suggesting the shell may play a direct and active role in the function of the encapsulated cargo. Furthermore, we used cryo-EM to show that cargo proteins use a form of symmetry-matching to facilitate encapsulation and define stoichiometry. In the case of the Thermotoga maritima encapsulin, the decameric cargo protein with fivefold symmetry preferentially binds to the pentameric-axis of the icosahedral shell. Taken together, these observations suggest the shell is not simply a passive barrier-it also plays a significant role in the structure and function of the cargo enzyme.

Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. SIGNIFICANCE: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

The purpose of this study was twofold: to examine the influence of instructional leadership on teachers' reports of the use of differentiated instruction in their schools and to investigate whether higher levels of differentiated instruction positively predicted student achievement. We collected teacher survey data from a sample of 95 high-poverty, rural elementary schools in Michigan and student achievement data from the state's standardized assessments. Comparing a series of means-as-outcomes models, our findings indicated that instructional leadership was positively and significantly related to teachers' reports of differentiated instructional practices regardless of school demographics and prior student achievement. Further, using multilevel structural equation modeling we found that differentiated instruction was a positive and significant predictor of student achievement. These findings are consistent with the conceptual understanding that leaders can influence schoolwide instructional practices associated with improved student achievement. We discuss significant implications of the findings for researchers and practitioners.

Estuaries have strong physicochemical gradients that lead to complex variability and often high rates of biogeochemical processes, and they are also often impacted by humans. Yet, our understanding of estuarine biogeochemistry remains skewed towards temperate latitudes. We examined seasonal and spatial variability in dissolved organic matter (DOM) and nutrients along a partly eutrophic, agricultural–urban estuary system in Southeast Asia: the Johor River and the East Johor Strait. Dissolved organic carbon (DOC) and coloured DOM (CDOM) showed non-conservative mixing, indicating significant DOM inputs along the estuary. The CDOM spectral slopes and CDOM : DOC ratios suggest that terrigenous, soil-derived DOM dominates along the Johor River, while phytoplankton production and microbial recycling are important DOM sources in the Johor Strait. CDOM properties were not unambiguous source indicators in the eutrophic Johor Strait, which is likely due to heterotrophic CDOM production. Nitrate concentrations showed conservative mixing, while nitrite concentrations peaked at intermediate salinities of 10–25. Ammonium concentrations decreased with salinity in the Johor River but increased up to 50 µ mol L -1 in the Johor Strait, often dominating the dissolved inorganic nitrogen (DIN) pool. Phosphate concentrations were low (<0.5 µ mol L -1) throughout the Johor River but increased in the Johor Strait, where DIN : phosphate ratios were typically ≥ 16 : 1. This suggests that the Johor Strait may experience phosphorus limitation and that internal recycling is likely important for maintaining high nutrient concentrations in the Johor Strait. Overall, our results indicate that the Johor River and Johor Strait are clearly not part of the same estuarine mixing continuum and that nutrient recycling processes must be quantified to understand nutrient dynamics in the Johor Strait. Moreover, our results highlight the need for better techniques for DOM source tracing in eutrophic estuaries. [ABSTRACT FROM AUTHOR]

Background: Pre-visit planning entails completing necessary tasks prior to clinic appointments. Community pharmacists (CPs) have unique knowledge about patients' medication use but do not routinely provide drug therapy reviews before clinic visits. Objectives: (1) Create and implement a business partnership between a CP and family medicine clinic (FMC) for CP provision of pre-visit medication reviews, and (2) describe the billing experience for shared patients in the FMC chronic care management (CCM) program. Methods: A prospective 8-month study in one community pharmacy and FMC in Iowa. Eligible patients were enrolled in the clinic CCM program and received their prescriptions at the CP. CPs were granted access to the clinic electronic health record (EHR), performed medication reviews, and recorded drug therapy recommendations (DTRs) in the clinic EHR. FMC physicians reviewed CP DTRs before the patient encounter. Time tracking software in the EHR recorded CP and FMC time performing CCM services. CCM revenue was prorated between parties. FMC physicians completed a survey about their experience. Results: Overall, there were 129 CP reviews performed for 95 patients. These reviews resulted in 169 DTRs and 76% were accepted by the physician. There were 71 CCM claims billed and CCM revenue was $3596 ($1796 FMC, $1800 CP). More than 90% of physicians (N = 11) indicated they reviewed CP DTRs before the patient encounter and agreed they were helpful to their practice. Conclusion: CPs completed pre-visit medication reviews and made accepted medication therapy recommendations. CCM billing provided a mechanism for CPs to receive revenue for their services. [ABSTRACT FROM AUTHOR]