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Abstract Background Insulin resistance and diabetes are associated with an increased risk of frailty, and frailty is associated with cardiovascular disease and premature mortality. We aim to investigate the impact of long‐term insulin resistance trajectories on future frailty and cardiovascular risk among young adults. Methods In total, 3168 participants with a 30‐year follow‐up period. The baseline period covered the first 15 years as the exposure period. Insulin resistance was determined using the homeostasis model assessment for insulin resistance (HOMA‐IR), and three trajectories (low, moderate, and high) were constructed. The subsequent 15 years constituted the event accrual period. Frailty was assessed using a deficit accumulation mode, and cardiovascular outcomes were obtained from the 15‐year event accrual period. Results The mean age of all 3168 participants was 41.0 (37.0–43.0) years, with 1750 (55.2%) being women. Participants in the high level of insulin resistance trajectory had an increased prevalence of frailty (OR: 1.55, 95% CI: 1.05–2.30, P = 0.028). Although no statistically significant associations were observed after full adjustment, single‐factor analysis indicated association between the moderate and high trajectories and frailty progression. Additionally, participants with high level of insulin resistance trajectory were associated with an increased risk of cardiovascular disease, coronary heart disease, and stroke. A notable correlation between HOMA‐IR trajectory and cardiovascular diseases was still discernible within the subgroup where the frailty index ≥0.12 (HR: 2.12, 95% CI: 1.17–3.83, P = 0.013) (P for interaction >0.05). Conclusions Long‐term high level of insulin resistance is associated with high prevalence of frailty, and an increased risk of cardiovascular events. Emphasizing the importance of early prevention and intervention for abnormal glucose metabolism in young adults to prevent frailty and cardiovascular disease.

Abstract Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis‐on‐a‐chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real‐time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P‐selectin activation compared to connector material, polycarbonate. This ECMO thrombosis‐on‐a‐chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti‐thrombotic biomaterials to ultimately reduce medical device thrombosis, anti‐thrombotic drug use and therefore bleeding complications, leading to safer blood‐contacting medical devices.

Background: Postoperative infection is a complication of spinal fusion surgery resulting in increased patient morbidity. Strategies including intraoperative application of powdered vancomycin have been proposed to reduce the incidence of infection; however, such antimicrobial effects are short-lived. Methods: Instrumentation of the L4–L5 vertebrae was performed mimicking pedicle screw and rod fixation in 30 rats. Titanium instrumentation inoculated with either PBS or 1×105 CFU bioluminescent MRSA, along with biomimetic bone grafts infused with varying concentrations of vancomycin and 125 µg of rhBMP-2 (BioMim-rhBMP-2-VCM) were implanted prior to closure. Infection was quantified during the six-week postoperative period using bioluminescent imaging. Arthrodesis was evaluated using micro-CT. Results: Infected animals receiving a bone graft infused with low-dose (0.18 mg/g) or high-dose vancomycin (0.89 mg/g) both exhibited significantly lower bioluminescent signal over the six-week postoperative period than control animals inoculated with MRSA and implanted with bone grafts lacking vancomycin (p=.019 and p=.007, respectively). Both low and high-dose vancomycin-infused grafts also resulted in a statistically significant reduction in average bioluminescence when compared to control animals (p=.027 and p=.047, respectively), independent of time. MicroCT analysis of animals from each group revealed pseudoarthrosis only in the control group, suggesting a correlation between infection and pseudoarthrosis. MRSA-inoculated control animals also had significantly less bone volume formation on micro-CT than the PBS-inoculated control cohort (p

Experimental assays are used to determine if compounds cause a desired activity in cells. Here the authors demonstrate that computational methods can predict compound bioactivity given their chemical structure, imaging and gene expression data from historic screening libraries.

Whole-genome recoding has been shown to enable nonstandard amino acids, biocontainment and viral resistance in bacteria. Here the authors extend this to human cells using base editing to convert TAG to TAA for 33 essential genes via a single transfection followed by examining base-editing genome-wide.

Perigastric and intramural gastric hematomas rarely occur, with most cases associated with trauma, coagulopathy, and peptic ulcer disease. Furthermore, hematomas in the upper gastrointestinal tract are commonly located in the esophagus and duodenum. In this case report, we describe a hematoma masquerading as a gastric tumor on esophagogastroduodenoscopy (EGD) in a 54-year-old male presenting with melena. Initial computed tomography (CT) imaging suggested gastrointestinal stromal tumor (GIST) as the probable cause. We performed endoscopic ultrasound (EUS) with findings consistent with a perigastric hematoma, which aligned with the patient’s diagnosis of splenic vein thrombosis (SVT) and numerous collateral vessels communicating with the hematoma. Interventional radiology (IR) was consulted for further management, although we ultimately chose a conservative approach.

Conjecture II.3.6 of Spohn in [47] and Lecture 7 of Jensen–Yau in [35] ask for a general derivation of universal fluctuations of hydrodynamic limits in large-scale stochastic interacting particle systems. However, the past few decades have witnessed only minimal progress according to [26]. In this paper, we develop a general method for deriving the so-called Boltzmann–Gibbs principle for a general family of nonintegrable and nonstationary interacting particle systems, thereby responding to Spohn and Jensen–Yau. Most importantly, our method depends mostly on local and dynamical, and thus more general/universal, features of the model. This contrasts with previous work [6, 8, 24, 34], all of which rely on global and nonuniversal assumptions on invariant measures or initial measures of the model. As a concrete application of the method, we derive the KPZ equation as a large-scale limit of the height functions for a family of nonstationary and nonintegrable exclusion processes with an environment-dependent asymmetry. This establishes a first result to Big Picture Question 1.6 in [54] for nonstationary and nonintegrable ‘speed-change’ models that have also been of interest beyond KPZ [18, 22, 23, 38].

Lipid metabolism is a complex process crucial for energy production resulting in high levels of acyl-coenzyme A (acyl-CoA) molecules in the cell. Acyl-CoAs have also been implicated in inflammation, which could be possibly linked to lipoxygenase (LOX) biochemistry by the observation that an acyl-CoA was bound to human platelet 12-lipoxygenase via cryo-EM. Given that LOX isozymes play a pivotal role in inflammation, a more thorough investigation of the inhibitory effects of acyl-CoAs on lipoxygenase isozymes was judged to be warranted. Subsequently, it was determined that C18 acyl-CoA derivatives were the most potent against h12-LOX, human reticulocyte 15-LOX-1 (h15-LOX-1), and human endothelial 15-LOX-2 (h15-LOX-2), while C16 acyl-CoAs were more potent against human 5-LOX. Specifically, oleoyl-CoA (18:1) was most potent against h12-LOX (IC50 = 32 μM) and h15-LOX-2 (IC50 = 0.62 μM), stearoyl-CoA against h15-LOX-1 (IC50 = 4.2 μM), and palmitoleoyl-CoA against h5-LOX (IC50 = 2.0 μM). The inhibition of h15-LOX-2 by oleoyl-CoA was further determined to be allosteric inhibition with a Ki of 82 +/− 70 nM, an α of 3.2 +/− 1, a β of 0.30 +/− 0.07, and a β/α = 0.09. Interestingly, linoleoyl-CoA (18:2) was a weak inhibitor against h5-LOX, h12-LOX, and h15-LOX-1 but a rapid substrate for h15-LOX-1, with comparable kinetic rates to free linoleic acid (kcat = 7.5 +/− 0.4 s−1, kcat/KM = 0.62 +/− 0.1 µM−1s−1). Additionally, it was determined that methylated fatty acids were not substrates but rather weak inhibitors. These findings imply a greater role for acyl-CoAs in the regulation of LOX activity in the cell, either through inhibition of novel oxylipin species or as a novel source of oxylipin-CoAs.

Virtual reality (VR) and augmented reality (AR) have evolved since their introduction to medicine in the 1990s. More powerful software, the miniaturization of hardware, and greater accessibility and affordability enabled novel applications of such virtual tools in surgical practice. This scoping review aims to conduct a comprehensive analysis of the literature by including all articles between 2018 and 2021 pertaining to VR and AR and their use by plastic and craniofacial surgeons in a clinician-as-user, patient-specific manner. From the initial 1637 articles, 10 were eligible for final review. These discussed a variety of clinical applications: perforator flaps reconstruction, mastectomy reconstruction, lymphovenous anastomosis, metopic craniosynostosis, dermal filler injection, auricular reconstruction, facial vascularized composite allotransplantation, and facial artery mapping. More than half (60%) involved VR/AR use intraoperatively with the remainder (40%) examining preoperative use. The hardware used predominantly comprised HoloLens (40%) and smartphones (40%). In total, 9/10 Studies utilized an AR platform. This review found consensus that VR/AR in plastic and craniomaxillofacial surgery has been used to enhance surgeons’ knowledge of patient-specific anatomy and potentially facilitated decreased intraoperative time via preoperative planning. However, further outcome-focused research is required to better establish the usability of this technology in everyday practice.

The transcription-coupled repair pathway removes transcription-blocking DNA lesions, but how transcription is restored following DNA repair is not clear. Here the authors reveal that the PAF1 complex, while dispensable for the repair process, restores transcription after DNA damage.

iCn3D was initially developed as a web-based 3D molecular viewer. It then evolved from visualization into a full-featured interactive structural analysis software. It became a collaborative research instrument through the sharing of permanent, shortened URLs that encapsulate not only annotated visual molecular scenes, but also all underlying data and analysis scripts in a FAIR manner. More recently, with the growth of structural databases, the need to analyze large structural datasets systematically led us to use Python scripts and convert the code to be used in Node. js scripts. We showed a few examples of Python scripts at https://github.com/ncbi/icn3d/tree/master/icn3dpython to export secondary structures or PNG images from iCn3D. Users just need to replace the URL in the Python scripts to export other annotations from iCn3D. Furthermore, any interactive iCn3D feature can be converted into a Node. js script to be run in batch mode, enabling an interactive analysis performed on one or a handful of protein complexes to be scaled up to analysis features of large ensembles of structures. Currently available Node. js analysis scripts examples are available at https://github.com/ncbi/icn3d/tree/master/icn3dnode. This development will enable ensemble analyses on growing structural databases such as AlphaFold or RoseTTAFold on one hand and Electron Microscopy on the other. In this paper, we also review new features such as DelPhi electrostatic potential, 3D view of mutations, alignment of multiple chains, assembly of multiple structures by realignment, dynamic symmetry calculation, 2D cartoons at different levels, interactive contact maps, and use of iCn3D in Jupyter Notebook as described at https://pypi.org/project/icn3dpy.

Flooding management requires collecting real-time onsite information widely and rapidly. As an emerging data source, social media demonstrates an advantage of providing in-time, rich data in the format of texts and photos and can be used to improve flooding situation awareness. The present study shows that social media data, with additional information processed by Artificial Intelligence (AI) techniques, can be effectively used to track flooding phase transition and locate emergency incidents. To track phase transition, we train a computer vision model that can classify images embedded in social media data into four categories - preparedness, impact, response, and recovery - that can reflect the phases of disaster event development. To locate emergency incidents, we use a deep learning based natural language processing (NLP) model to recognize locations from textual content of tweets. The geographic coordinates of the recognized locations are assigned by searching through a dedicated local gazetteer rapidly compiled for the disaster affected region based on the GeoNames gazetteer and the US Census data. By combining image and text analysis, we filter the tweets that contain images of the “Impact” category and high-resolution locations to gain the most valuable situation information. We carry out a manual examination step to complement the automatic data processing and find that it can further strengthen the AI-processed results to support comprehensive situation awareness and to establish a passive hotline to inform rescue and search activities. The developed framework is applied to the flood of Hurricane Harvey in the Houston area.

Abstract Background Extensive myocardial calcification has a low incidence rate, but when the patients do have extensive myocardial cases, the prognosis is usually poor. Several sepsis-related extensive myocardial calcification cases have been reported, but there are cases of biventricular calcifications that are caused by multiple cases besides bacteremia and the treatment for it has a low percentage of success. Case presentation A 9 year old girl had an extensive biventricular calcification which is caused by multiple factors including multiple organ failure (heart, lung, liver, and kidney), aseptic cardiomyopathy, systemic inflammatory response syndrome, pulmonary hemorrhage, viral encephalitis. In this case study, the massive myocardial calcification present in the patient was classified as dystrophic. After the patient was transferred to the Intensive care unit, a series of rescue treatments such as anti-inflammatory factor storm were implemented to protect the organs. In the end, the patient was rescued from the rescue treatment procedure. After 18 months of follow-up, it was observed that the patient’s heart function returned to normal and it was observed that there was no change in myocardial calcification in the patient. Conclusion In this case study, it showcased a case of the diffused biventricular calcification that caused by multiple factors. Furthermore, the precise role of calcification on cardiac function was largely unknown and there has to be further follow-up observation on the patient.

Abstract Background α3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models. Methods The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology. Results We showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues. Conclusion LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

The pathogenesis of esophageal injury in gastroesophageal reflux disease (GERD) is incompletely understood. We modeled exposure of human esophageal myofibroblasts (HEMFs) to gastroesophageal reflux by repeated treatment with pH 4.5 and pH 4.5 bile salts and determined the effects on the epithelium in a 3D organotypic-like air-liquid interface model. Total, basal and supra-basal thickness of the epithelium were measured and immunostaining for p63, for basal (CK 14) and supra-basal (CK 4) squamous differentiation markers, and for cell proliferation (PCNA) were performed. Epithelial cell proliferation in response to HEMF conditioned media was also assessed in 2D culture. In the 3D organotypic model, total epithelial thickness increased similarly with pH 4.5 and pH 4.5 bile salt treated versus untreated and bile salt treated HEMF conditioned media. Epithelial p63 immunostaining was increased and multilayered. There was expansion of the CK14+ basal and CK4+ supra-basal layers in the epithelium established with conditioned media from pH 4.5 and pH 4.5 bile salt treated HEMFs versus untreated HEMF conditioned media. PCNA + cells per μm of tissue were unchanged in the basal layer across all treatment conditions while PCNA + cells per total DAPI + cells were decreased. In 2D culture, basal epithelial proliferation decreased with conditioned media from pH 4.5 and pH 4.5 bile salt treated HEMFs compared to conditioned media from untreated HEMF conditioned media. Secreted factors from HEMFs treated with acidic stimuli encountered in GERD increase epithelial thickness compared to secreted factors from untreated HEMFs and expand both basal and supra-basal layers. Our findings demonstrate for the first time paracrine regulation of the squamous epithelium from acid stimulated HEMFs. The effects of secreted factors from acid treated HEMFs on basal cell proliferation in this model and the mechanism mediating the increase in epithelial thickness merit further investigation.

Iatrogenic injury to the urinary system is a known complication of gynecologic surgery; therefore, intraoperative cystoscopy is frequently performed to assess for such injuries. However, if an abnormality is seen, the differential diagnosis extends beyond iatrogenic causes. A 42-year-old patient underwent a total abdominal hysterectomy and had absent efflux from the right ureteral orifice on cystoscopy. While iatrogenic injury was initially suspected, the intraoperative workup (including intravenous pyelography (IVP)) that ensued led to an empiric diagnosis of right ureteral atresia with ipsilateral renal atrophy that was then confirmed on postoperative imaging. When an abnormality is seen on cystoscopy following gynecologic surgery, it is important to maintain a broad differential diagnosis and to pursue an intraoperative workup with early involvement and close collaboration with urology.

Abstract We have previously shown myofibroblasts subjacent to the squamous epithelium in the normal human esophagus and an increase in esophagitis. Myofibroblast contribution to bone morphogenetic protein (BMP) signaling and to paracrine mediated epithelial-mesenchymal interactions in the human esophagus remains incompletely defined. We investigated BMP4 and BMP inhibitor GREM1 gene expression and protein levels in previously characterized human esophageal myofibroblast primary cultures and in a human esophageal myofibroblast cell line. We adapted human esophageal myofibroblast conditioned media into a 3D organotypic model to investigate the effect of myofibroblast secreted factors on squamous epithelial morphology, proliferation, differentiation and BMP signaling. Human esophageal myofibroblasts constitutively secrete GREM1 and increase BMP4 expression and BMP4 secretion in response to epithelial Hedgehog ligand SHH. Detection of secreted BMP4 is decreased in the presence of GREM1. Myofibroblast conditioned media increases epithelial proliferation and expression of basal markers p63 and CK14 leading to an overall increase in epithelial thickness. Epithelial BMP signaling increases with myofibroblast conditioned media. These findings were partially reversed with GREM1 inhibition. Our results demonstrate that myofibroblasts are potential sources of GREM1 and of BMP4 in the human esophagus and that human esophageal myofibroblast-epithelial paracrine interactions contribute in part to the regulation of epithelial growth.

Abstract: Concurrent genetic lesions exist in a majority of patients with hematologic malignancies. Among these, somatic mutations that activate RAS oncogenes and inactivate the epigenetic modifier ten-eleven translocation 2 (TET2) frequently co-occur in human chronic myelomonocytic leukemias (CMMLs) and acute myeloid leukemias, suggesting a cooperativity in malignant transformation. To test this, we applied a conditional murine model that endogenously expressed oncogenic NrasG12D and monoallelic loss of Tet2 and explored the collaborative role specifically within hematopoietic stem and progenitor cells (HSPCs) at disease initiation. We demonstrate that the 2 mutations collaborated to accelerate a transplantable CMML-like disease in vivo, with an overall shortened survival and increased disease penetrance compared with single mutants. At preleukemic stage, N-RasG12D and Tet2 haploinsufficiency together induced balanced hematopoietic stem cell (HSC) proliferation and enhanced competitiveness. NrasG12D/+/Tet2+/− HSCs displayed increased self-renewal in primary and secondary transplantations, with significantly higher reconstitution than single mutants. Strikingly, the 2 mutations together conferred long-term reconstitution and self-renewal potential to multipotent progenitors, a pool of cells that usually have limited self-renewal compared with HSCs. Moreover, HSPCs from NrasG12D/+/Tet2+/− mice displayed increased cytokine sensitivity in response to thrombopoietin. Therefore, our studies establish a novel tractable CMML model and provide insights into how dysregulated signaling pathways and epigenetic modifiers collaborate to modulate HSPC function and promote leukemogenesis.

Regulation of gene expression by DNA-binding transcription factors is essential for proper control of growth and development in all organisms. In this study, we annotate and characterize growth and developmental phenotypes for transcription factor genes in the model filamentous fungus Neurospora crassa. We identified 312 transcription factor genes, corresponding to 3.2% of the protein coding genes in the genome. The largest class was the fungal-specific Zn2Cys6 (C6) binuclear cluster, with 135 members, followed by the highly conserved C2H2 zinc finger group, with 61 genes. Viable knockout mutants were produced for 273 genes, and complete growth and developmental phenotypic data are available for 242 strains, with 64% possessing at least one defect. The most prominent defect observed was in growth of basal hyphae (43% of mutants analyzed), followed by asexual sporulation (38%), and the various stages of sexual development (19%). Two growth or developmental defects were observed for 21% of the mutants, while 8% were defective in all three major phenotypes tested. Analysis of available mRNA expression data for a time course of sexual development revealed mutants with sexual phenotypes that correlate with transcription factor transcript abundance in wild type. Inspection of this data also implicated cryptic roles in sexual development for several cotranscribed transcription factor genes that do not produce a phenotype when mutated.

Melanoma is a deadly skin cancer that becomes especially difficult to treat after it metastasizes. Timely identification of melanoma is critical for effective therapy, but histopathologic diagnosis can frequently pose a significant challenge to this goal. Therefore, auxiliary diagnostic tools are imperative to facilitating prompt recognition of malignant lesions. Melanoma develops as result of a number of genetic mutations, with UV radiation often acting as a mutagenic risk factor. Novel methods of genetic testing have improved detection of these molecular alterations, which subsequently revealed important information for diagnosis and prognosis. Rapid detection of genetic alterations is also significant for choosing appropriate treatment and developing targeted therapies for melanoma. This review will delve into the understanding of various mutations and the implications they may pose for clinical decision making.

The original article [1] contains an error in Fig. 2 whereby Fig. 2D has mistakenly been omitted. Fig. 2 can be viewed in its entirety – including Fig. 2D – in this Correction article.

Brain neurons and tissues respond to sublethal injury by activating endogenous protective pathways. Recently, following the failure of a large number of clinical trials for protective strategies against stroke that aim to inhibit a specific ischemia response pathway, endogenous neuroprotection has emerged as a more promising and hopeful strategy for development of therapeutics against stroke and neurodegenerative disorders. Neuroglobin (Ngb) is an oxygen-binding globin protein that is highly and specifically expressed in brain neurons. Accumulating evidence have clearly demonstrated that Ngb is an endogenous neuroprotective molecule against hypoxic/ischemic and oxidative stress-related insults in cultured neurons and animals, as well as neurodegenerative disorders such as Alzheimer’s disease, thus any pharmacological strategy that can up-regulate endogenous Ngb expression may lead to novel therapeutics against these brain disorders. In this review, we summarize recent studies about the biological function, regulation of gene expression, and neuroprotective mechanisms of Ngb. Furthermore, strategies for identification of chemical compounds that can up-regulate endogenous Ngb expression for neuroprotection against stroke and neurodegenerative disorders are discussed.

We assess whether forests contribute indirectly to the dietary diversity of rural households by supporting diverse agricultural production systems. We applied our study in a landscape mosaic in Southern Ethiopia that was divided into three zones of increasing distance to Munesa Forest - "near," "intermediate," and "distant." A variety of research tools and methods, including remote sensing, participatory methods, farm survey, and yield assessment, were employed. Diets of households were more diverse in the near zone than in the other two zones (6.58 ± 1.21, 5.38 ± 1.02, and 4.41 ± 0.77 food groups consumed daily in the near, intermediate, and distant zones, respectively). This difference was not explained by food items collected from Munesa Forest but by biomass flows from the forest to farmlands. Munesa Forest contributed an average of 6.13 ± 2.90 tons of biomass per farm and per year to the farms in the near zone, in the form of feed and fuelwood. Feed from the forest allowed for larger livestock herds in the near zone compared with the other two zones, and fuelwood from the forest reduced the need to use cattle dung as fuel in the near zone compared with the two other zones. These two biomass flows contributed to the availability of more manure to farmers closer to the forest (908 ± 853 kg farm-1, 771 ± 717 kg farm-1, and 261 ± 487 kg farm-1 in the near, intermediate, and distant zones, respectively). In turn, increased manure enabled a larger percentage of farms to cultivate a diversified homegarden (87, 64, and 39% of farms in the near, intermediate, and distant zones, respectively). Homegardens and livestock products provided the greater contribution to household dietary diversity closer to the forest.

The membrane occupation and recognition nexus protein 1 (MORN1) is highly conserved among apicomplexan parasites and is associated with several structures that have a role in cell division. Here we dissected the role of MORN1 using the relatively simple budding process of Toxoplasma gondii as a model. Ablation of MORN1 in a conditional null mutant resulted in pronounced defects suggesting a central role for MORN1 in apicoplast segregation and in daughter cell budding. Lack of MORN1 resulted in double-headed parasites. These Janus-headed parasites form two complete apical complexes but fail to assemble a basal complex. Moreover, these parasites were capable of undergoing several more budding rounds resulting in the formation of up to 16-headed parasites conjoined at the basal end. Despite this segregation defect, the mother's cytoskeleton was completely disassembled in every budding round. Overall this argues that successful completion of the budding is not required for cell cycle progression. None of the known basal complex components, including a set of recently identified inner membrane complex (IMC) proteins, localized correctly in these multi-headed parasites. These data suggest that MORN1 is essential for assembly of the basal complex, and that lack of the basal complex abolishes the contractile capacity assigned to the basal complex late in daughter formation. Consistent with this hypothesis we observe that MORN1 mutants fail to efficiently constrict and divide the apicoplast. We used the null background provided by the mutant to dissect the function of subdomains of the MORN1 protein. This demonstrated that deletion of a single MORN domain already prevented the function of MORN1 whereas a critical role for the short linker between MORN domains 6 and 7 was identified. In conclusion, MORN1 is required for basal complex assembly and loss of MORN1 results in defects in apicoplast division and daughter segregation.