Clinic study on macular epiretinal membrane in patients under the age of 40 years.

BACKGROUND: To describe the risk factors and clinical characteristics of macular epiretinal membrane (MEM) disease in patients up to the age of 40 years and to evaluate the therapeutic effect of IVTA on MEM. METHODS: Clinical records were reviewed and the etiology of each case and the age distribution data were collected in this retrospective, cohort study. The clinical characteristics of MEM and the factors affecting VA were analyzed. Additionally, we contrasted the effects of MEM peeling with and without intravitreal triamcinolone acetonide on visual acuity (VA) and central foveal thickness (CFT). RESULTS: In young patients, the incidence of partial posterior vitreous detachment (P-PVD) was considerably higher in IMEM than SMEM (P = 0.007). Furthermore, patients with stage 3 MEM had lower BCVA values than patients with stage 4 MEM (P < 0.001). Patients who live in urban had lower BCVA values than patients in rural (P < 0.001). Patients with IS/OS integrity had lower BCVA values than patients without IS/OS integrity (P < 0.001). The BCVA values in patients with IMEM were significantly lower than those of patients with SMEM (P < 0.001). BCVA was associated most commonly with etiology (P = 0.001), followed by region (P = 0.002). All patients had a decrease in logMAR Vas and CFT, but the combination of intraoperative IVTA resulted in a more significant decrease in logMAR Vas (P = 0.007) and CFT (P = 0.046). CONCLUSION: In young patients, the incidence of P-PVD was significantly higher in IMEM cases than in SMEM cases. The region, MEM stage, IS/OS integrity, and etiology influenced VA. Etiology was associated most commonly with BCVA. In individuals under 40, the combination of intraoperative IVTA resulted in a more significant decrease in logMAR Vas and CFT.

Foxn4 is a temporal identity factor conferring mid/late-early retinal competence and involved in retinal synaptogenesis.

During development, neural progenitors change their competence states over time to sequentially generate different types of neurons and glia. Several cascades of temporal transcription factors (tTFs) have been discovered in Drosophila to control the temporal identity of neuroblasts, but the temporal regulation mechanism is poorly understood in vertebrates. Mammalian retinal progenitor cells (RPCs) give rise to several types of neuronal and glial cells following a sequential yet overlapping temporal order. Here, by temporal cluster analysis, RNA-sequencing analysis, and loss-of-function and gain-of-function studies, we show that the Fox domain TF Foxn4 functions as a tTF during retinogenesis to confer RPCs with the competence to generate the mid/late-early cell types: amacrine, horizontal, cone, and rod cells, while suppressing the competence of generating the immediate-early cell type: retinal ganglion cells (RGCs). In early embryonic retinas, Foxn4 inactivation causes down-regulation of photoreceptor marker genes and decreased photoreceptor generation but increased RGC production, whereas its overexpression has the opposite effect. Just as in Drosophila, Foxn4 appears to positively regulate its downstream tTF Casz1 while negatively regulating its upstream tTF Ikzf1. Moreover, retina-specific ablation of Foxn4 reveals that it may be indirectly involved in the synaptogenesis, establishment of laminar structure, visual signal transmission, and long-term maintenance of the retina. Together, our data provide evidence that Foxn4 acts as a tTF to bias RPCs toward the mid/late-early cell fates and identify a missing member of the tTF cascade that controls RPC temporal identities to ensure the generation of proper neuronal diversity in the retina.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Tauopathy induces degeneration and impairs regeneration of sensory nerves in the cornea.

The cornea is transparent and innervated by a dense collection of sensory nerves originating from the ocular branch of the trigeminal nerve. This study was designed to comprehensively analyze alterations of corneal sub-basal nerve plexus in a mouse model of tauopathy (P301L transgenic mice) to test the possibility of using corneal nerves as a biomarker for tauopathy. Corneal sensitivity, thickness and epithelial wound healing were measured non-invasively by aeshesiometer, optical coherence tomography and fluorescein staining, respectively. Tau, corneal nerves and immune cells were examined by immunohistochemistry or Western blot. At the early stage of tauopathy, although corneal sensitivity, thickness and nerve fiber density were not greatly altered, corneal nerve abnormalities were observed in the peripheral region of young P301L mice. With aging, the density of abnormal nerves increased, while corneal sensitivity, epithelial thickness, nerve fiber density and length decreased in middle-aged P301L mice compared with WT mice. After corneal epithelial injury in young mice, no difference in reepithelialization was observed between two groups of mice, however, the regeneration of corneal nerves in P301L mice lagged behind WT mice, which was reflected by delayed recovery of corneal sensitivity, decreased corneal nerve density and length and density of CD45+ dendriform cells in P301L mice. In conclusion, our data provide compelling evidence that corneal nerves were changed in a mouse model of tauopathy in an age-dependent manner. Moreover, tau overexpression impairs corneal nerve regeneration. These results suggest that cornea may serve as a promising ocular site for the early diagnosis of tauopathy.

Longitudinal characterization of retinal vasculature alterations with optical coherence tomography angiography in a mouse model of tauopathy.

Tauopathies are a family of neurodegenerative diseases which predominately afflict the rapidly growing aging population suffering from various brain disorders including Alzheimer's disease, frontotemporal dementia with parkinsonism-17 and Pick disease. As the only visually accessible region of the central nervous system, in recent years, the retina has attracted extensive attention for its potential as a target for visualizing and quantifying emerging biomarkers of neurodegenerative diseases. Our previous study has found that retinal vascular inflammation and leakage occur at the very early stage of tauopathic mouse model. Here, we aimed to non-invasively visualize age-dependent alterations of retinal vasculature assessing the potential for using changes in retinal vasculature as the biomarker for the early diagnosis of tauopathy. Optical coherence tomography angiography (OCTA), a non-invasive depth-resolved high-resolution imaging technique was used to visualize and quantify tauopathy-induced alterations of retinal vasculature in P301S transgenic mice overexpressing the P301S mutant form of human tau and age-matched wild type littermate mice at 3, 6 and 10 months of age. We observed significant alterations of vascular features in the intermediate capillary plexus (ICP) and deep capillary plexus (DCP) but not in the superficial vascular complex (SVC) of P301S mice at early stages of tauopathy. With aging, alterations of vascular features in P301S mice became more prominent in all three vascular plexuses. Staining of retinal vasculature in flatmounts and trypsin digests of P301S mice at 10 months of age revealed decreased vessel density and increased acellular capillary formation, indicating that vascular degeneration also occurs during tauopathy. Overall, our results demonstrate that the changes in retinal vascular features accelerate during the progression of tauopathy. Vessels in the ICP and DCP may be more susceptible to tauopathy than vessels in the SVC. Since changes in retinal vasculature often precede tau pathology in the brain, non-invasive identification of retinal vascular alterations with OCTA may be a useful biomarker for the early diagnosis of tauopathy and monitoring its progression.

CXCR3 deletion aggravates corneal neovascularization in a corneal alkali-burn model.

Corneal neovascularization can cause devastating consequences including vision impairment and even blindness. Corneal inflammation is a crucial factor for the induction of corneal neovascularization. Current anti-inflammatory approaches are of limited value with poor therapeutic effects. Therefore, there is an urgent need to develop new therapies that specifically modulate inflammatory pathways and inhibit neovascularization in the cornea. The interaction of chemokines and their receptors plays a key role in regulating leukocyte migration during inflammatory response. CXCR3 is essential for mediating the recruitment of activated T cells and microglia/macrophages, but the role of CXCR3 in the initiation and promotion of corneal neovascularization remains unclear. Here, we showed that the expression of CXCL10 and CXCR3 was significantly increased in the cornea after alkali burn. Compared with WT mice, CXCR3-/- mice exhibited significantly increased corneal hemangiogenesis and lymphangiogenesis after alkali burn. In addition, exaggerated leukocyte infiltration and leukostasis, and elevated expression of inflammatory cytokines and angiogenic factor were also found in the corneas of CXCR3-/- mice subjected to alkali burn. With bone marrow (BM) transplantation, we further demonstrated that the deletion of CXCR3 in BM-derived leukocytes plays a key role in the acceleration of alkali burn-induced corneal neovascularization. Taken together, our results suggest that upregulation of CXCR3 does not exhibit its conventional action as a proinflammatory cytokine but instead serves as a self-protective mechanism for the modulation of inflammation and maintenance of corneal avascularity after corneal alkali burn.

The efficacy and safety of intravitreal injection of Ranibizumab as pre-treatment for vitrectomy in proliferative diabetic retinopathy with vitreous hemorrhage.

BACKGROUND: Intravitreal injection of anti-vascular endothelial growth factor (VEGF) has become first line therapy for diabetic macular edema. This study evaluated the efficacy and safety of intravitreal injection of Ranibizumab (IVR) as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy (PDR) patients with vitreous hemorrhage. METHODS: This pilot randomized controlled trial included 48 eyes with vitreous hemorrhage resulting from active PDR. Eyes were treated with IVR 1 or 3 days before vitrectomy or a sham subconjunctival injection 3 days before surgery. The occurrence of new tractional retinal detachment (TRD), total operation time, and intraoperative findings were compared. The concentrations of VEGF and connective tissue growth factor (CTGF) in aqueous humor and plasma collected at the time of IVR and vitrectomy were determined by ELISA. RESULTS: None of the patients who received IVR experienced new TRD. Ranibizumab injection improved intraoperative outcomes. The mean concentrations of VEGF in aqueous humor were significantly lower after than before IVR in patients who received IVR 1 and 3 days before surgery (P < 0.001 each). The CTGF/log10 (VEGF) ratio was significantly higher after than before IVR in patients who received IVR 3 days before vitrectomy (P = 0.046). CONCLUSION: Preoperative IVR is an effective and safe strategy for the surgical treatment of severe PDR combined with vitreous hemorrhage. IVR 1 and 3 days before surgery can significantly reduce VEGF content in aqueous humor and effectively improve intraoperative conditions without causing TRD. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry. Name of the registry: Exploratory analysis of effect of intravitreal ranibizumab as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy. TRIAL REGISTRATION NUMBER: ChiCTR-ONC-16009520. Date of registration: October 20, 2016. URL of trial registry record: http://www.chictr.org.cn/searchprojen.aspx.

Application of an innovative grid-based surveillance strategy to ensure elimination and prevent reintroduction of malaria in high-risk border communities in China.

Grid management is a grassroots governance strategy widely implemented in China since 2004 to improve the government's efficiency to actively find and solve problems among populated regions. A grid-based strategy surveillancing high-risk groups, including mobile and migrant populations (MMPs), in the China-Myanmar border region has played an indispensable role in promoting and consolidating the malaria elimination efforts by tracking and timely identification of potential importation or re-establishment of malaria among MMPs. A sequential mixed methods was implementated to explore the operational mechanism and best practices of the grid-based strategy including through the focus group discussions (FGDs), comparison of before and after the implementation of a grid-based strategy in the field sites, and data collection from the local health system.This paper distills the implementation mechanism and highlights the role of the grid-based strategy in the elimination and prevention of re-establishment of malaria transmission.

Plasma lipid levels and risk of primary open angle glaucoma: a genetic study using Mendelian randomization.

BACKGROUND: The causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG. METHODS: Two-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs. RESULTS: Using the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (ß = - 0.00026; 95% CI = -0.00062, 0.00011; P = 0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (ß = 0.00023; 95% CI = -0.00015, 0.00061; P = 0.238; IVW method) or TG levels (ß = - 0.00028; 95% CI = -0.00071, 0.00015; P = 0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: The present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.

Detection of novel piroplasmid species and Babesia microti and Theileria orientalis genotypes in hard ticks from Tengchong County, Southwest China.

To reveal the genetic diversity of Babesia microti and Theileria orientalis in Southwest China, we conducted a molecular survey of piroplasms in hard ticks in a China-Myanmar border county. Host infesting and questing ticks were collected from Tengchong County in 2013 and 2014. Piroplasm infection in ticks was detected by PCR, and then, phylogenetic analysis was conducted to study the genetic diversity of the pathogens identified in ticks. All in all, six piroplasm species comprising of B. microti; B. orientalis; a novel Babesia species designated Babesia sp. Tengchong, China; T. orientalis; T. luwenshuni; and an as yet undescribed piroplasmid species referred to as Piroplasmid sp. Tengchong, China, have been identified after screening goat- and cattle-attached ticks. In addition, B. bigemina has been identified by screening questing ticks. Phylogenetic analysis based on the 18S rRNA and partial ß-tubulin gene revealed two novel potentially zoonotic genotypes designated B. microti Tengchong-Type A and B. The T. orientalis genotypes identified in the present study represent the seven known genotypes 1-5, 7, and N3 as revealed by phylogenetic analysis of 18S rRNA and MPSP genes. Importantly, an additional genotype designated N4 has also been identified in this study, which brings the number of recognized T. orientalis genotypes to a total of twelve. Thus, besides the two novel species, Babesia sp. Tengchong, China, closely related to Babesia species isolated from yak and Piroplasmid sp. Tengchong, China, our study demonstrates that additional novel B. microti and T. orientalis genotypes exist in Southwest China.

Autologous Neurosensory Retinal Transplantation for Unclosed and Large Macular Holes.

PURPOSE: The aim of this study was to demonstrate the surgical technique and clinical outcome of autologous neurosensory retinal patch transplantation for recurrent large macular hole (MH)-induced retinal detachment after failed surgery with internal limiting membrane (ILM) removal or transplantation. METHODS: We reviewed 5 patients with recurrent MH-induced retinal detachment after failed surgeries with ILM removal or transplantation who underwent vitrectomy combined with autologous neurosensory retinal patch transplantations and were followed up over 6 months. In the autologous neurosensory retinal patch transplantation procedure, a small piece of neurosensory retina was removed and transplanted inside the MH. The anatomic outcomes of MH-induced retinal detachment were evaluated by fundus examinations and optical coherence tomography. The pre-operative and postoperative best-corrected visual acuities (BCVAs) were compared and the MH closure rates were measured as the main outcomes. RESULTS: A total of 5 patients (3 men and 2 women; average age 35.4 ± 18.72 years) were included in our study. Complete MH sealing was achieved in 5 eyes after autologous neurosensory retinal patch transplantations, and no complications were observed. The mean BCVA was 2.38 ± 0.57 (range 1.6-3) before surgery, and 1.46 ± 0.51 (range 1-2) at 6 postoperative months. There was a significant difference in BCVA before versus after the surgery (p < 0.05, paired t test). CONCLUSIONS: Autologous neurosensory retinal patch transplantation is an effective addition to the surgical options for large MH-induced retinal detachment after failed surgery with ILM removal or transplantation.

Effectiveness of flipped classroom combined with team-, case-, lecture- and evidence-based learning on ophthalmology teaching for eight-year program students.

BACKGROUND: This study aimed to investigate the benefits and challenges of the flipped classroom combined with team-, case-, lecture- and evidence-based learning (FC-TCLEBL) for ophthalmology teaching for eight-year program students. METHODS: FC-TCLEBL and the traditional lecture-based classroom (LBC) were compared based on student and teacher feedback questionnaires, student learning burden, and scores on standardized tests as well as their effects on the abilities of clinical thinking, scientific research, active-learning, practical application, humanistic care and communication with patients. RESULTS: Both the students and teachers were more satisfied with the FC-TCLEBL model. More students in the FC-TCLEBL group agreed that the course helped them to develop skills in creative thinking, problem solving, and teamwork. Students in the FC-TCLEBL group spent significantly more time preparing for class than those in the LBC group, but the time spent on review was significantly lower in the FC-TCLEBL group. The students from the FC-TCLEBL group performed better in a post-test on diabetic retinopathy (DR) as compared to the LBC group. CONCLUSIONS: FC-TCLEBL teaching model is effective and suitable for ophthalmology teaching.

Dynamic landscape of alternative polyadenylation during retinal development.

The development of the central nervous system (CNS) is a complex process that must be exquisitely controlled at multiple levels to ensure the production of appropriate types and quantity of neurons. RNA alternative polyadenylation (APA) contributes to transcriptome diversity and gene regulation, and has recently been shown to be widespread in the CNS. However, the previous studies have been primarily focused on the tissue specificity of APA and developmental APA change of whole model organisms; a systematic survey of APA usage is lacking during CNS development. Here, we conducted global analysis of APA during mouse retinal development, and identified stage-specific polyadenylation (pA) sites that are enriched for genes critical for retinal development and visual perception. Moreover, we demonstrated 3'UTR (untranslated region) lengthening and increased usage of intronic pA sites over development that would result in gaining many different RBP (RNA-binding protein) and miRNA target sites. Furthermore, we showed that a considerable number of polyadenylated lncRNAs are co-expressed with protein-coding genes involved in retinal development and functions. Together, our data indicate that APA is highly and dynamically regulated during retinal development and maturation, suggesting that APA may serve as a crucial mechanism of gene regulation underlying the delicate process of CNS development.

Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFß signaling to specify V2b interneurons in the spinal cord.

During development of the ventral spinal cord, the V2 interneurons emerge from p2 progenitors and diversify into two major subtypes, V2a and V2b, that play key roles in locomotor coordination. Dll4-mediated Notch activation in a subset of p2 precursors constitutes the crucial first step towards generating neuronal diversity in this domain. The mechanism behind the asymmetric Notch activation and downstream signaling events are, however, unknown at present. We show here that the Ascl1 and Neurog basic helix-loop-helix (bHLH) proneural factors are expressed in a mosaic pattern in p2 progenitors and that Foxn4 is required for setting and maintaining this expression mosaic. By binding directly to a conserved Dll4 enhancer, Foxn4 and Ascl1 activate Dll4 expression, whereas Neurog proteins prevent this effect, thereby resulting in asymmetric activation of Dll4 expression in V2 precursors expressing different combinations of proneural and Foxn4 transcription factors. Lineage tracing using the Cre-LoxP system reveals selective expression of Dll4 in V2a precursors, whereas Dll4 expression is initially excluded from V2b precursors. We provide evidence that BMP/TGFß signaling is activated in V2b precursors and that Dll4-mediated Notch signaling is responsible for this activation. Using a gain-of-function approach and by inhibiting BMP/TGFß signal transduction with pathway antagonists and RNAi knockdown, we further demonstrate that BMP/TGFß signaling is both necessary and sufficient for V2b fate specification. Our data together thus suggest that the mosaic expression of Foxn4 and proneural factors may serve as the trigger to initiate asymmetric Dll4-Notch and subsequent BMP/TGFß signaling events required for neuronal diversity in the V2 domain.

Shifting from control to elimination: analysis of malaria epidemiological characteristics in Tengchong County around China-Myanmar border, 2005-2014.

BACKGROUND: Tengchong County experienced a decreasing malaria prevalence period in 2005-2014 but the factors contributing to the trend are unclear. Herein, the malaria epidemiological data in years of 2005-2014 were collected and analysed, in order to provide evidence for subsequent effective strategic planning of malaria elimination that may be referenced by other counties with the similar elimination programmes along the China-Myanmar border. METHODS: A retrospective study was conducted to explore malaria-endemic characteristics in years 2005-2014 in Tengchong County. All individual cases from a web-based reporting system were reviewed and analysed. Local infections and imported cases were obtained from an annual reporting system. RESULTS: In total, 8321 confirmed malaria cases were recorded in this period, and 91.5% of them were reported during 2005-2010. Plasmodium vivax was the major species (n = 5867, 70.5%). Most cases (92.9%) were found in males, mainly in the age group 30-34 years. Only five deaths resulting from Plasmodium falciparum were reported, of which three occurred in 2005. The cases were mainly reported in the townships of Wuhe (18.5%), Mangbang (12.8%) and Gudong (9.3%). In addition, 147 local malaria (1.8%) and 8174 imported malaria (98.2%) were observed during 2005-2014. However, the proportion of imported malaria was more than 95% all the time and no local transmission has been observed since 2013. Moreover, Myanmar was the main imported source, with 716 cases (94.6%, 716/757) from Myanmar in 2011-2014. CONCLUSIONS: Tengchong County has made achievements in controlling malaria, with incidence at historically its lowest level. However, imported malaria has increased and poses a great threat to malaria elimination. To achieve the elimination goal and prevent the re-introduction of malaria, surveillance systems need to be well planned and managed to ensure timely case detection and prompt response targeted to the mobile and migrate population at elimination stage.

[Evaluation of Measures and Achievements of Malaria Control in Tengchong City, Yunnan Province during 2010-2015].

Objective: To evaluate the measures and achievements of malaria control in Tengchong City during 2010-2015. Methods: The malaria control information on epidemiology, foci disposal, blood detection of febrile patients, and medical treatment during 2010-2015 in Tengchong City was collected and analyzed using Microsoft Excel 2010. Results: In 2010-2015, 1 654 malaria cases were reported in Tengchong City, including 18 indigenous cases, 22 domestically mobile cases, and 1 614 imported cases from abroad, of whom 1 584 cases （98.1%） were imported from Myanmar. Most of the cases were vivax malaria（76.2%, 1 261/1 654）. No indigenous malaria cases were reported from 2013 to 2015. Blood test was conducted for 80 655 febrile patients, with a positive detection rate of 2.1%（1 654/80 655）. The positive detection rate was highest in 2010 （2.8%, 700/24 861）, lowest in 2011（1.4%, 341/23 623）, and decreased from 2012 to 2015. In addition, 1 654 cases were directly reported through online system. The 24-h case report rate during 2013-2015 was 100%. A total of 1 191 cases were investigated. The 3-day case investigation rate during 2013-2015 was 100%. A total of 1 351 endemic foci were investigated. The 7-day foci disposal rate during 2014-2015 was 100%. Conclusion: No indigenous transmission has been reported for three years in Tengchong City. However, the imported malaria remains an important problem.

Transmission Risk from Imported Plasmodium vivax Malaria in the China-Myanmar Border Region.

Malaria importation and local vector susceptibility to imported Plasmodium vivax infection are a continuing risk along the China-Myanmar border. Malaria transmission has been prevented in 3 border villages in Tengchong County, Yunnan Province, China, by use of active fever surveillance, integrated vector control measures, and intensified surveillance and response.

Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors.

The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. During mouse retinogenesis, early retinal progenitors give rise to several cell types, including ganglion, amacrine, horizontal, cone, and rod cells. It is unknown at present how each of these fates is selected from the multiple neuronal fates available to the early progenitor. By using a combination of bioinformatic, genetic, and biochemical approaches, we investigated the mechanism by which Foxn4 selects the amacrine and horizontal cell fates from multipotential retinal progenitors. These studies indicate that Foxn4 has an intrinsic activity to suppress the alternative photoreceptor cell fates of early retinal progenitors by selectively activating Dll4-Notch signaling. Gene expression and conditional ablation analyses reveal that Dll4 is directly activated by Foxn4 via phylogenetically conserved enhancers and that Dll4 can partly mediate the Foxn4 function by serving as a major Notch ligand to expand the progenitor pool and limit photoreceptor production. Our data together define a Foxn4-mediated molecular and signaling pathway that underlies the suppression of alternative cell fates of early retinal progenitors.

Onecut1 is essential for horizontal cell genesis and retinal integrity.

Horizontal cells are interneurons that synapse with photoreceptors in the outer retina. Their genesis during development is subject to regulation by transcription factors in a hierarchical manner. Previously, we showed that Onecut 1 (Oc1), an atypical homeodomain transcription factor, is expressed in developing horizontal cells (HCs) and retinal ganglion cells (RGCs) in the mouse retina. Herein, by knocking out Oc1 specifically in the developing retina, we show that the majority (∼80%) of HCs fail to form during early retinal development, implying that Oc1 is essential for HC genesis. However, no other retinal cell types, including RGCs, were affected in the Oc1 knock-out. Analysis of the genetic relationship between Oc1 and other transcription factor genes required for HC development revealed that Oc1 functions downstream of FoxN4, in parallel with Ptf1a, but upstream of Lim1 and Prox1. By in utero electroporation, we found that Oc1 and Ptf1a together are not only essential, but also sufficient for determination of HC fate. In addition, the synaptic connections in the outer plexiform layer are defective in Oc1-null mice, and photoreceptors undergo age-dependent degeneration, indicating that HCs are not only an integral part of the retinal circuitry, but also are essential for the survival of photoreceptors. In sum, these results demonstrate that Oc1 is a critical determinant of HC fate, and reveal that HCs are essential for photoreceptor viability, retinal integrity, and normal visual function.

Prognosis of South Asian Buccal Mucosa Cancer Patients in the United States: Association of Race with Overall Survival.

BACKGROUND: Squamous Cell Carcinoma (SCC) of the buccal mucosa and gingiva accounts for approximately 10% of oral and pharyngeal cancers diagnosed in the United States each year, with a disproportionally higher incidence in individuals of South Asian descent. However, little has been documented regarding trends pertaining to overall survival. Thus, this research serves to identify predictors of survival and determine if overall survival (OS) differs for South Asians compared to other races once they develop non-metastatic buccal mucosa or gingiva squamous cell carcinoma. METHODS: A population-based, cohort study of patients registered in the National Cancer Database® (NCDB) between the years 2004-2016 was performed. Kaplan-Meyer Survival Curves were executed to examine overall survival, while univariable (UVA) and multivariable analysis (MVA) was performed to determine the effect of multiple variables on OS. RESULTS: South Asians had longer median OS at 88.7 months, compared to 58.6 months and 38.3 months for Caucasians and African Americans respectively (p<0.001). In UVA, race was highly significant, but when the cohort was selected to include only those who had undergone surgical resection, no statistically significant difference remained. On MVA, lack of surgery, older age, higher grade, higher T and N stage, use of chemotherapy, higher comorbidity scores were associated with worse OS, but race was not significant. CONCLUSION: South Asians in the US with non-metastatic buccal mucosa or gingiva SCC have better OS compared to Caucasians or African Americans, likely due to younger age at diagnosis (median 59 vs. 71 and 62 years old) and more frequent surgical resection (75% vs. 72% and 64%). In MVA, South Asians have similar OS as Caucasians.