Surgical Outcomes of IOL Iris Suture Fixation in Eyes with Residual Capsule Support.

PURPOSE: To evaluate the safety and refractive outcomes of eyes following IOL iris suture fixation (ISF). SETTING: Private Practice, Los Angeles, CA. DESIGN: Non-randomized and unmasked retrospective chart review. METHODS: We included eyes that underwent IOL exchange or repositioning with ISF with at least 270 degrees of capsular support. We excluded eyes with less than 270 degrees of capsular support, and eyes with iris damage. The primary outcome measures included incidence of cystoid macular edema (CME), IOL dislocation requiring refixation, and chronic inflammation. Secondary outcome measures included worsening IOP control, retinal tear or detachment, worsening of CDVA, and corneal decompensation. Refractive outcomes for 26 subgrouped eyes included mean and median spherical equivalent refraction accuracy (SERA), and % eyes within 0.5D and 1D of the refractive target. RESULTS: The study included 53 eyes of 50 patients. CME: 2/53 (3.8%), IOL dislocation requiring refixation: 2/53 (3.8%), chronic inflammation: 1/53 (1.9%), worsening IOP control: 5/53 (9.4%), retinal tear or detachment: 2/53 (3.8%). No patient experienced worsening of CDVA from baseline or corneal decompensation. Mean SERA ± standard deviation: -0.35 ± 0.29D, median SERA: -0.37D. Of the 26 eyes subgrouped for refractive analysis, 73% were within 0.5D and 100% were within 1D of the desired refractive outcome. CONCLUSIONS: ISF can offer stability for sulcus fixated IOLs provided there is some residual capsule support. Although there are measurable complications, there is a relatively low side effect profile. The refractive error tended to be myopic, indicating the need for further refinement of IOL power predictive formulae.

Clinical outcomes and complications following intraocular lens exchange in the setting of an open or intact posterior capsule.

PURPOSE: To assess whether there are added risks when performing intraocular lens (IOL) exchange in the setting of an open posterior capsule (OPC) when compared with a closed posterior capsule (CPC) IOL exchange. SETTING: Private practice, Los Angeles, California. DESIGN: Nonrandomized and unmasked retrospective chart review. METHODS: Eyes undergoing IOL exchange solely to relieve optical symptoms, with open or intact posterior capsules, were included. Eyes undergoing IOL exchange due to IOL malposition or dislocation were excluded. Eyes with preexisting, uncontrolled glaucoma and inflammation and eyes with a visual potential worse than 20/40 (Snellen) were also excluded. The main outcome measures were the postoperative complications compared between the OPC and CPC groups. RESULTS: 90 eyes of 75 patients undergoing IOL exchange were included in this study; 38/90 eyes had an OPC, and 52/90 eyes had a CPC. 3/38 in the OPC group and 2/52 in the CPC group experienced worsening intraocular pressure control. 1/38 in the OPC group experienced chronic inflammation. 2/38 in the OPC group and 2/52 in the CPC group experienced cystoid macular edema. 1/52 in the CPC group experienced a retinal tear. Statistically or clinically significant differences in postoperative complications between the OPC and CPC groups were not found. CONCLUSIONS: In the hands of an experienced surgeon, IOL exchange with an OPC appear red to be just as safe as IOL exchange with a CPC; when deemed necessary, experienced surgeons may perform an IOL exchange safely in the presence of an OPC.

Complete genome sequence of a novel secovirid infecting cassava in the Americas.

We report the complete genome sequence of a field isolate of a novel bipartite secovirid infecting cassava in Colombia, provisionally named "cassava torrado-like virus" (CsTLV). The genome sequence was obtained using Oxford Nanopore Technology, and the 5' ends were confirmed by RACE. The RNA1 is 7252 nucleotides (nt) long, encoding a polyprotein of 2336 amino acids (aa) containing the typical "replication block", conserved torradovirus motifs, and a Maf/Ham1 domain, which is not commonly found in viral genomes. The RNA2 is 4469 nt long and contains two overlapping ORFs encoding proteins of 226 and 1179 aa, showing the characteristic genome arrangement of members of the genus Torradovirus.

Protocolo de rehabilitación multimodal en pacientes sometidos a cirugía electiva del tracto gastrointestinal. Estudio prospectivo comparativo multicéntrico / Multimodal rehabilitation protocol in patients undergoing elective surgery of the gastrointestinal tract. Prospective multicentre comparative study

Los protocolos de rehabilitación multimodal están diseñados para minimizar la disfunción de órganos y lograr la recuperación acelerada en el postoperatorio. Objetivo General: Determinar si la aplicación del protocolo de rehabilitación multimodal favorece la recuperación acelerada en pacientes quirúrgicos electivos en comparación con el manejo tradicional. Metodología: Se realizó un estudio multicéntrico aleatorizado con la participación de cuatro hospitales en diferentes regiones del país. La investigación fue de tipo prospectivo de corte longitudinal, comparativo, donde los pacientes fueron asignados al azar, un grupo estudio (n=142) a quienes se les aplicó el protocolo y un grupo control (n=100) manejados de acuerdo con conductas tradicionales. Resultados: La estancia hospitalaria para el grupo estudio fue de 1,8 ± 1,2 días, mientras que para el grupo control fue de 6,3 ± 3,87 días (p < 0,05). En cuanto a las complicaciones post operatorias el 88,7% de los pacientes del grupo estudio evolucionaron favorablemente y 11,26% presentaron complicaciones menores, mientras que 30% de los pacientes del grupo control presentaron complicaciones tales como infección de sitio quirúrgico 13%, dehiscencia de anastomosis 5% y vómitos 12% (p < 0,05). Conclusión: Con la aplicación del protocolo de rehabilitación multimodal se logró que la tasa de complicaciones fuera significativamente menor en el grupo estudio al compararla con el grupo control, por ello se sugiere la aplicación del mismo dentro de las realidades de nuestros hospitales, además de ser una excelente herramienta para lograr una recuperación más temprana en el post operatorio y disminuir la estancia hospitalaria(AU)

The multimodal rehabilitation protocols are designed to minimize organ dysfunction in the postoperative period and achieve accelerated postoperative recovery. General Objective: To determine whether the application of multimodal rehabilitations protocols promotes rapid recovery in elective surgical patients compared with traditional management. Methodology: A multicenter randomized involving four hospitals in different regions of the country study was conducted. The research was prospective, longitudinal, comparative court, patients were randomized in study group (n = 142) who applied the protocol and a control group (n = 100) managed according to traditional behaviors. Results: The hospital stay for the study group was 1.8 ± 1.2 days, while the control group the average was 6.3 ± 3.87 days (p < 0.05). Regarding postoperative complications, 88.7% of the study group patients evolved favorably and 11.26% presented minor complications, while 30% of the control group patients presented complications such as surgical site infection 13%, anastomotic dehiscence 5 % and vomiting 12% (p < 0.05).Conclusion: With the application of the multimodal rehabilitation protocol, it was achieved that the rate of complications was significantly lower in the study group when compared with the control group, therefore it is suggested to apply it within the realities of our hospitals, in addition to being an excellent tool to achieve an earlier recovery in the postoperative period and reduce hospital stay(AU)

Expectant management in non-severe pre-eclampsia, obstetric and perinatal outcomes in a high complexity hospital in Neiva (Colombia) / Manejo expectante en preeclampsia no severa, resultados obstétricos y perinatales en un hospital de alta complejidad, Neiva, Colombia

ABSTRACT Objective: To determine the incidence of preeclampsia and identify maternal and perinatal outcomes in patients with initial expectant management. Materials and methods: Historical cohort of pregnant women with non-severe preeclampsia seen in a public high-complexity referral institution between June 2015 and May 2016. Convenience sampling was used. Sociodemographic, clinical and paraclinical characteristics were measured as well as maternal and perinatal outcomes; the incidence of non-severe preeclampsia is determined and a descriptive analysis is performed. Results: The incidence rate ratio of non-severe preeclampsia was 3%. 86 pregnant women with a mean age of 28 years (SD ± 8.1) were included in the cohort. The mean gestational age at the time of diagnosis was 29 weeks (SD ± 3.1). 47.7% of the pregnant women with an initial diagnosis of non-severe preeclampsia converted to severe preeclampsia and 27 neonates experienced at least one complication, the most frequent being admission to the Neonatal Intensive Care Unit (27.9%). Conclusion: the major maternal complication in patients with non-severe preeclampsia was transition to severe preeclampsia identified in around half of the patients, and perinatal complications in around one third of the pregnant mothers. Therefore, a strict control of the patients with non-severe preeclampsia and expectant management is required.

RESUMEN Objetivo: determinar la incidencia de preeclampsia no severa e identificar los resultados maternos y perinatales en pacientes a quienes se les realizó manejo expectante como conducta inicial. Materiales y métodos: estudio de cohorte histórica, en gestantes con preeclampsia no severa que fueron atendidas en una institución pública de referencia de alta complejidad entre junio de 2015 y mayo de 2016. Se realizó muestreo por conveniencia. Se midieron las características sociodemográficas, clínicas y paraclínicas, los desenlaces maternos y perinatales; se determina la razón de incidencia de preeclampsia no severa y se realiza análisis descriptivo. Resultados: la razón de incidencia de preeclampsia no severa fue del 3%. Ingresaron a la cohorte 86 gestantes, con media de edad de 28 años (DE ± 8,1). La media de edad gestacional al momento del diagnóstico fue 29 semanas (DE ± 3,1). El 47,7% de las gestantes con diagnóstico inicial de preeclampsia sin características de severidad presentó conversión a preeclampsia severa y 27 recién nacidos presentaron al menos una complicación, la más frecuente fue el ingreso a Unidad de Cuidado Intensivo Neonatal en un 27,9%. Conclusión: de la mitad de las pacientes y complicaciones perinatales en cerca de un tercio de las gestantes, por lo que se requiere un estricto control de la pacientes con preclamsia no severa y manejo expectante.

Correction: Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.

[This corrects the article DOI: 10.1371/journal.pbio.1002197.].

The phenotype of peritoneal mouse macrophages depends on the mitochondria and ATP/ADP homeostasis.

Different macrophage subtypes have different morphologies/shapes and functions. Naïve M0 macrophages are elongated. Pro-inflammatory M1 that produce the bactericidal molecule iNos are round. Anti-inflammatory M2 macrophages that produce the pro-healing enzyme Arg-1 are highly elongated. We showed previously that the morphologies of M0 and M2 but not M1 macrophages are RhoA-dependent. Macrophage-specific deletion of RhoA causes the extreme elongation (hummingbird phenotype) of M0 and M2 but not M1 macrophages. The M1 and M2 macrophages also differ in their metabolic status. Here, we studied the effect of the oxidative phosphorylation inhibitors, antimycin A and oligomycin A, at a suboptimal dose, which depolarizes mitochondria but does not eliminate mitochondrial functions, on the mitochondria/energy production and phenotype of wild-type and RhoA-deleted M0, M1 and M2 peritoneal mouse macrophages. We found that, while untreated M1 macrophages had the lowest and the M2 had the highest level of ATP the ATP/ADP ratio was nearly identical between M0, M1 and M2 macrophages. Inhibitor treatment resulted in approximately 60% increase in ATP level and ATP/ADP ratio in M0 and M2 macrophages, and decrease in the level of filamentous (F) actin, and these changes correlated with a drastic shortening/tail retraction of M0 and M2 macrophages, and decreased expression of Arg-1 in M2 macrophages. The treatment of M1 macrophages caused only a 30% increase in the ATP level and ATP/ADP ratio, and while it did not affect the shape of M1 macrophages, it increased the production of iNos. This indicates that the maintenance of mouse macrophage phenotypes depends on mitochondrial function and ATP/ADP homeostasis.

Regulation of B cell fate, survival, and function by mitochondria and autophagy.

B cells are responsible for protective antibody production after differentiation into antibody-secreting cells during humoral immune responses. From early B cell development in the bone marrow, to their maturation in the periphery, activation in the germinal center, and differentiation into plasma cells or memory B cells, B cells display ever-changing functions and properties. Autophagy and mitochondria play important roles in B cell development, activation, and differentiation to accommodate the phenotypic and environmental changes encountered over the lifetime of the cell. Among their many functions, mitochondria and autophagy generate energy, mediate cell survival, and produce/eliminate reactive oxygen species that can serve as signal molecules to regulate differentiation. As B cells mature and differentiate into plasma or memory cells, both autophagic and mitochondrial functions undergo significant changes. In this review, we aim to provide an overview of the role of the autophagosome and mitochondria in regulating B cell fate, survival, and function. Moreover, we will discuss the interplay between these two highly metabolic organelles during B cell development, maturation, and differentiation.

Supervivencia de cáncer gástrico en el occidente de Honduras, estudio piloto: 2002-2012 / Survival of Gastric Cancer in Western Honduras Pilot study: 2002-2012

Antecedentes: El cáncer gástrico es la segunda causa de muerte por cáncer globalmente. En Honduras la incidencia en la década pasada fue de 39 y 21 por 100,000 habitantes para hombres y mujeres, respectivamente. En 2008 IARC (GLOBOCAN) colocó a Honduras como el país con más alta incidencia de cáncer gástrico en Latinoamérica. Objetivo: Determinar la supervivencia en pacientes diagnosticados con cáncer gástrico en el occidente de Honduras entre los años 2002-2012. Métodos: Se diseñó un es- tudio de cohorte retrospectivo de pacientes diagnosticados con cáncer gástrico en el Hospital de Occidente (2002-2012). Una muestra de 144 pacientes fue seleccionada de un total de 490 para obtener un nivel de confianza de 95%. La recolección de datos se obtuvo mediante autopsia verbal. Se analizaron los factores pronósticos de supervivencia mediante modelos de razón de riesgos proporcio - nales de Cox (CI:95%) Resultados: La relación hombre/mujer fue 2.8:1. La media de edad fue 63.29 años. La supervivencia global a cinco años fue 9.39%. Entre los pacientes que recibieron terapia dual (cirugía y quimioterapia), se encontró un aumento estadísti- camente significativo de la supervivencia (10.42%,p=0.048). Entre la localizaci ón proximal (28.95%) y distal (56.58%) se observó diferencia estadísticamente significativa (p=0.03). No hubo diferencia estadísticamente significativa entre hallazgos macroscópicos (Borrmann) y microscópicos (Lauren). Discusión: Este estudio representa el primer esfuerzo para estimar la supervivencia de cáncer gástrico en Honduras. La supervivencia podría estar ligada a la localización de la lesión primaria y al tipo de tratamiento. Se espera desarrollar estudios con mayor cobertura, para responder a estas preguntas...(AU)

Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.

We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.

[Survival of Gastric Cancer in Western Honduras Pilot study: 2002-2012]. / SUPERVIVENCIA DE CÁNCER GÁSTRICO EN EL OCCIDENTE DE HONDURAS ESTUDIO PILOTO: 2002­2012.

Background: Gastric cancer is the second leading cause of cancer death globally. In Honduras the incidence in the last decade was 39 and 21 per 100,000 inhabitants for men and women, respectively. In 2008 IARC (GLOBOCAN) placed Honduras as the country with the highest incidence of gastric cancer in Latin America. Methods: A retrospective cohort study of patients diagnosed with gastric cancer at the Hospital de Occidente between 2002-2012 was designed. A sample of 144 patients was selected from a total of 490 to obtain a confidence level of 95%. The data collection was obtained by verbal autopsy. Prognostic factors of survival were analyzed using Cox proportional hazards ratio models (CI: 95%). Outcomes: The male/female ratio was 2.8:1. The mean age was 63.29 years. Overall five-year survival was 9.39%. Among patients receiving dual therapy (surgery and chemotherapy), a statistically significant increase in survival was found (10.42%, p=0.048). Between the proximal (28.95%) and distal (56.58%) locations also a statistically significant difference was observed (p=0.03). There was no statistically significant difference in the macroscopic (Borrmann) and microscopic findings (Lauren). Disscusion: This study represents the first effort to estimate survival of gastric cancer in Honduras. Survival may be linked to the location of the primary lesion and the type of treatment. It is expected to develop studies with greater coverage, to answer these questions.

Dynamin Regulates Autophagy by Modulating Lysosomal Function.

Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ∼1200 chemically induced mutations on the X chromosome in Drosophila fat body clones and discovered that shibire (shi) plays an essential role in starvation-induced autophagy. shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome-lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation (ALR) through its excision activity. Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.

WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.

The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. Under energy-sufficient conditions, the TTT-Pontin/Reptin complex promotes mTORC1 dimerization and mTORC1-Rag interaction, which are critical for mTORC1 activation. We show that WAC is a regulator of energy-mediated mTORC1 activity. In a Drosophila screen designed to isolate mutations that cause neuronal dysfunction, we identified wacky, the homolog of WAC. Loss of Wacky leads to neurodegeneration, defective mTOR activity, and increased autophagy. Wacky and WAC have conserved physical interactions with mTOR and its regulators, including Pontin and Reptin, which bind to the TTT complex to regulate energy-dependent activation of mTORC1. WAC promotes the interaction between TTT and Pontin/Reptin in an energy-dependent manner, thereby promoting mTORC1 activity by facilitating mTORC1 dimerization and mTORC1-Rag interaction.

Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.

Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.

Correction: the retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration.

[This corrects the article DOI: 10.1371/journal.pbio.1001847.].

A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis.

Autophagy helps deliver sequestered intracellular cargo to lysosomes for proteolytic degradation and thereby maintains cellular homeostasis by preventing accumulation of toxic substances in cells. In a forward mosaic screen in Drosophila designed to identify genes required for neuronal function and maintenance, we identified multiple cacophony (cac) mutant alleles. They exhibit an age-dependent accumulation of autophagic vacuoles (AVs) in photoreceptor terminals and eventually a degeneration of the terminals and surrounding glia. cac encodes an α1 subunit of a Drosophila voltage-gated calcium channel (VGCC) that is required for synaptic vesicle fusion with the plasma membrane and neurotransmitter release. Here, we show that cac mutant photoreceptor terminals accumulate AV-lysosomal fusion intermediates, suggesting that Cac is necessary for the fusion of AVs with lysosomes, a poorly defined process. Loss of another subunit of the VGCC, α2δ or straightjacket (stj), causes phenotypes very similar to those caused by the loss of cac, indicating that the VGCC is required for AV-lysosomal fusion. The role of VGCC in AV-lysosomal fusion is evolutionarily conserved, as the loss of the mouse homologues, Cacna1a and Cacna2d2, also leads to autophagic defects in mice. Moreover, we find that CACNA1A is localized to the lysosomes and that loss of lysosomal Cacna1a in cerebellar cultured neurons leads to a failure of lysosomes to fuse with endosomes and autophagosomes. Finally, we show that the lysosomal CACNA1A but not the plasma-membrane resident CACNA1A is required for lysosomal fusion. In summary, we present a model in which the VGCC plays a role in autophagy by regulating the fusion of AVs with lysosomes through its calcium channel activity and hence functions in maintaining neuronal homeostasis.

Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.

Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease.

Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production.

Mitochondrial fusion and fission affect the distribution and quality control of mitochondria. We show that Marf (Mitochondrial associated regulatory factor), is required for mitochondrial fusion and transport in long axons. Moreover, loss of Marf leads to a severe depletion of mitochondria in neuromuscular junctions (NMJs). Marf mutants also fail to maintain proper synaptic transmission at NMJs upon repetitive stimulation, similar to Drp1 fission mutants. However, unlike Drp1, loss of Marf leads to NMJ morphology defects and extended larval lifespan. Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands. Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis. Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.

A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.

Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.