Increase in CFC-11 emissions from eastern China based on atmospheric observations.

The recovery of the stratospheric ozone layer relies on the continued decline in the atmospheric concentrations of ozone-depleting gases such as chlorofluorocarbons1. The atmospheric concentration of trichlorofluoromethane (CFC-11), the second-most abundant chlorofluorocarbon, has declined substantially since the mid-1990s2. A recently reported slowdown in the decline of the atmospheric concentration of CFC-11 after 2012, however, suggests that global emissions have increased3,4. A concurrent increase in CFC-11 emissions from eastern Asia contributes to the global emission increase, but the location and magnitude of this regional source are unknown3. Here, using high-frequency atmospheric observations from Gosan, South Korea, and Hateruma, Japan, together with global monitoring data and atmospheric chemical transport model simulations, we investigate regional CFC-11 emissions from eastern Asia. We show that emissions from eastern mainland China are 7.0 ± 3.0 (±1 standard deviation) gigagrams per year higher in 2014-2017 than in 2008-2012, and that the increase in emissions arises primarily around the northeastern provinces of Shandong and Hebei. This increase accounts for a substantial fraction (at least 40 to 60 per cent) of the global rise in CFC-11 emissions. We find no evidence for a significant increase in CFC-11 emissions from any other eastern Asian countries or other regions of the world where there are available data for the detection of regional emissions. The attribution of any remaining fraction of the global CFC-11 emission rise to other regions is limited by the sparsity of long-term measurements of sufficient frequency near potentially emissive regions. Several considerations suggest that the increase in CFC-11 emissions from eastern mainland China is likely to be the result of new production and use, which is inconsistent with the Montreal Protocol agreement to phase out global chlorofluorocarbon production by 2010.

PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins.

The lysosome is the final destination for degradation of endocytic cargo, plasma membrane constituents, and intracellular components sequestered by macroautophagy. Fusion of endosomes and autophagosomes with the lysosome depends on the GTPase Rab7 and the homotypic fusion and protein sorting (HOPS) complex, but adaptor proteins that link endocytic and autophagy pathways with lysosomes are poorly characterized. Herein, we show that Pleckstrin homology domain containing protein family member 1 (PLEKHM1) directly interacts with HOPS complex and contains a LC3-interacting region (LIR) that mediates its binding to autophagosomal membranes. Depletion of PLEKHM1 blocks lysosomal degradation of endocytic (EGFR) cargo and enhances presentation of MHC class I molecules. Moreover, genetic loss of PLEKHM1 impedes autophagy flux upon mTOR inhibition and PLEKHM1 regulates clearance of protein aggregates in an autophagy- and LIR-dependent manner. PLEKHM1 is thus a multivalent endocytic adaptor involved in the lysosome fusion events controlling selective and nonselective autophagy pathways.

Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure.

Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P < .005) and attenuated clot firmness (P < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV (P < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control (P < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.

What is the context? Statins such as Atorvastatin (ATV) are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol.The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases.Prenyl groups provide a membrane anchor that is essential for the correct membrane localization and function of these proteins.Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins.Rab27b and Rap1 are small GTPase proteins in platelets that are involved in the secretion of platelet granules and integrin activation.What is new?In this study, we found that ATV impairs prenylation of Rab27b and Rap1a and attenuates platelet function.These effects were partially rescued by GGPP, indicating the involvement of the mevalonate pathway.Platelet aggregation and degranulation was significantly attenuated by ATV.The impact of statins on platelet function altered clot formation, structure and contraction generating a clot that was more susceptible to degradation.What is the impact?This study demonstrates a novel mechanism whereby statins alter platelet responses and ultimately clot structure and stability.

Observational evidence for interhemispheric hydroxyl-radical parity.

The hydroxyl radical (OH) is a key oxidant involved in the removal of air pollutants and greenhouse gases from the atmosphere. The ratio of Northern Hemispheric to Southern Hemispheric (NH/SH) OH concentration is important for our understanding of emission estimates of atmospheric species such as nitrogen oxides and methane. It remains poorly constrained, however, with a range of estimates from 0.85 to 1.4 (refs 4, 7-10). Here we determine the NH/SH ratio of OH with the help of methyl chloroform data (a proxy for OH concentrations) and an atmospheric transport model that accurately describes interhemispheric transport and modelled emissions. We find that for the years 2004-2011 the model predicts an annual mean NH-SH gradient of methyl chloroform that is a tight linear function of the modelled NH/SH ratio in annual mean OH. We estimate a NH/SH OH ratio of 0.97 ± 0.12 during this time period by optimizing global total emissions and mean OH abundance to fit methyl chloroform data from two surface-measurement networks and aircraft campaigns. Our findings suggest that top-down emission estimates of reactive species such as nitrogen oxides in key emitting countries in the NH that are based on a NH/SH OH ratio larger than 1 may be overestimated.

Quantitative Assessment of Molecular Transport through Sub-3 nm Silica Nanochannels by Scanning Electrochemical Microscopy.

Scanning electrochemical microscopy (SECM) has been proved to be a powerful technique to study molecular transport across ionic channels in biomembranes and artificial nanoporous membranes. In this work SECM was used to study the dynamics of molecular transport across the ultrathin silica nanoporous membrane consisting of sub-3 nm diameter perpendicular channels. We focused on the quantitative assessment of permselectivity and permeability of the membrane and the effect of radial electrical double layer (EDL) on them. By SECM imaging, it was phenomenologically observed that the membrane with negatively charged surface exhibited permselectivity to anionic molecule, for instance hexacyanoruthenate(II) (Ru(CN)64-). And the permselective transport of Ru(CN)64- was obviously more favored at a higher concentration of KCl. Precise membrane permeability to Ru(CN)64- was quantitatively determined by overlapping experimental SECM approach curves with the ones generated by finite element simulations. The high permeability up to 35 µm s-1 was ascribed to the straight channel structure and ultrahigh channel density of 4 × 1012 cm-2. Moreover, the permeability was varied from 35 µm s-1 to 2.5 µm s-1 when decreasing the concentration of KCl from 1.0 to 0.01 M, corroborating the electrostatic origin of membrane permselectivity. On the other hand, the simulated concentration profiles at both sides of the membrane suggested that the molecular transport across the membrane was mainly driven by the large transmembrane concentration gradient while the tip-induced transport was relatively negligible. These results help to quantitatively understand the molecular transport selectivity and dynamics across nanoporous membranes and to rationally design artificial molecular sieving membranes.

Analysing single live cells by scanning electrochemical microscopy.

Single live cell analysis methods provide information on the characteristics of individual cells, yielding not only bulk population averages but also their heterogeneity. Scanning electrochemical microscopy (SECM) offers single live cell activities along its topography with high accuracy probe tip positioning. Both intracellular and extracellular processes can be electrochemically examined through the use of SECM. This non-invasive technique allows for high resolution mapping of electrochemical measurements in or around the cell sample of interest. Reactive oxygen species and reactive nitrogen species can be determined in a non-invasive label-free method and utilized as a probe for cellular pathology and physiology. Membrane permeability and rate of membrane species transport can be quantified in SECM. The cell response to external stressors can be monitored and modelled. SECM is able to offer nanoscale mapping and low concentration detection, providing a powerful bioanalytical tool for live cell studies. Herein we present an overview of recent progress in the imaging and characterization of single live cells using SECM.

Pesticide exposure and risk of systemic lupus erythematosus in an urban population of predominantly African-American women.

OBJECTIVE: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. METHODS: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. RESULTS: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty-three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28-3.93). CONCLUSION: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings.

Continued Emissions of the Ozone-Depleting Substance Carbon Tetrachloride From Eastern Asia.

Carbon tetrachloride (CCl4) is an ozone-depleting substance, accounting for about 10% of the chlorine in the troposphere. Under the terms of the Montreal Protocol, its production for dispersive uses was banned from 2010. In this work we show that, despite the controls on production being introduced, CCl4 emissions from the eastern part of China did not decline between 2009 and 2016. This finding is in contrast to a recent bottom-up estimate, which predicted a significant decrease in emissions after the introduction of production controls. We find eastern Asian emissions of CCl4 to be 16 (9-24) Gg/year on average between 2009 and 2016, with the primary source regions being in eastern China. The spatial distribution of emissions that we derive suggests that the source distribution of CCl4 in China changed during the 8-year study period, indicating a new source or sources of emissions from China's Shandong province after 2012.

Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine.

A bone imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, and antiprenylation activities has been created, including a novel linking strategy. The linking chemistry allows attachment of a diverse selection of dyes fluorescent in the visible to near-infrared range to any of the three clinically important heterocyclic bisphosphonate bone drugs (risedronate, zoledronate, and minodronate or their analogues). The resultant suite of conjugates offers multiple options to "mix and match" parent drug structure, fluorescence emission wavelength, relative bone affinity, and presence or absence of antiprenylation activity, for bone-related imaging applications.

Current and future implications of basic and translational research on amyloid-ß peptide production and removal pathways.

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid ß-peptide (Aß). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aß produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aß. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aß. We also briefly outline how the emerging knowledge about the pathways involved in Aß generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".

Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL.

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.

Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase.

Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function.

Islet amyloid inhibitors improve glucose homeostasis in a transgenic mouse model of type 2 diabetes.

Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of ß-cell mass in type 2 diabetes. Prevention of IAPP formation represents a potential treatment to increase ß-cell survival and function. The IAPP inhibitory peptide, D-ANFLVH, has been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D-ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of ß-cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in ß-cell survival and validate the application of anti-amyloid compounds as therapeutic strategies to maintain normal insulin secretion in patients with type 2 diabetes.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

Calcium-Dependent Hyperexcitability in Human Stem Cell-Derived Rett Syndrome Neuronal Networks.

Background: Mutations in MECP2 predominantly cause Rett syndrome and can be modeled in vitro using human stem cell-derived neurons. Patients with Rett syndrome have signs of cortical hyperexcitability, such as seizures. Human stem cell-derived MECP2 null excitatory neurons have smaller soma size and reduced synaptic connectivity but are also hyperexcitable due to higher input resistance. Paradoxically, networks of MECP2 null neurons show a decrease in the frequency of network bursts consistent with a hypoconnectivity phenotype. Here, we examine this issue. Methods: We reanalyzed multielectrode array data from 3 isogenic MECP2 cell line pairs recorded over 6 weeks (n = 144). We used a custom burst detection algorithm to analyze network events and isolated a phenomenon that we termed reverberating super bursts (RSBs). To probe potential mechanisms of RSBs, we conducted pharmacological manipulations using bicuculline, EGTA-AM, and DMSO on 1 cell line (n = 34). Results: RSBs, often misidentified as single long-duration bursts, consisted of a large-amplitude initial burst followed by several high-frequency, low-amplitude minibursts. Our analysis revealed that MECP2 null networks exhibited increased frequency of RSBs, which produced increased bursts compared with isogenic controls. Bicuculline or DMSO treatment did not affect RSBs. EGTA-AM selectively eliminated RSBs and rescued network burst dynamics. Conclusions: During early development, MECP2 null neurons are hyperexcitable and produce hyperexcitable networks. This may predispose them to the emergence of hypersynchronic states that potentially translate into seizures. Network hyperexcitability depends on asynchronous neurotransmitter release that is likely driven by presynaptic Ca2+ and can be rescued by EGTA-AM to restore typical network dynamics.

Designing an intervention for women with systemic lupus erythematosus from medically underserved areas to improve care: a qualitative study.

OBJECTIVE: Systemic lupus erythematosus (lupus) disproportionately affects women, racial/ethnic minorities and low-income populations. We held focus groups for women from medically underserved communities to discuss interventions to improve care. METHODS: From our Lupus Registry, we invited 282 women, ≥18 years, residing in urban, medically underserved areas. Hospital-based clinics and support groups also recruited participants. Women were randomly assigned to three focus groups. Seventy-five-minute sessions were recorded, transcribed and coded thematically using interpretative phenomenologic analysis and single counting methods. We categorized interventions by benefits, limitations, target populations and implementation questions. RESULTS: Twenty-nine women with lupus participated in three focus groups, (n = 9, 9, 11). 80% were African American and 83% were from medically underserved zip codes. Themes included the desire for lupus education, isolation at the time of diagnosis, emotional and physical barriers to care, and the need for assistance navigating the healthcare system. Twenty of 29 participants (69%) favored a peer support intervention; 17 (59%) also supported a lupus health passport. Newly diagnosed women were optimal intervention targets. Improvements in quality of life and mental health were proposed outcome measures. CONCLUSION: Women with lupus from medically underserved areas have unique needs best addressed with an intervention designed through collaboration between community members and researchers.

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts.

Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.

Assembly of the presenilin γ-/ε-secretase complex.

The presenilin complex is composed of four core proteins (presenilin 1 or presenilin 2, APH1, nicastrin, and PEN2). Several endogenous proteins have been reported to selectively modulate the function of the presenilin complexes; these include transmembrane trafficking protein, 21-KD (TMP21), CD147 antigen (basigin), the γ-secretase-activating protein (gSAP), and the orphan G-protein-coupled receptor 3. Because the structure and assembly of these complexes underlies their activity, this review will discuss current work on the assembly of the complex and on presenilin-interacting proteins that regulate secretase activity.

Biosynthesis of a novel C30 carotenoid in Bacillus firmus isolates.

AIMS: Pigmented Bacillus spp. with probiotic properties have been isolated. In the yellow-/orange-coloured strains, the carotenoid pigments present have been characterized. In contrast, the carotenoids present in the Bacillus isolates coloured red await identification. The present article reports progress on the elucidation of the pigment biosynthetic pathway in these red-pigmented Bacillus firmus strains. METHODS AND RESULTS: A combination of UV/Vis, chromatographic and mass spectrometry (MS) has revealed the properties of the predominant pigment and the end-point carotenoid of the pathway to be methyl 4,4'-diapolycopene-dioate after transmethylation. The diglycosyl ester of 4,4'-diapolycopene-dioate persists in vivo prior to chemical treatment. Different mutants and inhibitor treatment were employed to establish the C30 biosynthesis pathway with all precursors and intermediates to 4,4'-diapolycopene-dioate detected, which include 4,4'-diapophytene and all desaturation intermediates to 4,4'-diapolycopene and 4,4'-diapolycopene-dialdehyde. To cultures synthesizing the 4,4'-diapolycopene-dioate derivative and those in which its formation was inhibited, oxidative stress was induced by peroxide treatment. Conditions that decreased the growth rate of the pigmented cells by only 30% caused a complete growth inhibition of the culture devoid of the 4,4'-diapolycopene-dioate derivative. CONCLUSION: This finding demonstrates the diversity of C30 carotenoid biosynthesis in Bacillus species and the antioxidative function of the 4,4'-diapolycopene-dioate derivative in B. firmus cells. SIGNIFICANCE AND IMPACT OF THE STUDY: It could be shown that the C30 4,4'-diapolycopene-dioate derivatives protect pigmented B. firmus from peroxidative reactions. Under oxidative conditions, this can be an ecological advantage over nonpigmented (=noncarotenogenic) strains that are equally abundant.

Multielectrode Arrays for Functional Phenotyping of Neurons from Induced Pluripotent Stem Cell Models of Neurodevelopmental Disorders.

In vitro multielectrode array (MEA) systems are increasingly used as higher-throughput platforms for functional phenotyping studies of neurons in induced pluripotent stem cell (iPSC) disease models. While MEA systems generate large amounts of spatiotemporal activity data from networks of iPSC-derived neurons, the downstream analysis and interpretation of such high-dimensional data often pose a significant challenge to researchers. In this review, we examine how MEA technology is currently deployed in iPSC modeling studies of neurodevelopmental disorders. We first highlight the strengths of in vitro MEA technology by reviewing the history of its development and the original scientific questions MEAs were intended to answer. Methods of generating patient iPSC-derived neurons and astrocytes for MEA co-cultures are summarized. We then discuss challenges associated with MEA data analysis in a disease modeling context, and present novel computational methods used to better interpret network phenotyping data. We end by suggesting best practices for presenting MEA data in research publications, and propose that the creation of a public MEA data repository to enable collaborative data sharing would be of great benefit to the iPSC disease modeling community.