A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

A fluid biomarker reveals loss of TDP-43 splicing repression in pre-symptomatic ALS.

Loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well-documented in postmortem tissues of amyotrophic lateral sclerosis (ALS), yet whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects functional loss of TDP-43, and thus detection of cryptic exon-encoded peptides in cerebrospinal fluid (CSF) could reveal the earliest stages of TDP-43 dysregulation in patients. Here, we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in C9ORF72-associated ALS, including pre-symptomatic mutation carriers. In contrast to neurofilament light and heavy chain proteins, cryptic HDGFL2 accumulates in CSF at higher levels during early stages of disease. Our findings indicate that loss of TDP-43 splicing repression occurs early in disease progression, even pre-symptomatically, and that detection of HDGFL2's cryptic neoepitope may serve as a prognostic test for ALS which should facilitate patient recruitment and measurement of target engagement in clinical trials.

Human biting mosquitoes and implications for West Nile virus transmission.

BACKGROUND: West Nile virus (WNV), primarily vectored by mosquitoes of the genus Culex, is the most important mosquito-borne pathogen in North America, having infected thousands of humans and countless wildlife since its arrival in the USA in 1999. In locations with dedicated mosquito control programs, surveillance methods often rely on frequent testing of mosquitoes collected in a network of gravid traps (GTs) and CO2-baited light traps (LTs). Traps specifically targeting oviposition-seeking (e.g. GTs) and host-seeking (e.g. LTs) mosquitoes are vulnerable to trap bias, and captured specimens are often damaged, making morphological identification difficult. METHODS: This study leverages an alternative mosquito collection method, the human landing catch (HLC), as a means to compare sampling of potential WNV vectors to traditional trapping methods. Human collectors exposed one limb for 15 min at crepuscular periods (5:00-8:30 am and 6:00-9:30 pm daily, the time when Culex species are most actively host-seeking) at each of 55 study sites in suburban Chicago, Illinois, for two summers (2018 and 2019). RESULTS: A total of 223 human-seeking mosquitoes were caught by HLC, of which 46 (20.6%) were mosquitoes of genus Culex. Of these 46 collected Culex specimens, 34 (73.9%) were Cx. salinarius, a potential WNV vector species not thought to be highly abundant in upper Midwest USA. Per trapping effort, GTs and LTs collected > 7.5-fold the number of individual Culex specimens than HLC efforts. CONCLUSIONS: The less commonly used HLC method provides important insight into the complement of human-biting mosquitoes in a region with consistent WNV epidemics. This study underscores the value of the HLC collection method as a complementary tool for surveillance to aid in WNV vector species characterization. However, given the added risk to the collector, novel mitigation methods or alternative approaches must be explored to incorporate HLC collections safely and strategically into control programs.

Building International Capacity for Citizen Scientist Engagement in Mosquito Surveillance and Mitigation: The GLOBE Program's GLOBE Observer Mosquito Habitat Mapper.

The GLOBE Program's GLOBE Observer Mosquito Habitat Mapper is a no-cost citizen scientist data collection tool compatible with Android and iOS devices. Available in 14 languages and 126 countries, it supports mosquito vector surveillance, mitigation, and education by interested individuals and as part of participatory community surveillance programs. For low-resource communities where mosquito control services are inadequate, the Mosquito Habitat Mapper supports local health action, empowerment, and environmental justice. The tangible benefits to human health supported by the Mosquito Habitat Mapper have encouraged its wide adoption, with more than 32,000 observations submitted from 84 countries. The Mosquito Habitat Mapper surveillance and data collection tool is complemented by an open database, a map visualization interface, data processing and analysis tools, and a supporting education and outreach campaign. The mobile app tool and associated research and education assets can be rapidly deployed in the event of a pandemic or local disease outbreak, contributing to global readiness and resilience in the face of mosquito-borne disease. Here, we describe the app, the Mosquito Habitat Mapper information system, examples of Mosquito Habitat Mapper deployment in scientific research, and the outreach campaign that supports volunteer training and STEM education of students worldwide.

Effects of Scale on Modeling West Nile Virus Disease Risk.

Modeling vector-borne diseases is best conducted when heterogeneity among interacting biotic and abiotic processes is captured. However, the successful integration of these complex processes is difficult, hindered by a lack of understanding of how these relationships influence disease transmission across varying scales. West Nile virus (WNV) is the most important mosquito-borne disease in the United States. Vectored by Culex mosquitoes and maintained in the environment by avian hosts, the virus can spill over into humans and horses, sometimes causing severe neuroinvasive illness. Several modeling studies have evaluated drivers of WNV disease risk, but nearly all have done so at broad scales and have reported mixed results of the effects of common explanatory variables. As a result, fine-scale relationships with common explanatory variables, particularly climatic, socioeconomic, and human demographic, remain uncertain across varying spatial extents. Using an interdisciplinary approach and an ongoing 12-year study of the Chicago region, this study evaluated the factors explaining WNV disease risk at high spatiotemporal resolution, comparing the human WNV model and covariate performance across three increasing spatial extents: ultrafine, local, and county scales. Our results demonstrate that as spatial extent increased, model performance increased. In addition, only six of the 23 assessed covariates were included in best-fit models of at least two scales. These results suggest that the mechanisms driving WNV ecology are scale-dependent and covariate importance increases as extent decreases. These tools may be particularly helpful for public health, mosquito, and disease control personnel in predicting and preventing disease within local and fine-scale jurisdictions, before spillover occurs.

Longitudinal changes in resting state networks in early presymptomatic carriers of C9orf72 expansions.

Previous cross-sectional imaging studies found differences in brain structure and in resting state networks between presymptomatic carriers of mutations in C9orf72 (C9+) and healthy controls. We carried out a prospective longitudinal study of clinical and resting state functional imaging in a cohort of 15 presymptomatic C9+ carriers to determine whether differences in resting state connectivity prior to developing symptoms reflect static developmental differences or ongoing low-grade degenerative changes. Presymptomatic C9+ carriers were scanned at baseline with follow-up scanning at 6- and 18-months and compared to a cohort of 14 healthy controls scanned longitudinally. Resting state networks associated with manifest disease were visualized by comparing 27 symptomatic C9+ carriers to 34 healthy controls. Motor, salience, thalamic, and speech production networks were visualized using a seed-based analysis. Neurofilament light chain was measured in serum obtained at the time of the scans. Neither clinical measures of motor, cognitive, and behavioral function nor neurofilament levels changed over follow-up in presymptomatic C9+ carriers. In thalamic networks, there was a reduction in connectivity in presymptomatic carriers at all timepoints with a constant difference compared to healthy controls. In contrast, precuneus/posterior cingulate regions exhibited declining functional connectivity compared to controls over the 18-month follow-up, particularly in motor networks. These were regions that also exhibited reduced functional connectivity in symptomatic C9+ carriers. Reduced connectivity over time also occurred in small regions of frontal and temporal cortex within salience and thalamic networks in presymptomatic C9+ carriers. A few areas of increased connectivity occurred, including cortex near the motor seed and within the speech production network. Overall, changes in functional connectivity over time favor the explanation of ongoing low-grade alterations in presymptomatic C9+ carriers in most networks, with the exception of thalamic networks where functional connectivity reductions were stable over time. The loss of connectivity to parietal cortex regions in several different networks may be a distinct feature of C9orf72-related degeneration. Longitudinal studies of carriers who phenoconvert will be important to determine the prognostic significance of presymptomatic functional connectivity alterations.

Standardized Operational Evaluations of Catch Basin Larvicides from Seven Mosquito Control Programs in the Midwestern United States During 2017.

During June to September 2017, 7 mosquito control programs in the midwestern United States evaluated a total of 9 catch basin larvicide formulations using similar protocols. Treated basins were monitored among study sites to observe when larvicides failed to control mosquitoes in 25% or more basins within a site. Overall, when monitoring occurred within the maximum label duration of the larvicides, sites treated with a single larvicide tablet or briquet surpassed the 25% fail threshold more often than pellet and granular larvicide formulations. In 438 of the study basins, the depth from sump bottom to catch basin lid was measured. In basins that were deeper than 5 ft (1.5 m), larvicides failed to control mosquitoes significantly more often than those 5 ft or shallower.

Meet the next generation. Interview by Alison Whyte.

Nursing Standard profiles five nursing students who embarked on their studies at the University of Liverpool in September 2008. Readers will be able to find out about their experiences half way through the course and again at the end.