ObjectiveThe lack of standardized reference range for the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index has limited its clinical application. This study defines the reference range of HOMA-IR index in an adult Hispanic population based with machine learning methods.MethodsThis study investigated a Hispanic population of 1854 adults, randomly selected on the basis of 2000 Census tract data in the city of Brownsville, Cameron County. Machine learning methods, support vector machine (SVM) and Bayesian Logistic Regression (BLR), were used to automatically identify measureable variables using standardized values that correlate with HOMA-IR; K-means clustering was then used to classify the individuals by insulin resistance.ResultsOur study showed that the best cutoff of HOMA-IR for identifying those with insulin resistance is 3.80. There are 39.1% individuals in this Hispanic population with HOMA-IR>3.80.ConclusionsOur results are dramatically different using the popular clinical cutoff of 2.60. The high sensitivity and specificity of HOMA-IR>3.80 for insulin resistance provide a critical fundamental for our further efforts to improve the public health of this Hispanic population.

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TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although the overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. Here we identify Asp174 as a cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that the endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43. A myotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases and is characterized by muscle weakness due to the degeneration of both upper and lower motor neurons. Although the pathogenic mechanism of ALS remains unresolved, the RNA-binding protein TDP-43 has been shown to accumulate in cytoplasmic inclusions in the affected regions of the spinal cord and brain in patients with ALS and frontotemporal lobar degeneration (FTLD), respectively 1,2 . Subsequently, mutations linked with ALS and FTLD have been identified in the gene that encodes TDP-43, which has confirmed the significance of TDP-43 in the pathogenesis of these diseases 3,4 . Most of these mutations occur within or near the carboxyl-terminal (C-terminal) glycine-rich domain (GRD) of TDP-43, except for the D169G point mutation that resides in RNA recognition motif 1 (refs 3,4). TDP-43 is normally localized predominantly in the nucleus. However, in ALS and FTLD patients with TDP-43-positive cytoplasmic inclusions, the protein is abnormally phosphorylated, ubiquitinated and truncated. This results in the accumulation of an B25-kDa C-terminal fragment (CTF25), in addition to other minor CTFs and the full-length TDP-43, in cytoplasmic aggregates. CTFs are hallmarks of forms of disease whose pathology is associated exclusively with abnormalities in TDP-43 and are observed in patients with not only ALS and FTLD but also Alzheimer's disease 5 . Amino-terminal (N-terminal) analysis of CTFs obtained from brain autopsies of patients with FTLD has resulted in the identification of three cleavage sites, Arg208, Asp219 and Asp247, which give rise to CTFs 6,7 . However, the expected sizes of the resulting CTFs are less than 25 kDa, which suggests that CTF25 is probably cleaved at a different position.TDP-43 is a widely expressed 414-amino acid (a.a.) protein comprised of two RNA recognition motifs (RRM1 at a.a. 106-176 and RRM2 at a.a. 191-262) and the GRD 8,9 . The chronic stabilization...

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