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  • Altogether our study emphasizes the ambiguity of inflammator


    Altogether, our study emphasizes the ambiguity of inflammatory responses in the complex interplay of parenchymal Paxilline and infiltrating immune cells in the liver. While CXCR6-mediated immune cell recruitment aggravates classical models of acute or chronic liver injury in mice, their genetic depletion enhances cell death, inflammation and proliferation of hepatocytes in the NEMOLPC-KO background. These data demonstrate a novel role of CXCR6 for stress responses in hepatocytes, independent from the functions of CXCR6 on immune cells. The following are the supplementary data related to this article.
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    Introduction Diabetes mellitus is a metabolic disorder involving hyperglycemia that results from insulin deficiency, insulin resistance, or both and can cause many complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Approximately 2% of all diabetes patients have monogenic diabetes, which is caused by single-gene mutations that reduce pancreatic β cell function or increase insulin resistance. Unfortunately, this form of diabetes is often misdiagnosed as either type 1 or type 2 diabetes mellitus [1]. Furthermore, monogenic diabetes is commonly classified into neonatal diabetes mellitus (ND), maturity-onset diabetes of the young (MODY), and other rare forms of genetic mutation-related diabetes, making differential diagnosis difficult depending on the age of onset [2]. The onset of ND, for example, is typically within the first 6 months of life, and the disease can manifest transient or permanent symptoms. In fact, transient ND often spontaneously remits before 18 months of age, while permanent ND (PND) persists and requires life-long therapy. Notably, approximately 70% of all transient ND cases are caused by the overexpression of an imprinted region on chromosome 6q24 [3], whereas approximately 25% are due to activating mutations of the potassium voltage-gated channel, subfamily J, member 11 (KCNJ11) or ATP binding cassette subfamily C member 8 (ABCC8) genes [4]. The remaining 5% of cases are known to be caused by mutations of the insulin (INS) gene, the ZFP57 zinc finger protein (ZFP57) gene, or other unknown causes [5]. PND is also known to be caused by activating mutations of KCNJ11 [6] or ABCC8 [7], mutations of INS [5,8], or homozygous or compound heterozygous mutations of glucokinase (GCK) [9]. Interestingly, patients with KATP channel (KCNJ11 or ABCC8) mutations are typically more responsive to a high-dose oral sulfonylurea treatment and are able to discontinue insulin therapy [10,11]. Type 1B diabetes (T1BD) is a non-autoimmune disease and accounts for about 10% of all type 1 diabetes diagnoses. Mutations of KCNJ11 and INS have also been associated with T1BD in a Japanese population study [12]. However, the genetic similarities and differences between these T1BD patients and those with ND have not been fully established. Sanger sequencing is currently the standard method used to detect gene mutations in monogenic diabetes, whereby candidate genes are sequentially tested according to incidence and phenotype of the disease. Because monogenic diabetes is an umbrella term for multiple genetic etiologies, its genetic diagnosis and comparison to other forms of diabetes is challenging. Next-generation sequencing uses massive parallel sequencing and simultaneously analyzes millions of DNA fragments from a single sample. It is high-throughput and able to sequence an entire genome in a short time period [13]. Recently, whole exome sequencing (WES) was used to diagnose various Mendelian disorders, including monogenic diabetes [14,15]. Thus, with the advent of this new technology, the genetic comparison of various forms of diabetes has become possible.
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    Discussion The diagnostic rates of clinical genetic disorders with heterogeneous etiologies are 5–15% by karyotype analysis [22], 15–20% by chromosomal microarray analysis [23], 3–47% by Sanger sequencing for single-gene [15], 31.4% by next-generation sequencing, and 24.8% by WES [15]. The diagnostic rate of the present study was 36%. Excluding the T1BD patients, we found three mutations in five cases of PND, a diagnostic rate of 60%. These superior diagnostic rates for all the patients and the PND subset are likely due to stringent phenotyping.