Zinc Transporter Research Articles

6560 Atypical Diabetes Mellitus in a Mother-Son Pair with Multiple Autoimmune Conditions & Pathogenic Variant in BCL11B Inherited from the Mother

Abstract Disclosure: R. Elrajabi: None. N. Gurtunca: None. The etiology of diabetes can be challenging to determine at times and misdiagnosis is common in all age groups. To provide the right treatment and enhance glycemic control, which results in better outcomes and fewer comorbidities, an accurate diagnosis is crucial. We describe a mother-son pair who share a pathogenic variant in BCL11B gene with multiple autoimmune conditions including atypical autoimmune DM. A 13 year old young boy with a history of 33-week prematurity, developmental delay, autoimmune hypothyroidism, and vitiligo presented with concerns for DM given mother’s recent diagnosis of DM treated with Metformin and GLP-1 receptor agonist with poor control of her DM. His mother has a learning disability, hypothyroidism, alopecia totalis, vitiligo and hypertension. Interestingly, he and his mother share a genetic variant in BCL11B gene detected on whole exome sequencing sent as part of the workup of developmental delay. His weight and height were in the 13.5% and 13.9% centiles, respectively. He has vitiligo, but other than that, the physical examination was unremarkable. He is prepubertal. HbA1c was high, 6.4% despite the presence of anemia. An oral glucose tolerance test (OGTT) was consistent with DM as was his repeat HbA1c of 7.1%. He had elevated IA 2, zinc transporter 8, and GAD 65 antibodies, all consistent with autoimmune DM. He was admitted to the hospital and started on both long-acting and short acting insulin via multiple daily injections. BCL11B is a transcription factor that is expressed in all T cells and regulates important processes involved in T cell growth, survival, and function, including Treg cells and Foxp3 activity. Autoimmune diseases have been linked to abnormal Treg activity and Foxp3 deficiency. BCL11B functions as a checkpoint required for T cell lineage commitment while minimizing natural killer cell potential. Impaired BCL11B activity at a young age result in severe whole-body autoimmunity, defined by a fully stimulated immune system similar to animals lacking functioning Treg cells. DM associated with BCL11B variant has not previously been reported. If we follow the theory that autoimmunity affects beta cell function or mass, this patient's and his mother's DM and autoimmune disorders are most likely connected to the BCL11B variation they share. Presentation: 6/2/2024

8070 Atypical New Onset Diabetes Mellitus in a Young Male: Is this LADA vs Type 1 or Type 2?

Abstract Disclosure: S.K. Devineni: None. S. Shaik: None. J.L. Gilden: None. Background: Recent literature suggests that autoantibody seropositivity is common in new onset autoimmune Diabetes Mellitus (DM), especially in younger patients. Latent autoimmune diabetes of adults (LADA), a form of adult-onset autoimmune DM. is considered a mix of type 1 and type 2 DM, sharing similar immune cell characteristics to both subtypes. Unlike type 1, LADA patients do not require insulin for glycemic control for the first six months after diagnosis. Unlike type 2, LADA patients are positive for single islet autoantibody, glutamic acid decarboxylase (GAD), and anti-gliadin antibodies. Patients with LADA often present with symptoms (polyuria, polydipsia, nocturia, fatigue, and visual changes). We present a case of new onset Diabetes Mellitus in a young male, autoantibody seronegative, at the time of diagnosis. Case report: A 19-year-old Caucasian male was sent to the Emergency Department with a serum blood glucose (BG) level of 579 mg% after routine blood tests. He denied any clinical symptoms and serum levels showed no elevation in ketones, nor bicarbonate levels, ruling out ketoacidosis. His hemoglobin A1c at that time was 14.7%. He denied prior knowledge of personal or family history of DM. or other autoimmune disorders. However, it was discovered that routine labs done 1 ½ months earlier on a Health Screen revealed BG=295 mg% with urine positive for ketones (80 mg/dl) and glucose (>1000 mg/dL). Physical Exam: (HT=178 cm; WT=79 Kg) was unremarkable. Autoantibodies for GAD 65, islet-cell, Zinc transporter 8, and Islet Antigen 2 were all negative. He was hospitalized for 9 days. BG levels were difficult to control and required increasing doses of both long acting and short acting insulin. He was discharged with insulin therapy (30 units of glargine at nighttime and 12 units of premeal aspart). One week later, the patient ate several gummy bears as a nighttime snack and subsequently woke up in the middle of the night feeling shaky and having blurry vision. BG was greater than 300 mg%. In the emergency room, he. received intravenous fluids. No insulin was given as his BG normalized and he was discharged. Later, a continuous glucose monitor revealed multiple hypoglycemic episodes. The patient was living in a situation where he only had limited access to certain foods, and thus his insulin regimen was decreased (28 units glargine and 10 units aspart for meals) Conclusion: We present the case of new onset atypical DM in a young patient whose insulin sensitivity and risk factors seem to resemble a pattern of type 1 DM; despite seronegative autoantibodies We predict that he may eventually seroconvert to type 1 DM. It is also possible that he may have an unusual presentation of LADA or type 2 DM, although he had no hyperglycemic symptoms. Presentation: 6/3/2024

SENP1 mediates zinc-induced ZnT6 deSUMOylation at Lys-409 involved in the regulation of zinc metabolism in Golgi apparatus

Zinc (Zn) transporters contribute to the maintenance of intracellular Zn homeostasis in vertebrate, whose activity and function are modulated by post-translational modification. However, the function of small ubiquitin-like modifier (SUMOylation) in Zn metabolism remains elusive. Here, compared with low Zn group, a high-Zn diet significantly increases hepatic Zn content and upregulates the expression of metal-response element-binding transcription factor-1 (MTF-1), Zn transporter 6 (ZnT6) and deSUMOylation enzymes (SENP1, SENP2, and SENP6), but inhibits the expression of SUMO proteins and the E1, E2, and E3 enzymes. Mechanistically, Zn triggers the activation of the MTF-1/SENP1 pathway, resulting in the reduction of ZnT6 SUMOylation at Lys 409 by small ubiquitin-like modifier 1 (SUMO1), and promoting the deSUMOylation process mediated by SENP1. SUMOylation modification of ZnT6 has no influence on its localization but reduces its protein stability. Importantly, deSUMOylation of ZnT6 is crucial for controlling Zn export from the cytosols into the Golgi apparatus. In conclusion, for the first time, we elucidate a novel mechanism by which SUMO1-catalyzed SUMOylation and SENP1-mediated deSUMOylation of ZnT6 orchestrate the regulation of Zn metabolism within the Golgi apparatus.

9390 Does Znt8a Have An Association With The Duration Of Diabetes? Case Series And Literature Review

Abstract Disclosure: N.M. Rivera Vargas: None. C.S. Botero Suarez: None. S.K. Suryanarayanan: None. S. Saad-Omer: None. Context: Latent autoimmune Diabetes of adults (LADA) is a form of autoimmune diabetes with features of Type 2 Diabetes but positive autoantibodies resembling Type 1 Diabetes. Latent autoimmune diabetes in adults (LADA), has a mixed phenotype with positive islet-cell antibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), protein tyrosine phosphatase autoantibodies (IA2A), insulin autoantibodies (IAA), or zinc transporter-8 autoantibodies (ZnT8A). Since the discovery of ZnT8A, the relevance and clinical utility of this marker has sparked interest. Although ZnT8A is used as a complementary diagnostic aid in children, its utility in adults seems to be unclear. Objective: We report a case series of 26 subjects referred to the Orlando VA Endocrine clinic with measured ZnT8A. We hypothesize that higher ZnT8A will be found in adult autoimmune diabetes with newly diagnosed diabetes rather than those with a longer duration of diabetes. We also explore the association between ZnT8A and family history, duration of diabetes, diabetes complications, and C-peptide levels. Method: A case series of 26 adult patients with diabetes mellitus with a positive ZnT8A (≥15 U/mL). We reviewed medical records of these cases to include ZnT8A levels, years of diabetes diagnosis, C-peptide levels, and diabetes complications. Patients were classified into subgroups based on ZnT8A levels into < 350 U/mL or ≥ 350 U/mL. Results: The 26 patients reviewed had a mean (SD) age of 46 (13) years. The mean (SD) duration of diabetes was 16 (12) years, and HbA1C was 8.4 (1.1) %. Poisson regression analysis showed a statistically significant inverse relationship between ZnT8A and years of diabetes (regression coefficient: -0.028; 95% confidence interval: -0.03 to -0.25; p-value <0.001). Diabetic ketoacidosis was present in 35% of subjects, while diabetic neuropathy was noted in 58% of subjects with positive ZnT8A. Patients with a high ZnT8Ab above 350 U/mL displayed a weak trend towards a lower C-peptide mean (p-value 0.42), and lower prevalence of DKA (p-value 0.42) which was not statistically significant. Conclusion: In this case series of patients with adult-onset diabetes, there seems to be a statistically significant inverse relationship between ZnT8A levels and duration of diabetes suggesting a reduction of ZnT8A levels over time. Although limited by a small number of subjects, this may suggest the need for screening with autoantibodies in the setting of diabetes earlier in the disease process. Presentation: 6/2/2024

8197 A Captivating Case Report of Teprotumumab Induced Hyperglycemic Hyperosmolar State

Abstract Disclosure: K.M. Tuna: None. J.P. Perdomo Rodriguez: None. Introduction: Teprotumumab, a monoclonal antibody targeting the IGF-1 receptor, is increasingly utilized for moderate to severe thyroid eye disease. Initial trials noted mild hyperglycemia in patients with diabetes, while recent trials revealed a significant elevation in Hemoglobin A1c (HbA1c) among those with diabetes or pre-diabetes post-infusion. Here, we discuss a case of a patient with diet-controlled diabetes who developed hyperglycemic hyperosmolar state (HHS) two months after Teprotumumab infusion. Case Presentation: A 43-year-old male, with class III obesity, obstructive sleep apnea, dyslipidemia, coronary artery disease, and diet-controlled diabetes (HbA1c 6.5%) presented with worsening proptosis, decreased color vision, severe visual field depression. Laboratory evaluation revealed elevated TSH (6.3 mIU/ml), normal free T4 (0.67 ng/dl, ref: 0.60-1.2 ng/dl), and undetectable Thyroid Stimulating Immunoglobulin (<0.1 IU/L). Blood cell count, renal and liver function tests were normal. Due to high clinical suspicion of thyroid eye disease, he was treated with timolol, dorzolamide, brimonidine, and methylprednisolone 1g daily for 3 days. Glycemic control was achieved with 30 units of daily insulin while on pulse steroids. On outpatient ophthalmology follow-up, Teprotumumab was initiated and he received 2 doses. Eight weeks later, the patient was hospitalized with altered mental status caused by HHS (glucose 617 mg/dl, serum osmolality 316 osm). HbA1c was found to be significantly increased to 12% and the patient required 150 units total daily insulin and metformin upon discharge. Of note, the patient did not have significant weight changes during this time. GAD, IA2, and Zinc Transporter-8 antibodies were obtained prior to discharge and results are pending. Discussion: The IGF-1 receptor, a partial homologue of the insulin receptor, plays a pivotal role in glucose homeostasis. Inhibiting this receptor can lead to hyperglycemia. Initial randomized controlled trials (RCTs) reported a 10% incidence of mild hyperglycemia. A recent RCT from a cohort of 42 patients demonstrated a 50% incidence of hyperglycemia, in which two-thirds of the patients remained in a dysglycemic state with one patient with pre-existing prediabetes developing diabetic ketoacidosis (DKA). Our patient mirrored this scenario with no identifiable confounding factors. Conclusion: Teprotumumab-induced hyperglycemia, though rare, can lead to life-threatening complications. Baseline glycemic assessment, identification of high-risk patients, and comprehensive discussions on risks and benefits are crucial before initiating therapy. Close monitoring, especially in those with prediabetes, is recommended. Patient education plays a pivotal role in early symptom recognition, averting delayed diagnoses, and subsequent hospitalization. Presentation: 6/3/2024

Activating transcription factor 4 plays a major role in shaping the transcriptional response to isoginkgetin in HCT116 cells

Activating transcription factor 4 (ATF4) plays a central role in the integrated stress response (ISR) and one overlapping branch of the unfolded protein response (UPR). We recently reported that the splicing inhibitor isoginkgetin (IGG) induced ATF4 protein along with several known ATF4-regulated transcripts in a response that resembled the ISR and UPR. However, the contribution of ATF4-dependent and -independent transcriptional responses to IGG exposure was not known. Here we used RNA-sequencing in HCT116 colon cancer cells and an isogenic subline lacking ATF4 to investigate the contribution of ATF4 to IGG-induced changes in gene expression. Approximately 85% of the IGG-responsive DEGs in HCT116 cells were also differentially expressed in response to the ER stressor thapsigargin (Tg) and these were enriched for genes associated with the UPR and ISR. Most of these were positively regulated by IGG with impaired responses in the ATF4-deficient cells. Nonetheless, there were DEGs that responded similarly in both cell lines. The ATF4-independent IGG-induced DEGs included several metal responsive transcripts encoding metallothionines and a zinc transporter. Taken together, the predominant IGG response was ATF4-dependent in these cells and resembled the UPR and ISR while a second less prominent response involved the ATF4-independent regulation of metal responsive mRNAs.

Oxylipin dynamics in dairy cows during clinical ketosis and after treatment with niacin and flunixin meglumine

Dairy cows with clinical ketosis (CK) exhibit metabolic changes, including intense adipose tissue (AT) lipolysis and systemic insulin resistance that increase plasma BHB and free fatty acids (FFA). Cows with CK also have systemic inflammation, predisposing them to inflammatory and infectious diseases. This inflammatory process is modulated in part by oxidized fatty acids (oxylipins) that regulate all aspects of inflammation. Oxylipin profiles have been characterized in healthy periparturient cows, but their dynamics during CK are unknown. CK is an acute metabolic disease requiring clinical therapy, commonly including propylene glycol (PG) as a gluconeogenic agent. Recently, we showed that including lipolysis inhibitors such as niacin (NIA) and flunixin meglumine (FM) improved CK recovery. These drugs may modulate oxylipin biosynthesis by regulating the release of PUFA (oxylipin substrates) and cyclooxygenase activity. However, their impact on oxylipin profiles in cows with CK is unknown. The objective of this study was to determine the dynamics of specific linoleic and arachidonic acid-derived oxylipins during CK and following therapy with PG, NIA, and FM. Multiparous Jersey cows (n = 72; 7.1 DIM) with CK from a commercial dairy were sampled. Inclusion criteria were CK symptoms (lethargy, depressed appetite, and reduced rumen fill) and blood BHB ≥ 1.2 mmol/L. CK cows (n = 24/treatment) were randomly assigned to one of the 3 treatments: 1) PG:310 g orally once daily for 5 d, 2) PG+NIA:24 g orally once daily for 3 d, 3) PG+NIA+FM:1.1 mg/kg IV once daily for 3 d. Healthy cows (HC; n = 24) matched by lactation and DIM (±2 d) were also included. Plasma oxylipins were quantified at enrollment and 7d (d7) later using HPLC-MS/MS. At enrollment, CK had higher concentrations of arachidonic acid (AA) derived 5- and 20-HETE, 8,9-, 11,12-, and 14–15-DHET, and lower concentrations of linoleic acid (LA) derived 12,13-EpOME, 13-oxoODE 9,10- and 12,13-DiHOME. Integrated analysis of biological pathways and oxylipin profiles using Ingenuity Pathway Analysis (IPA) revealed AA metabolism as the top pathway activated during CK. By d7, treatment with PGNIAFM restored plasma PUFAs and oxylipins to profiles similar to HC. IPA analysis showed that PGNIAFM activated the zinc transporter SLC30A7, associated with reduced activation of the AA pathway. Results indicate that higher FA availability during CK, driven in part by dysregulated lipolysis, increases the pool of substrates for oxylipin biosynthesis. These oxylipins may play a role in both metabolic dysregulation and restoring homeostasis during CK. Inhibiting lipolysis and cyclooxygenase activity with NIA and FM can alter AA and LA-derived oxylipins biosynthesis. These findings underscore the potential use of lipolysis inhibitors NIA and FM in CK therapeutics and highlight the importance of understanding oxylipin pathways in the pathogenesis of CK.

Identification of Genomic Regions Conferring Enhanced Zn and Fe Concentration in Wheat Varieties and Introgression Lines Derived from Wild Relatives.

Wild and cultivated relatives of wheat are an important source of genetic factors for improving the mineral composition of wheat. In this work, a wheat panel consisting of modern bread wheat varieties, landraces, and introgression lines with genetic material of the wheat species Triticum timopheevii, T. durum, T. dicoccum, and T. dicoccoides and the synthetic line T. kiharae was used to identify loci associated with the grain zinc (GZnC) and iron (GFeC) content. Using a BLINK model, we identified 31 and 73 marker-trait associations (MTAs) for GZnC and GFeC, respectively, of which 19 were novel. Twelve MTAs distributed on chromosomes 1B, 2A, 2B, 5A, and 5B were significantly associated with GZnC, five MTAs on 2A, 2B, and 5D chromosomes were significantly associated with GFeC, and two SNPs located on 2A and 2B were related to the grain concentration of both trace elements. Meanwhile, most of these MTAs were inherited from At and G genomes of T. timopheevii and T. kiharae and positively affected GZnC and GFeC. Eight genes related to iron or zinc transporters, representing diverse gene families, were proposed as the best candidates. Our findings provide an understanding of the genetic basis of grain Zn and Fe accumulation in species of the Timopheevi group and could help in selecting new genotypes containing valuable loci.

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit: a proof-of-concept study (the T1Early study)

ObjectiveType 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D,...

ZIP8 A391T Crohn’s Disease-Linked Risk Variant Induces Colonic Metal Ion Dyshomeostasis, Microbiome Compositional Shifts, and Inflammation

BackgroundThe pathogenesis of Crohn’s disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohn’s disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal–luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation.MethodsTo evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). We first examined trace element abundance in the colonic mucosal epithelium and lumen of homozygous A393T and wild-type (WT) mice to determine if the variant affected metal distribution. We also performed 16S rRNA gene sequencing on colon samples at 2 months, 3–4 months, and 12 months of age, and conducted histological scoring of colon tissue collected from 5-month and 10-month old mice.ResultsConsistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. 16S rRNA gene sequencing of colon samples revealed variant-linked effects on microbiome beta diversity in 2-month-, 3–4-month-, and 12-month-old mice. Histological scoring showed spontaneous intestinal inflammation in 10-month but not in 5-month-old mice. Lastly, predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc-, and cobalt-dependent pathways in A393T mice compared to wild-type controls.ConclusionThese results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers.Graphical

Beta cell specific ZnT8 gene deficiency and resulting loss in zinc content significantly improve insulin secretion

Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood.A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets.These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.

SLC39A8.p.(Ala391Thr) is associated with poorer cognitive ability: a cross-sectional study of schizophrenia and the general UK population.

The missense SNP NC_000004.12:g.102267552C>T (SLC39A8.p.(Ala391Thr), rs13107325) in SLC39A8, which encodes a zinc transporter, has been linked to schizophrenia and is the likely causal variant for one of the genome-wide association loci associated with the disorder. We tested whether the schizophrenia-risk allele at p.(Ala391Thr) was associated with schizophrenia-related phenotypes, including positive, negative, and disorganised symptoms, cognitive ability, educational attainment, and age of psychosis onset, within three schizophrenia cohorts (combined N=1,232) and, with equivalent phenotypes, in a sample of population controls (UK Biobank, N=355,069). We used regression analyses controlling for age, sex, and population stratification. Within the schizophrenia cohorts, after correction for multiple testing, p.(Ala391Thr) was not significantly associated with any schizophrenia-related phenotypes. In the unaffected participants from the UK Biobank, the schizophrenia-risk allele at p.(Ala391Thr) was associated with significantly poorer cognitive ability and fluid intelligence, a lower probability of obtaining GCSEs or a degree-level qualification, and fewer years in education. There was no association between p.(Ala391Thr) and self-reported psychotic experiences in this cohort. The schizophrenia-risk allele was associated with poorer cognitive ability, but not psychotic experiences, in a volunteer sample drawn from of the general population. To determine whether p.(Ala391Thr) is associated with cognitive phenotypes in people with schizophrenia, and to understand the role of p.(Ala391Thr) in the aetiology of cognitive impairment in schizophrenia, larger independent samples are required.

Ionic Covalent Organic Framework Membrane as Active Separator for Highly Reversible Zinc-Sulfur Battery.

Zinc-sulfur (Zn-S) batteries exhibit a high theoretical energy density, nontoxicity, and cost-effectiveness, demonstrating significant potential for integration into large-scale energy storage systems. However, the phenomenon of polysulfide (including dissolved S8 and Sx2-) shuttling is a major issue that results in rapid capacity decay and a short lifespan, limiting the practical performance of sulfur-based batteries. Herein, we fabricated an ionic covalent organic framework (iCOF) membrane as an active separator for the Zn-S battery. Sulfonic acid groups were introduced to the COF membrane, providing abundant negative charge sites in its pore wall. By combining size sieving and charge interaction between the polysulfide and pore wall, the iCOF membrane inhibited the crossover of polysulfides to the Zn metal anode without affecting the transport of metal ions. The Zn-S battery with the iCOF membrane as the separator shows a high-performance and low attenuation rate of 0.05% per cycle over 300 cycles at 2.5 A g-1. This study emphasizes the significance of separator design in enhancing Zn-S batteries and showcases the potential of functionalized framework materials for the development of high-performance energy storage systems.

Electrospun Quasi‐Composite Polymer Electrolyte with Hydoxyl‐Anchored Aluminosilicate Zeolitic Network for Dendrite Free Lithium Metal Batteries

AbstractAll‐solid‐state lithium metal batteries have reshaped emerging safe battery technologies. However, their low metal ion transport and unstable electrode electrolyte interface make their mass production a huge question. To bridge the emerging solid state and traditional liquid electrolytes, we focus on Quasi‐Composite Polymer electrolytes (QCPE). Herein, we develop QCPE with active 3D alumino‐silicate zeolitic ion conduction pathways embedded in a polymer matrix using two techniques‐ solution casting and electrospinning. Electrospun QCPE outperforms Solution cast QCPE by achieving high amorphous behavior. Prompt elimination of solvent during electrospinning decreases bulk resistance and increases its ionic conductivity. The Zeolitic pathway anchored by hydroxyl groups of PVA polymer acts as a highway for Li+ ions. It exhibits highly stable platting stripping vs Li+/Li for 450 hours with low overpotential, confirming the interfacial compatibility and dendrite‐free cycling at lithium metal anode. Controlled lithium‐ion nucleation regulated by evenly distributed zeolitic pathway is an interesting front of this work. To test QCPE's performance in Lithium metal battery (LMB), the electrospun QCPE is used to fabricate LMB with LiFePO4 cathode. This battery system delivered a high capacity of 155 mAh g−1 at 0.1 C. In addition to the high performance, electrospun QCPE production is scalable at an industrial scale.

The WFS1-ZnT3-Zn2+ Axis Regulates the Vicious Cycle of Obesity and Depression.

Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural-specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high-fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity-induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD-induced obesity and associated depression. Thus, a WFS1-ZnT3-Zn2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.

In vivo silencing of intestinal DMT1 mitigates iron loading in β-thalassemia intermedia (Hbbth3/+) mice

Abstractβ-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit β (HBB) gene. In β-thalassemia intermedia (βTI), a non–transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1). In mice, DMT1 mediates normal iron absorption under physiological conditions and excessive iron absorption in pathological iron overload (eg, hereditary hemochromatosis). Here, we hypothesized that DMT1 drives elevated iron absorption in βTI. Accordingly, we crossed Hbbth3/+ mice, a preclinical model of βTI, with intestine-specific DMT1-knockout mice. Ablation of intestinal DMT1 in Hbbth3/+ mice caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia. DMT1 is thus required for iron absorption and iron loading in Hbbth3/+ mice. Based upon these outcomes, we further logically postulated that in vivo knockdown of intestinal DMT1 would mitigate iron loading in Hbbth3/+ mice. Ginger-derived, lipid nanoparticles carrying DMT1-specific (or control) small interfering RNAs (siRNAs) were administered by oral, intragastric gavage to 4-week-old Hbbth3/+ mice daily for 16 days. siRNA treatment reduced DMT1 expression by >80% and blunted iron loading, as indicated by significant reductions in liver iron and serum ferritin (which reflect body iron stores). These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in βTI.

Genome-Wide Analysis of the Nramp Gene Family in Kenaf (Hibiscus cannabinus): Identification, Expression Analysis, and Response to Cadmium Stress.

Kenaf (Hibiscus cannabinu) is a grass bast fiber crop that has the ability to tolerate and accumulate heavy metals, and it has been considered as a potential heavy metal accumulator and remediation plant. Nramp is a natural resistance-related macrophage, which plays an important role in the transport of divalent metal ions, plant growth and development, and abiotic stress. In this study, the Nramp gene family of kenaf was analyzed at the whole genome level. A total of 15 HcNramp genes were identified. They are distributed unevenly on chromosomes. Phylogenetic analysis classified 15 HcNramp proteins into 3 different subfamilies. All proteins share specific motif 4 and motif 6, and the genes belonging to the same subfamily are similar in structure and motif. The promoters are rich in hormone response, meristem expression, and environmental stress response elements. Under different treatments, the expression levels of HcNramp genes vary in different tissues, and most of them are expressed in roots first. These findings can provide a basis for understanding the potential role of the Nramp gene family in kenaf in response to cadmium (Cd) stress, and are of great significance for screening related Cd tolerance genes in kenaf.

Traditionally produced tempeh harbors more diverse bacteria with more putative health-promoting properties than industrially produced tempeh

In recent years, there has been a significant shift towards industrialization in food production, resulting in the implementation of higher hygiene standards globally. Our study focused on examining the impact of hygiene standards on tempeh, a popular Rhizopus-based fermented soybean product native to Indonesia, and now famous around the world. We observed that tempeh produced with standardized hygiene measures exhibited a microbiome with comparable bacterial abundances but a markedly different community structure and function than traditionally produced tempeh. In detail, we found a decreased bacterial abundance of lactobacilli and enterobacteria, bacterial diversity, different indicator taxa, and significantly changed community structure in industrial tempeh. A similar picture was found for functional analysis: the quantity of bacterial genes was similar but qualitative changes were found for genes associated with human health. The resistome of tempeh varied based on its microbiome composition. The higher number of antimicrobial resistance genes in tempeh produced without standardized hygiene measures mainly belong to multidrug efflux pumps known to occur in plant-based food. Our findings were confirmed by functional insights into genomes and metagenome-assembled genomes from the dominant bacteria, e.g. Leuconostoc, Limosilactobacillus, Lactobacillus, Enterococcus, Paenibacillus, Azotobacter and Enterobacter. They harboured an impressive spectrum of genes important for human health, e.g. for production of vitamin B1, B7, B12, and K, iron and zinc transport systems and short chain fatty acid production. In conclusion, industrially produced tempeh harbours a less diverse microbiome than the traditional one. Although this ensures production at large scales as well as biosafety, in the long-term it can lead to potential effects for human gut health.

The dynamic roles of intracellular vacuoles in heavy metal detoxification by Rhodotorula mucilaginosa.

Rhodotorula mucilaginosa (Rho) can develop a range of strategies to resist the toxicity of heavy metals. This study aimed to investigate the physiological responses and transcriptomic regulation of the fungus under different heavy metal stresses. This study applied transmission electron microscopy and RNA-seq to investigate the fungal resistance to Pb, Cd, and Cu stresses. Under Pb stress, the activated autophagy-related genes, vesicle-fusing ATPase, and vacuolar ATP synthase improved vacuolar sequestration. This offsets the loss of lipids. However, the metal sequestration by vacuoles was not improved under Cd stress. Vacuolar fusion was also inhibited following the interference of intravacuolar Ca2+ due to their similar ionic radii. Cu2+ showed the maximum toxic effects due to its lowest cellular sorption (as low as 7%) with respect to Pb2+ and Cd2+, although the efflux pumps and divalent metal ion transporters partially contributed to the detoxification. Divalent cation transporters and vacuolar sequestration are the critical strategies for Rho to resist Pb stress. Superoxide dismutase (SOD) is the main strategy for Cd resistance in Rho. The intracellular Cu level was decreased by efflux pump and divalent metal ion transporters.

Single and combined effects of titanium (TiO2) and zinc (ZnO) oxide nanoparticles in the rainbow trout gill cell line RTgill-W1.

Understanding the environmental impact of nanoparticle (NP) mixtures is essential to accurately assess the risk they represent for aquatic ecosystems. However, although the toxicity of individual NPs has been extensively studied, information regarding the toxicity of combined NPs is still comparatively rather scarce. Hence, this research aimed to investigate the individual and combined toxicity mechanisms of two widely consumed nanoparticles, zinc oxide (ZnO NPs) and titanium dioxide (TiO2 NPs), using an in vitro model, the RTgill-W1 rainbow trout gill epithelial cell line. Sublethal concentrations of ZnO NPs (0.1µgmL-1) and TiO2 (30µgmL-1) and a lethal concentration of ZnO NPs causing 10% mortality (EC10, 3µgmL-1) were selected based on cytotoxicity assays. Cells were then exposed to the NPs at the selected concentrations alone and to their combination. Cytotoxicity assays, oxidative stress markers, and targeted gene expression analyses were employed to assess the NP cellular toxicity mechanisms and their effects on the gill cells. The cytotoxicity of the mixture was identical to the one of ZnO NPs alone. Enzymatic and gene expression (nrf2, gpx, sod) analyses suggest that none of the tested conditions induced a strong redox imbalance. Metal detoxification mechanisms (mtb) and zinc transportation (znt1) were affected only in cells exposed to ZnO NPs, while tight junction proteins (zo1 and cldn1), and apoptosis protein p53 were overexpressed only in cells exposed to the mixture. Osmoregulation (Na + /K + ATPase gene expression) was not affected by the tested conditions. The overall results suggest that the toxic effects of ZnO and TiO2 NPs in the mixture were significantly enhanced and could result in the disruption of the gill epithelium integrity. This study provides new insights into the combined effects of commonly used nanoparticles, emphasizing the importance of further investigating how their toxicity may be influenced in mixtures.