An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.

BACKGROUND: Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the "opposite" voltage-sensing properties of hERG and HCN remains unknown. RESULTS: We found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y. CONCLUSIONS: Our data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.

Effects of elevated levels of intracellular nitric oxide on Pseudomonas aeruginosa biofilm in chronic skin wound and slow-killing infection models.

Nitric oxide (NO), produced through the denitrification pathway, regulates biofilm dynamics through the quorum sensing system in Pseudomonas aeruginosa. NO stimulates P. aeruginosa biofilm dispersal by enhancing phosphodiesterase activity to decrease cyclic di-GMP levels. In a chronic skin wound model containing a mature biofilm, the gene expression of nirS, encoding nitrite reductase to produce NO, was low, leading to reduced intracellular NO levels. Although low-dose NO induces biofilm dispersion, it is unknown whether it influences the formation of P. aeruginosa biofilms in chronic skin wounds. In this study, a P. aeruginosa PAO1 strain with overexpressed nirS was established to investigate NO effects on P. aeruginosa biofilm formation in an ex vivo chronic skin wound model and unravel the underlying molecular mechanisms. Elevated intracellular NO levels altered the biofilm structure in the wound model by inhibiting the expression of quorum sensing-related genes, which was different from an in vitro model. In Caenorhabditis elegans as a slow-killing infection model, elevated intracellular NO levels increased worms' lifespan by 18%. Worms that fed on the nirS-overexpressed PAO1 strain for 4 h had complete tissue, whereas worms that fed on empty plasmid-containing PAO1 had biofilms on their body, causing severe damage to the head and tail. Thus, elevated intracellular NO levels can inhibit P. aeruginosa biofilm growth in chronic skin wounds and reduce pathogenicity to the host. Targeting NO is a potential approach to control biofilm growth in chronic skin wounds wherein P. aeruginosa biofilms are a persistent problem.

Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy.

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 µM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm2), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent.

The enhanced bandgap and birefringence of rare-earth phosphates XPO4 (X = Sc, Y, La, and Lu): a first-principles investigation.

Rare-earth phosphates were thought to be good candidates as ultraviolet/deep ultraviolet optical materials due to their relatively large bandgap and optical properties. In this paper, the authors screened out a family of XPO4 (X = Sc, Y, La, and Lu) compounds with an enhanced bandgap (HSE06 bandgap ≥ 7.61 eV) and birefringence (0.0934-0.2003@1064 nm) using first-principles calculations. The origin of enhanced optical properties was investigated using projected density of states, distortion indices, and Born effective charges. The results show that the PO4 anionic groups and X-O polyhedra give the main contribution in determining the optical properties, and the PO4 anionic groups give more contribution than other functional basic units. The spin-orbit interaction was also investigated. Similar band structures were found after spin-orbit coupling (SOC) was considered, and slightly enhanced birefringence was found when SOC was applied to these rare-earth phosphates.

Discovery of novel Akt1 inhibitors by an ensemble-based virtual screening method, molecular dynamics simulation, and in vitro biological activity testing.

Akt1, as an important member of the Akt family, plays a controlled role in cancer cell growth and survival. Inhibition of Akt1 activity can promote cancer cell apoptosis and inhibit tumor growth. Therefore, in this investigation, a multilayer virtual screening approach, including receptor-ligand interaction-based pharmacophore, 3D-QSAR, molecular docking, and deep learning methods, was utilized to construct a virtual screening platform for Akt1 inhibitors. 17 representative compounds with different scaffolds were identified as potential Akt1 inhibitors from three databases. Among these 17 compounds, the Hit9 exhibited the best inhibitory activity against Akt1 with inhibition rate of 33.08% at concentration of 1 µM. The molecular dynamics simulations revealed that Hit9 and Akt1 could form a compact and stable complex. Moreover, Hit9 interacted with some key residues by hydrophobic, electrostatic, and hydrogen bonding interactions and induced substantial conformation changes in the hinge region of the Akt1 active site. The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol-1, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

Loss of TIMP3, but not TIMP4, exacerbates thoracic and abdominal aortic aneurysm.

AIMS: Aorta exhibits regional heterogeneity (structural and functional), while different etiologies for thoracic and abdominal aortic aneurysm (TAA, AAA) are recognized. Tissue inhibitor of metalloproteinases (TIMPs) regulate vascular remodeling through different mechanisms. Region-dependent functions have been reported for TIMP3 and TIMP4 in vascular pathologies. We investigated the region-specific function of these TIMPs in development of TAA versus AAA. METHODS & RESULTS: TAA or AAA was induced in male and female mice lacking TIMP3 (Timp3-/-), TIMP4 (Timp4-/-) or in wildtype (WT) mice by peri-adventitial elastase application. Loss of TIMP3 exacerbated TAA and AAA severity in males and females, with a greater increase in proteinase activity, smooth muscle cell phenotypic switching post-AAA and -TAA, while increased inflammation was detected in the media post-AAA, but in the adventitia post-TAA. Timp3-/- mice showed impaired intimal barrier integrity post-AAA, but a greater adventitial vasa-vasorum branching post-TAA, which could explain the site of inflammation in AAA versus TAA. Severity of TAA and AAA in Timp4-/- mice was similar to WT mice. In vitro, Timp3 knockdown more severely compromised the permeability of human aortic EC monolayer compared to Timp4 knockdown or the control group. In aneurysmal aorta specimens from patients, TIMP3 expression decreased in the media in AAA, and in adventitial in TAA specimens, consistent with the impact of its loss in AAA versus TAA in mice. CONCLUSION: TIMP3 loss exacerbates inflammation, adverse remodeling and aortic dilation, but triggers different patterns of remodeling in AAA versus TAA, and through different mechanisms.

The additional role of [68Ga]Ga-FAPI-04 PET/CT in patients with unknown primary lesion with a negative or equivocal [18F]FDG.

PURPOSE: [18F]FDG PET/CT to detect unknown primary lesions is essential for clinical management but still has limitations. [68Ga]Ga-FAPI is a tumor-stromal imaging agent that provides a promising alternative to [18F]FDG for the assessment of malignancies. We aimed to investigate whether [68Ga]Ga-FAPI PET/CT has an additional role in identifying unknown primary lesions with negative or equivocal [18F] FDG PET/CT results. METHODS: This single-center prospective clinical study was conducted between March 2020 and March 2022 at Southwest Medical University Hospital. Patients underwent [18F]FDG PET/CT for the identification of unknown primary lesions. They underwent repeat [68Ga]Ga-FAPI PET/CT when [18F]FDG PET/CT results were negative or equivocal. Histopathological examination, surgery, or clinical follow-up (at least 3 months) for FAPI-positive lesions. The diagnostic efficacy of [68Ga]Ga-FAPI in identifying unknown primary lesions was evaluated. RESULTS: A total of 44 participants (median age, 57 ± 12 [SD]; 22 [50%] men) were evaluated. Thirteen of the 44 patients had equivocal [18F]FDG PET/CT findings, while the diagnosis was clear on [68Ga]Ga-FAPI PET/CT. [68Ga]Ga-FAPI PET/CT also revealed primary lesions in additional 17 patients with negative [18F]FDG PET/CT findings. In fourteen of 44 patients, no primary lesion was detected by either tracer. On this basis, we analyzed 94 lymph node metastatic lesions. The mean SUVmax of lymph node metastases on [68Ga] Ga-FAPI PET/CT and [18F]FDG PET/CT were 9.2 ± 5.1, 7.9 ± 4.8 (p = 0.03) and the mean TBR were 9.1 ± 5.2, 4.9 ± 3.1 (p < 0.01), respectively. CONCLUSION: [68Ga]Ga-FAPI PET/CT showed great potential for identifying unknown primary lesions and has the potential to improve the detection rate of unknown primary lesions with negative or equivocal for [18F]FDG findings. TRIAL REGISTRATION: ClinicalTrial.gov. Identifier: ChiCTR2100044131.

PLAU contributes to the development of cholangiocarcinoma via activating NF-κB signaling pathway.

Cholangiocarcinoma (CCA) is a type of epithelial cancer with poor outcomes and late diagnosis. Accumulating evidence has demonstrated the promoting role of plasminogen activator, urokinase (PLAU) in several tumor types, while its function in CCA is largely unknown. The expression of PLAU in CCA was determined by data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database and further confirmed in human tissues using immunohistochemical (IHC) staining. Moreover, PLAU-silencing CCA cell models were constructed for subsequent functional assays in vitro and in vivo. PLAU expression in CCA was significantly higher than that in normal tissues. High PLAU expression was positively correlated with poor patients' survival. PLAU knockdown remarkably suppressed proliferation and migration of CCA cells, whereas enhanced apoptosis. Consistently, tumor growth in mice injected with PLAU-silencing CCA cells was also impaired. Furthermore, we revealed that the activation of NF-κB signaling was required for PLAU-induced malignant phenotypes of CCA cells. Inhibiting the high expression of PLAU in CCA may be a potential entry point for targeted therapy in CCA patient.

Li3B8O13X (X = Cl and Br): Two New Noncentrosymmetric Crystals with Large Birefringence Induced by BO3 Units.

Enthusiasm for the exploration of nonlinear alkali metal borates remains high. Focusing on the Li-B-O-X (X = Cl and Br) system, two examples of noncentrosymmetric borates, Li3B8O13Cl and Li3B8O13Br, were obtained using a high-temperature solution method under vacuum conditions. Structurally, the Li3B8O13X crystals exhibit two independent alternately arranged three-dimensional B-O network structures formed by the basic building block unit B8O16. The performance measurements demonstrate their short ultraviolet cutoff edges. The theoretical calculation indicates that the BO3 units dominate the contribution to their large optical anisotropy with the birefringence, 0.094 and 0.088@1064 nm for Li3B8O13Cl and Li3B8O13Br, respectively.

Ionic Liquids-Driven Cluster-to-Cluster Conversion of Polyhydrido Copper(I) Clusters Cu7H5 to Cu8H6 and Cu12H9.

Although ionic liquids (ILs) are of prime interest for the synthesis of various nanomaterials, they are scarcely utilized for the polyhydrido copper(I) [Cu(I)H] clusters. Herein, two air-stable Cu(I)H clusters, [Cu8H6(dppy)6](NTf2)2 (Cu8H6) and {Cu12H9(dppy)6[N(CN)2]3} (Cu12H9), are synthesized in high yields for the first time from the ILs-driven conversion of an unprecedented cluster [Cu7H5(dppy)6](ClO4)2 (Cu7H5) by a facile three-layers diffusion crystal (TLDC) method, strategically introducing IL-NTf2 and IL-N(CN)2 as two types of unusual interfacial crystallized templates, respectively. Their structures are fully characterized by various spectroscopic methods and X-ray crystallography, which shows that the anion of IL plays an important role as an anion template and an anion ligand in controlling the structural conversion of Cu(I)H clusters. Their photophysical properties are also investigated, and it is found that all reported clusters exhibit red luminescence with λem ranging from 600 to 690 nm.

Enhancing endocannabinoid signalling in astrocytes promotes recovery from traumatic brain injury.

Traumatic brain injury is an important risk factor for development of Alzheimer's disease and dementia. Unfortunately, no effective therapies are currently available for prevention and treatment of the traumatic brain injury-induced Alzheimer's disease-like neurodegenerative disease. This is largely due to our limited understanding of the mechanisms underlying traumatic brain injury-induced neuropathology. Previous studies showed that pharmacological inhibition of monoacylglycerol lipase, a key enzyme degrading the endocannabinoid 2-arachidonoylglycerol, attenuates traumatic brain injury-induced neuropathology. However, the mechanism responsible for the neuroprotective effects produced by inhibition of monoacylglycerol lipase in traumatic brain injury remains unclear. Here we first show that genetic deletion of monoacylglycerol lipase reduces neuropathology and averts synaptic and cognitive declines in mice exposed to repeated mild closed head injury. Surprisingly, these neuroprotective effects result primarily from inhibition of 2-arachidonoylglycerol metabolism in astrocytes, rather than in neurons. Single-cell RNA-sequencing data reveal that astrocytic monoacylglycerol lipase knockout mice display greater resilience to traumatic brain injury-induced changes in expression of genes associated with inflammation or maintenance of brain homeostasis in astrocytes and microglia. The monoacylglycerol lipase inactivation-produced neuroprotection is abrogated by deletion of the cannabinoid receptor-1 or by adeno-associated virus vector-mediated silencing of astrocytic peroxisome proliferator-activated receptor-γ. This is further supported by the fact that overexpression of peroxisome proliferator-activated receptor-γ in astrocytes prevents traumatic brain injury-induced neuropathology and impairments in spatial learning and memory. Our results reveal a previously undefined cell type-specific role of 2-arachidonoylglycerol metabolism and signalling pathways in traumatic brain injury-induced neuropathology, suggesting that enhanced 2-arachidonoylglycerol signalling in astrocytes is responsible for the monoacylglycerol lipase inactivation-produced alleviation of neuropathology and deficits in synaptic and cognitive functions in traumatic brain injury.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Association between post-stroke smoking and stroke recurrence in first-ever ischemic stroke survivors: based on a 10-year prospective cohort.

BACKGROUND: Whether smoking is a risk factor for ischemic stroke (IS) recurrence in IS survivors is still uncovered, and evidences are sparse. Meanwhile, an add-on effect of clopidogrel was observed in myocardial infarction patients who smoked, but whether the paradox exists in IS patients is still unsolved. The objectives of this study are to explore the association between smoking behavior after index stroke and IS recurrence and to explore whether the paradox exists. METHODS: A prospective cohort of first-ever IS patients was conducted between 2010 and 2019. The prognosis and smoking features of enrolled patients were obtained via telephone follow-up every 3 months. Fine-gray model with interaction terms was applied to measure the relationships between stroke recurrence and smoking behaviors after index stroke and to explore the add-on effect of clopidogrel in smoking patients. RESULTS: There were 171 (24.26%) recurrences and 129 (18.30%) deaths during follow-up in 705 enrolled IS patients. One hundred forty-six (20.71%) patients smoked after index stroke. The hazard ratios (HRs) and 95% confidence intervals (CIs) of interaction terms between antiplatelet drug and follow-up smoking (smoking status and daily smoking amount) were 1.092 (95% CI: 0.524, 2.276) and 0.985 (95% CI: 0.941, 1.031), respectively. A significantly higher risk of recurrence was observed in patients with a higher daily smoking amount during follow-up (per cigarette), with HR being 1.027 (95% CI: 1.003, 1.052). CONCLUSIONS: Smoking could elevate the risk of IS recurrence, and IS survivor should be advised to quit or smoke less. Add-on effect of clopidogrel may not exist in smoking strokers taking clopidogrel.

Characterization of Polysaccharides from the Pericarp of Zanthoxylum bungeanum Maxim by Saccharide Mapping and Their Neuroprotective Effects.

The pericarp of Zanthoxylum bungeanum maxim (PZM) is a commonly used spice and herbal medicine in China. In the present study, the structural characteristics of PPZM were investigated by saccharide mapping after enzymatic digestion by using high-performance thin layer chromatography (HPTLC) and polysaccharide analysis by using carbohydrate gel electrophoresis (PACE). The mechanisms of protective effects of PPZM on Aß25-35-induced oxidative damage were explored in PC12 cells. The results showed that PPZM contained 1,4-α-D-galactosidic, 1,4-α-D-galactosiduronic, and (1→4)-ß-D-glucosidic linkages. Pretreatment with PPZM significantly increased the cell viability of Aß25-35-injured PC12 cells. Flow cytometry and Hoechst/PI staining indicated that PPZM gradually relieved the apoptosis of the Aß25-25-treated cells. PPZM markedly decreased the ROS level of PC12 cells and suppressed Aß25-35-induced oxidative stress by increasing the SOD level, and decreasing the level of MDA and LDH. The mRNA expressions of caspase-3 and Bax were significantly downregulated, and Bcl-2 expression was upregulated by treatment with PPZM. PPZM significantly increased the mRNA expression of Nrf2 and HO-1 in Aß25-35 treated cells. The results indicated that PPZM alleviated apoptosis and oxidative stress induced by Aß25-25 through the inhibition of mitochondrial dependent apoptosis and activation of Nrf2/HO-1 pathway. PPZM can be used as a potential protective agent against Aß25-25-induced neurotoxicity.

Emergent Zero-Fluoroscopy Mapping and Thoracoscopic Ectomy of Appendage in Pregnant Women with Life-Threatening Atrial Tachycardia: A Case Report and Literature Review.

Background: Focal atrial tachycardia (AT) originating from the right atrial appendage (RAA), often persistent and refractory, is clinically rare in pregnant woman, and the therapy is much more challenging. We report that a pregnant woman presented with hypotension due to persistent and refractory atrial tachycardia and was successfully cured by a multidisciplinary treatment (MDT) approach, consisting of a combination of zero-fluoroscopy mapping and thoracoscopic atrial appendectomy. We also carried out a literature review of this topic. Methods and Results: A 26-year-old woman in pregnancy at 21 weeks presented with severe palpitation and hypotension due to persistent rapid supraventricular tachycardia (SVT). Since adenosine triphosphate could not terminate the tachycardia, a catheter ablation procedure was planned and finally canceled when the zero-fluoroscopy mapping using Carto 3TM system revealed an atrial tachycardia originating from the RAA. Thoracoscopic RAA ectomy was recommended after multidisciplinary consultation and successfully performed without fluoroscopy. EnsiteTM velocity mapping system was used for accurately locating the origin of the arrhythmia during ectomy. The woman finally produced a healthy baby during follow-up. Conclusions: Focal AT originating from appendage in pregnant patients can be persistent, refractory, and life-threatening; traditional strategies, such as medicine or catheter ablation, are limited in this situation. MDT measures, using a thoracoscopic ectomy and zero-fluoroscopy three-dimensional electroanatomical mapping technique, is minimally invasive and a promising strategy.

High Neutralizing Antibody Levels Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1 and BA.2 After UB-612 Vaccine Booster.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has caused high rates of breakthrough infections in those previously vaccinated with ancestral strain coronavirus disease 2019 (COVID-19) vaccines. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increased neutralizing antibody levels by 131-, 61-, and 49-fold against ancestral SARS-CoV-2 and the Omicron BA.1 and BA.2 variants, respectively. Based on the receptor-binding domain protein binding antibody responses, the UB-612 third-dose booster may lead to an estimated approximately 95% efficacy against symptomatic COVID-19 caused by the ancestral strain. Our results support UB-612 as a potential potent booster against current and emerging SARS-CoV-2 variants.

[Relationship between immune regulation and structure of polysaccharides].

Polysaccharides have significant immunomodulatory activity and have good development value in food and medicine fields. At present, there are many studies on the chemical structure and immune activity of polysaccharides, but the relationship between them of polysaccharides has not been fully explained, which limits the further development and utilization of polysaccharide resources. The immune activity of polysaccharides is closely related to their own structure. This paper systematically summarized the relationship between the relative molecular weight, monosaccharide composition, glycosidic bond types, chemical modification, and advanced conformation of polysaccharides and the immune regulation, aiming to provide references for the profound study of polysaccharide structure-activity relationship and utilization of polysaccharides.

Implications of Sm22α-Cre expression in keratinocytes and unanticipated inflammatory skin lesion in a model of atherosclerosis.

Genetically modified mice are widely used to recapitulate human diseases. Atherosclerosis can be induced in mice with low-density lipoprotein receptor (Ldlr)-deficiency and a high-fat diet (HFD). Disintegrin and metalloproteinase-17 (ADAM17) in the smooth muscle cell (SMC) contribute to vascular pathologies, and hence its role in atherosclerosis was investigated. Adam17 deletion in SMCs by Sm22α-Cre driver (Ldlr-/-/Adam17Sm22Cre) and HFD resulted in severe skin lesions in >70% of mice, associated with skin inflammation, which was not observed in Ldlr-/--HFD, nor in mice with SMC deficiency of Adam17 by a different Cre driver (Ldlr-/-/Adam17Myh11Cre). We found that Sm22α is highly expressed in keratinocytes (compared with SMCs), which could underlie the observed skin lesion in Ldlr-/-/Adam17Sm22Cre-HFD. Although expression of Sm22α in non-SMCs has been reported, this is the first study demonstrating a severe side effect resulting from the off-target expression of Sm22α-Cre, resulting in ADAM17 loss in keratinocytes that led to a moribund state.NEW & NOTEWORTHY Although Sm22α-Cre is commonly used to target gene deletion in smooth muscle cells, Sm22α-derived Adam17 deletion resulted in unexpected severe skin lesions following high-fat diet feeding in a model of atherosclerosis. Adam17 deletion by a different SMC driver, Myh11-Cre, did not result in skin lesions in the same atherosclerosis model. Sm22α is highly expressed in keratinocytes, causing ectopic loss of ADAM17 in keratinocytes that caused significant epidermal lesions when combined with a high-fat diet.

Clinical value of the expression levels of protein tyrosine phosphatase non-receptor type 22.6 mRNA in peripheral blood mononuclear cells in Crohn's disease.

OBJECTIVE: To explore the relationship between the expression levels of protein tyrosine phosphatase non-receptor type (PTPN) 22.6 mRNA in peripheral blood mononuclear cells (PBMCs) and the disease activity as well as clinical characteristics in Crohn's disease (CD) patients. METHODS: A total of 480 subjects were enrolled. Data were collected including baseline information, expression levels of PTPN22.6 mRNA in PBMCs for all subjects, C-reactive protein (CRP) levels in serum, clinical characteristics, and disease activity for all patients. Expression levels of PTPN22.6 mRNA in PBMCs, CRP levels in serum, clinical characteristics according to Montreal Classification [8], and Crohn's disease activity index (CDAI) were the primary observation outcomes. RESULTS: The expression levels of PTPN22.6 mRNA (P = 0.032) in PBMCs and serum CRP levels (P < 0.001) were significantly higher in active CD patients than in inactive CD patients (P = 0.032). Correlation analysis showed that there was a positive correlation between expression levels of PTPN22.6 mRNA and CDAI value (r = 0.512, P = 0.003), as well as expression levels of PTPN22.6 mRNA and CRP levels in the CD group (r = 0.456, P = 0.006). There were significantly higher expression levels of PTPN22.6 mRNA in PBMCs in patients with structuring behavior than that in patients with non-stricturing and non-penetrating (NSNP) behaviors (P = 0.018) and penetrating behaviors (P = 0.024). CONCLUSIONS: The expression levels of PTPN22.6 mRNA can be used as an indicator to help predict CD diagnosis, disease activity, serum CRP level, and behavior type of CD disease.

TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer's disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aß formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.