ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

Acidified Nitrogen Self-Doped Porous Carbon with Superprotonic Conduction for Applications in Solid-State Proton Battery.

Solid proton electrolytes play a crucial role in various electrochemical energy storage and conversion devices. However, the development of fast proton conducting solid proton electrolytes at ambient conditions remains a significant challenge. In this study, a novel acidified nitrogen self-doped porous carbon material is presented that demonstrates exceptional superprotonic conduction for applications in solid-state proton battery. The material, designated as MSA@ZIF-8-C, is synthesized through the acidification of nitrogen-doped porous carbon, specifically by integrating methanesulfonic acid (MSA) into zeolitic imidazolate framework-derived nitrogen self-doped porous carbons (ZIF-8-C). This study reveals that MSA@ZIF-8-C achieves a record-high proton conductivity beyond 10-2  S cm-1 at ambient condition, along with good long-term stability, positioning it as a cutting-edge alternative solid proton electrolyte to the default aqueous H2 SO4 electrolyte in proton batteries.

Phylogeography of cultivated and wild ophiopogon japonicus based on chloroplast DNA: exploration of the origin and sustainable cultivation.

BACKGROUND: Ophiopogon japonicus, mainly planted in Sichuan (CMD) and Zhejiang (ZMD) province in China, has a lengthy cultivation history. During the long period of domestication, the genetic diversity of cultivated O. japonicus has substantially declined, which will affect the population continuity and evolutionary potential of this species. Therefore, it is necessary to clarify the phylogeography of cultivated O. japonicus to establish a theoretical basis for the utilization and conservation of the genetic resources of O. japonicus. RESULT: The genetic diversity and population structure of 266 O. japonicus individual plants from 23 sampling sites were analyzed based on 4 chloroplast DNA sequences (atpB-rbcL, rpl16, psbA-trnH and rpl20-5'rps12) to identify the effects of domestication on genetic diversity of cultivars and determine their geographic origins. The results showed that cultivated O. japonicus and wild O. japonicus had 4 and 15 haplotypes respectively. The genetic diversity of two cultivars (Hd = 0.35700, π = 0.06667) was much lower than that of the wild populations (Hd = 0.76200, π = 0.20378), and the level of genetic diversity in CMD (Hd = 0.01900, π = 0.00125) was lower than that in ZMD (Hd = 0.06900, π = 0.01096). There was significant difference in genetic differentiation between the cultivated and the wild (FST = 0.82044), especially between the two cultivars (FST = 0.98254). This species showed a pronounced phylogeographical structure (NST > GST, P < 0.05). The phylogenetic tree showed that the genetic difference between CMD and ZMD was not enough to distinguish the cultivars between the two producing areas by using O. amblyphyllus Wang et Dai as an outgroup. In addition, both CMD and ZMD have a closer relationship with wild populations in Sichuan than that in Zhejiang. The results of the TCS network and species distribution model suggested that the wild population TQ located in Sichuan province could serve as the ancestor of cultivated O. japonicus, which was supported by RASP analysis. CONCLUSION: These results suggest that cultivated O. japonicus has experienced dramatic loss of genetic diversity under anthropogenic influence. The genetic differentiation between CMD and ZMD is likely to be influenced by founder effect and strong artificial selection for plant traits. It appears that wild populations in Sichuan area are involved in the origin of not only CMD but also ZMD. In addition, we also raise some suggestions for planning scientific strategies for resource conservation of O. japonicus based on its genetic diversity and population structure.

Global dynamics of a tuberculosis model with age-dependent latency and time delays in treatment.

Since there exists heterogeneity in incubation periods of tuberculosis and a time lag between treatment and recovery. In this study, we develop a tuberculosis model that takes into account age-dependent latency and time delays in treatment to describe the transmission of tuberculosis. We first show that the solution semi-flow of the model is well-posed and has a global attractor [Formula: see text] within an infinite dimensional space [Formula: see text]. Then we define the basic reproduction number [Formula: see text] and prove that it determines the global dynamics of the model. If [Formula: see text], the global attractor [Formula: see text] reduces to the disease-free equilibrium state, indicating that the disease-free equilibrium state is globally asymptotically stable. When [Formula: see text], the semi-flow generated by the model is uniformly persistent, and there exists an interior global attractor [Formula: see text] for this uniformly persistent model. By constructing a suitable Lyapunov function and applying LaSalle's Invariance Principle, we show that the global attractor [Formula: see text] is reduced to the endemic equilibrium state, which means that the endemic equilibrium state is globally asymptotically stable. Based on the tuberculosis data in China from 2007 to 2020, we simulate the parameters and initial values of the proposed model. Furthermore, we calculate the sensitivity of [Formula: see text] to the parameters and find the most sensitive parameters to [Formula: see text]. Finally, we present an improved strategy to achieve the WHO's goal of reducing the incidence of tuberculosis by 90% by 2035 compared to 2015.

[Establishment of a Rat Model of Hypotension Induced by Reserpine].

Objective To determine the optimal dosage and intervention duration of reserpine to establish a rat model of hypotension.Methods According to the body weight and systolic blood pressure (SBP),60 male Wistar rats were assigned to six groups (n=10),including a control group and five observation groups with different doses.The control group was administrated with 10 ml/kg 0.5% sodium carboxymethyl cellulose solution,and the observation groups with 0.016,0.032,0.064,0.128,and 0.160 mg/kg reserpine suspensions,respectively.All the groups were administrated by gavage twice a day,and the body weights of rats were monitored daily.SBP and heart rate (HR) were measured before modeling and 1-6 weeks after administration.After 6 weeks of administration,the blood samples of inner canthus were collected.The levels of lactate dehydrogenase (LDH),creatine kinase MB isoenzyme (CK-MB),alanine aminotransferase,aspartate aminotransferase (AST),serum creatinine,and blood urea nitrogen (BUN) were measured by an autoanalyzer.Three rats in each group were randomly selected for observation of the changes in SBP after drug withdrawal and the rest rats were sacrificed for measurement of the levels of norepinephrine and dopamine in the brain.Results Compared with the control group,different doses of reserpine lowered the SBP of rats (F=28.492,P<0.001).The decline in SBP increased in a concentration-dependent manner.SBP reached the lowest value after 1 week,rose slightly later,and was stable after 3 weeks of administration.There was no significant difference in SBP between 0.016 mg/kg reserpine group and the control group after the 5th week (P>0.05).The SBP levels of rats in 0.032,0.064,0.128,and 0.160 mg/kg reserpine groups showed no significant difference between each other (P=0.204) and were lower than that in the control group (all P<0.001).One week after drug withdrawal,the SBP of rats in the observation groups rose to the baseline level and remained stable.HR showed similar changes among groups,first increasing and then decreasing.There was no significant difference in HR among different groups at the same time point (F=0.922,P=0.475).Compared with the control group,reserpine of different doses reduced the norepinephrine content in the hippocampus (all P<0.001),and 0.128 mg/kg (P=0.045) and 0.160 mg/kg (P=0.042) reserpine lowered the dopamine level in the striatum,which showed no significant differences between different reserpine groups(P=0.343,P=0.301).The levels of LDH,CK-MB,and BUN in the serum increased with the increase in reserpine concentration,and the levels of LDH (P=0.001),CK-MB (P=0.020),AST (P=0.007),and BUN (P=0.001) in the 0.160 mg/kg reserpine group were significantly different from those in the control group.Conclusions The rat model of hypotension can be induced by gavage with reserpine.The gavage with reserpine at a dose of 0.032 mg/kg,twice a day for three consecutive weeks is the optimal scheme for the modeling.After the model establishment,continuous administration is essential to maintain the hypotension.

KCC2 is required for the survival of mature neurons but not for their development.

The K+/Cl- cotransporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl- levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally, which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture, we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization, or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture.

Metal-Organic Framework-Derived N-Doped Porous Carbon for a Superprotonic Conductor at above 100 °C.

The development of proton conductors capable of working at above 100 °C is of great significance for proton exchange membrane electrolysis cells (PEMECs) and proton exchange membrane fuel cells (PEMFCs) but remains to be an enormous challenge to date. In this work, we demonstrate for the first time that the N-doped porous carbon derived from metal-organic frameworks (MOFs) with great superiority can be exploited for high-performing proton conductors at above 100 °C. Through the pyrolysis of ZIF-8, the N-doped porous carbon (ZIF-8-C) featuring high chemical resistance to Fenton's reagent was readily prepared and then served as a robust host to accommodate H3PO4 molecules for proton transport. Upon impregnation with H3PO4, the resulting PA@ZIF-8-C exhibits low water swelling and high proton conduction of over 10-2 S cm-1 at a temperature above 100 °C, which is superior to many reported proton conductors. This work provides a new approach for the design of high-performing proton conductors at above 100 °C.

[Research progress on role of traditional Chinese medicine in hepatic fibrosis based on miRNA-mediated activation of NLRP3 inflammasome].

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1ß and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

4-Methoxydalbergione is a potent inhibitor of human astroglioma U87 cells in vitro and in vivo.

Astroglioma is the most common primary tumor in the central nervous system without effective treatment strategies. Temozolomide (TMZ) is a chemotherapeutic drug to treat astroglioma but exhibits low potency and has side effects. Therefore, there is an urgent need to develop new compounds to treat astroglioma. Dalbergia sissoo Roxb was the source of Dalbergia odorifera in traditional Chinese medicine (TCM) and has been clinically used as an anti-tumor medicine. 4-Methoxydalbergione (4MOD) is purified from Dalbergia sissoo Roxb., and shows an inhibitory effect on osteosarcoma, but its effects on astroglioma have not been reported. Here, we evaluate its anti-astroglioma effects on both in vitro and in vivo models. In cultured astroglioma U87 cells, 4MOD inhibited cell proliferation and induced cell apoptosis in a time- and concentration-dependent manner. Compared with TMZ, 4MOD exhibited a tenfold greater potency of anti-astroglioma effects. 4MOD effectively stalled the cell cycle in G2 phase. Transcriptome sequencing (RNA-seq) showed that 4MOD upregulated 158 genes and downregulated 204 genes that are mainly enriched in cell membrane, cell division, cell cycle, p53, TNF, and MAPK signaling pathways, which may underlie its anti-tumor mechanisms. In a nude mouse xenograft model transplanted with U87 cells, 10 mg/kg 4MOD slowed down tumor growth rate, while at 30 mg/kg dose, it reduced tumor size. Collectively, this study demonstrates that 4MOD is a potent native compound that remarkably inhibits U87 astroglioma growth in both in vitro and in vivo models.

Anatomic study of carpal tunnel in adults using monoenergetic reconstruction of dual-energy computed tomography.

OBJECTIVE: To seek optimal keV settings for imaging carpal tunnel in adults by dual-energy computed tomography (DECT) monoenergetic technique; to describe anatomic characteristics of carpal tunnel and to observe correlation between carpal bony and soft tissue structures. METHODS: DECT images of 20 wrists (11 left and 9 right wrists; 14 men, mean age 26.93±1.38 years, range 23 to 28, and 6 women, mean age 24.17 ± 0.98 years, range 23 to 26) were evaluated. Monoenergetic images were reconstructed at 42, 62, 82, 102, 122, and 142 keV. Image quality was assessed along a 5-point Likert scale, and the highest-quality images were chosen for quantitative analysis. Two musculoskeletal radiologists performed both analyses independently. RESULTS: The optimal energy spectrum with the best contrast-to-noise ratio (CNR) for monoenergetic images were at 62 keV (19 wrists, 95%) and 61 keV (1 wrist, 5%). There was substantial interobserver agreement between the readers in the 5-point Likert scale analysis of image quality (k= 0.793). Bland-Altman plots also indicated good agreement between observers in quantitative analysis. Intra-category 1 and 2 correlation was mostly discovered at hamate hook level and middle level of pisiform (P < 0.05), while bony and soft tissue structures partly reached correlation (P < 0.05). CONCLUSIONS: The optimal energy spectrum for monoenergetic DECT imaging of carpal tunnel structures was 62 keV. DECT monoenergetic imaging could predict changes in soft tissue structures and demonstrate carpal tunnel anatomic structures.

Next generation sequencing of RB1gene for the molecular diagnosis of ethnic minority with retinoblastoma in Yunnan.

BACKGROUND: Retinoblastoma is a rare intraocular malignancy and typically initiated by inactivating biallelic mutations of RB1 gene. Each year, ~ 8000 children worldwide are diagnosed for retinoblastoma. In high-income countries, patient survival is over 95% while low-income countries is ~ 30%.If disease is diagnosed early and treated in centers specializing in retinoblastoma, the survival might exceed 95% and many eyes could be safely treated and support a lifetime of good vision. In China, approximate 1100 newly diagnosed cases are expected annually and 28 hospitals covering 25 provinces established centers classified by expertise and resources for better treatment options and follow-up. Comparing with other province of eastern China, Yunnan province is remote geographically. This might result that healthcare staff have low awareness of the role of genetic testing in management and screening in families. METHODS: The patients with retinoblastoma were selected in Yunnan. DNA from blood was used for targeted gene sequencing. Then, an in-house bioinformatics pipeline was done to detect both single nucleotide variants and small insertions/deletions. The pathogenic mutations were identified and further confirmed by conventional methods and cosegregation in families. RESULTS: Using our approach, targeted next generation sequencing was used to detect the mutation of these 12 probands. Bioinformatic predictions showed that nine mutations were found in our study and four were novel pathogenic variants in these nine mutations. CONCLUSIONS: It's the first report to describe RB1 mutations in Yunnan children with retinoblastoma. This study would improve role of genetic testing for management and family screening.

Regulation of flowering transition by alternative splicing: the role of the U2 auxiliary factor.

Flowering transition is regulated by complex genetic networks in response to endogenous and environmental signals. Pre-mRNA splicing is an essential step for the post-transcriptional regulation of gene expression. Alternative splicing of key flowering genes has been investigated in detail over the past decade. However, few splicing factors have been identified as being involved in flowering transition. Human heterodimeric splicing factor U2 snRNP auxiliary factor (U2AF) consists of two subunits, U2AF35 and U2AF65, and functions in 3' splice site recognition in mRNA splicing. Recent studies reveal that Arabidopsis U2AF65a/b and U2AF35a/b play important roles in the splicing of key flowering genes. We summarize recent advances in research on splicing-regulated flowering transition by focusing on the role of Arabidopsis U2AF in the splicing of key flowering-related genes at ambient temperature and in the abscisic acid signaling pathways.

IGF2BP1 silencing inhibits proliferation and induces apoptosis of high glucose-induced non-small cell lung cancer cells by regulating Netrin-1.

Non-small cell lung cancer (NSCLC) accompanied by diabetes is an important risk factor affecting the prognosis of patients with NSCLC in clinical practice. However, the effect of high glucose (HG) in the pathogenesis of NSCLC remains elusive. It has been found that the RNA-binding protein Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) plays important roles in various diseases, including NSCLC and diabetes. The aim of this study was to explore the role of IGF2BP1 in HG-treated NSCLC cells, and further investigate its underlying molecular mechanism. Results showed that IGF2BP1 was highly expressed in HG-treated NSCLC cells. Knockdown of IGF2BP1 inhibited cancer cell proliferation, migration and invasion, as well as induced cell cycle arrest and apoptosis. Besides, IGF2BP1 silencing decreased the Netrin-1 level in HG-treated NSCLC cells. Reintroduction of Netrin-1 expression rescued IGF2BP1 deficiency-induced cell proliferation reduction, migration suppression, cell cycle arrest and apoptosis. These findings suggest that IGF2BP1 silencing inhibits the occurrence of tumor events through down-regulating Netrin-1 expression, indicating that the IGF2BP1/Netrin-1 axis exerts an oncogenic role in HG-treated NSCLC cells.

Proton Conduction of an Acid-Resistant Open-Framework Chalcogenidometalate Hybrid in Anhydrous versus Humid Environments.

Solid proton conductors are broadly applicable to various electrochemical devices; therefore, it is highly desirable to develop robust materials with high proton conductivity under both anhydrous and humid environments within a wide temperature range. In this work, we investigated the proton conducting properties of a 3D open-framework chalcogenidometalate hybrid, [CH3NH3]2[H3O]Ag5Sn4Se12·C2H5OH (1), which exhibited both anhydrous and water-assisted proton conduction. Importantly, the excellent thermal and chemical stabilities of hybrid 1 are superior to many MOF-based proton conducting materials. This present study proved to be a considerable advance based on open-framework chalcogenidometalates in the design of robust solid proton conducting materials that are capable of operating under humid and anhydrous environments in a wide temperature range.

Design and Preparation of a Superior Proton Conductor by Confining Tetraethylenepentamine in the Pores of ZIF-8 To Induce Further Adsorption of Water and Carbon Dioxide.

In this work, we present a new strategy toward the design and preparation of a metal-organic framework- or porous coordination polymer-based superior proton conductor. We chose a robust metal-organic framework, ZIF-8, as the host and a flexible aliphatic alkylpolyamine, tetraethylenepentamine (TEPA), as the guest, and we successfully prepared an encapsulation compound TEPA@ZIF-8 via the facile insertion of TEPA into the pores of ZIF-8, which was characterized by microanalysis, thermogravimetric analysis, IR spectroscopy, N2, water vapor adsorption-desorption, and other methods. Each cage in ZIF-8 is occupied by ∼1.44 TEPA molecules, and the introduced TEPA further adsorbs H2O and CO2 from air to offer a superior proton conductor, TEPA@ZIF-8-H2CO3, with σ = 2.08 × 10-3 S cm-1 at 293 K and 99% relative humidity, and excellent proton conduction durability. Regarding ZIF-8, the proton conductivity of TEPA@ZIF-8-H2CO3 increases by 3 orders of magnitude at the same condition, and the activation energy decreases by 0.91 eV. Remarkably, TEPA@ZIF-8-H2CO3 also shows promising features for the detection of aqueous ammonia. This work provides more opportunities to achieve superior protonic conducting materials and suggests that MOF-based proton conductors possess great potential for applications in ammonia sensing.

[Research progress of visual prosthesis].

Vision is one of the most important human sensations about the surrounding world. Visual deprivation not only markedly affects the life of blind people, but also gives a heavy burden to their family and the society. A visual prosthesis is an electronic device that helps the blinds to regain visual perception by directly stimulating the visual pathway using the microelectrodes implanted into the body. In recent years, visual prostheses have been developed rapidly and some devices have already become clinically available. In this paper, we reviewed the history of visual prosthesis, introduced different visual prostheses classified according to the location of the implanted stimulating electrodes. Clinical study results as well as the functional status of the currently available visual prosthesis devices were also summarized.

[Relationship between macular morphology and visual function in diabetic macular edema].

OBJECTIVE: To investigate the changes and relation between macular morphology and macular visual function in different degrees of diabetic macular edema. METHODS: Seventy-eight eyes of 41 diabetic retinopathy patients were included and graded for diabetic macular edema as follows:31 were graded as no macular edema (NE), 26 as non-clinically significant macular edema (NCSME), and 21 as clinically significant macular edema (CSME). Best corrected visual acuity, macular sensitivity, and macular thickness of all included eyes were examed and quantified. Macular sensitivity and retinal fixation were investigated with MP-1 microperimetry. Optical coherence tomography (OCT) was used to quantify macular thickness. RESULTS: Macular thickness significantly increased and macular sensitivity markedly decreased from the NE to the CSME group (P < 0.01), Visual acuity obviously decreased in the CSME group (P < 0.01) compared to the NE and NCSME group, but there was no statistical difference between the NE group and NCSME group. Retinal fixation type was not significantly different among three groups. Visual acuity and macular sensitivity correlated significantly in these three groups (r = -0.751, P < 0.01; r = -0.583, P < 0.01; r = -0.679, P < 0.01). The correlations were noted between retinal sensitivity and macular thickness as well as between visual acuity and macular thickness in the CSME group (r = -0.465, P < 0.05; r = 0.599, P < 0.01), but not in the NE group or in the NCSME group. CONCLUSIONS: Patients will have retinal morphologic and functional changes in early stage of DME, both of which are significantly related as the disease develops. MP-1 microperimetry proved to be consistent with VA in the evaluation of visual function, and may be more sensitive to investigate the changes of macular visual function in the early stage of macular edema.

Combined NK-CIK and PD-1 inhibitor (nivolumab), an effective immunotherapy for treating intrahepatic lymphoepithelioma-like cholangiocarcinoma unassociated with EBV infection: Two case reports and a literature review.

Intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC) is a very rare malignant tumor arising from the biliary epithelium. To date, there has been a lack of evidence on the radiographical features, clinicopathological features, and treatment modalities of LELCC, with less than 28 cases of LELCC without Epstein-Barr virus (EBV) infection having been reported worldwide. The treatment of LELCC remains unexplored. Here, we present two cases of patients with LELCC without EBV infection who were treated by liver resection, chemotherapy, and immunotherapy and who achieved long survival time. The patients received surgery to remove the tumors and then adjuvant chemotherapy using the GS regimen and combined immunotherapy involving natural killer-cytokine-induced killer (NK-CIK) and nivolumab were performed. Both patients had a good prognosis with a survival time of more than 100 months and 85 months.

QiHuangYiShen Granules Modulate the Expression of LncRNA MALAT1 and Attenuate Epithelial-Mesenchymal Transition in Kidney of Diabetic Nephropathy Rats.

Background: QiHuangYiShen granules (QHYS), a traditional Chinese herbal medicine formula, have been used in clinical practice for treating diabetic kidney disease for several years by our team. The efficacy of reducing proteinuria and delaying the decline of renal function of QHYS has been proved by our previous studies. However, the exact mechanism by which QHYS exerts its renoprotection remains largely unknown. Emerging evidence suggests that lncRNA MALAT1 is abnormally expressed in diabetic nephropathy (DN) and can attenuate renal fibrosis by modulating podocyte epithelial-mesenchymal transition (EMT). Objective: In the present study, we aimed to explore whether QHYS could modulate lncRNA MALAT1 expression and attenuate the podocyte EMT as well as the potential mechanism related to the Wnt/ß-catenin signal pathway. Methods: SD rats were fed with the high-fat-high-sucrose diet for 8 weeks and thereafter administered with 30 mg/kg streptozotocin intraperitoneally to replicate the DN model. Quality control of QHYS was performed using high-performance liquid chromatography. QHYS were orally administered at 1.25, 2.5, and 5 g/kg doses, respectively, to the DN model rats for 12 weeks. Body weight, glycated haemoglobin, blood urea nitrogen, serum creatinine, 24-h proteinuria, and kidney index were measured. The morphologic pathology of the kidney was evaluated by Hematoxylin-eosin and Masson's trichrome staining. The expression level of lncRNA MALAT1 was determined by quantitative real-time polymerase chain reaction. In addition, the expression levels of podocyte EMT protein markers and Wnt/ß-catenin pathway proteins in renal tissues were evaluated by Western blotting and immunohistochemistry. Results: The results showed that QHYS significantly reduced 24-h proteinuria, blood urea nitrogen, kidney index, and ameliorated glomerular hypertrophy and collagen fiber deposition in the kidney of DN rats. Importantly, QHYS significantly downregulated the expression level of lncRNA MALAT1, upregulated the expression of nephrin, the podocyte marker protein, downregulated the expression of desmin and FSP-1, and mesenchymal cell markers. Furthermore, QHYS significantly downregulated the expression levels of Wnt1, ß-catenin, and active ß-catenin. Conclusion: Conclusively, our study revealed that QHYS significantly reduced proteinuria, alleviated renal fibrosis, and attenuated the podocyte EMT in DN rats, which may be associated with the downregulation of lncRNA MALAT1 expression and inhibition of the Wnt/ß-catenin pathway.