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The abundance of domesticated sheep varieties and phenotypes is largely the result of long-term natural and artificial selection. However, there is limited information regarding the genetic mechanisms underlying phenotypic variation induced by the domestication and improvement of sheep. In this study, to explore genomic diversity and selective regions at the genome level, we sequenced the genomes of 100 sheep across 10 breeds and combined these results with publicly available genomic data from 225 individuals, including improved breeds, Chinese indigenous breeds, African indigenous breeds, and their Asian mouflon ancestor. Based on population structure, the domesticated sheep formed a monophyletic group, while the Chinese indigenous sheep showed a clear geographical distribution trend. Comparative genomic analysis of domestication identified several selective signatures, including家绵羊丰富的品种和表型主要是长期自然和人工选择的结果。然而，关于绵羊在驯化和改良中所导致表型变异的遗传机制的研究有限。在该研究中，为了探讨绵羊的基因组多样性和选择信号，对10个品种的100只羊进行全基因组重测序，并结合公共数据库中公布的亚洲摩弗伦野羊、非洲地方绵羊品种、中国地方绵羊品种以及培育绵羊品种的225个个体的基因组数据进行研究。群体结构分析表明，家绵羊聚为单独的一类，而中国地方绵羊呈现明显的地理分布趋势。在驯化过程中，发现了与免疫反应（

Objective To evaluate high-frequency ultrasound (HFUS) features for diagnosing cutaneous squamous cell carcinoma (cSCC) as a spectrum of progressively advanced malignancies, including precursor actinic keratosis (AK), Bowen's disease (BD), and invasive squamous cell carcinoma (iSCC). Method In this retrospective study, 160 skin lesions diagnosed histopathologically (54 AK, 54 BD, and 52 iSCC) in 160 patients were included. The HFUS features of AK, BD, and iSCC were analyzed. The obtained data were evaluated using univariate and forward multivariate logistic regression analyses. Results The most significant HFUS features in AK were regular surface (odds ratio [OR], 8.42) and irregular basal border (OR, 6.36). The most significant HFUS features in BD were crumpled surface (OR, 19.62) and layer involvement confined to the epidermis (OR, 3.96). The most significant HFUS features in iSCC were concave surface (OR, 27.06), stratum corneum (SC) detachment (OR, 14.41), irregular basal border (OR, 4.01), and convex surface (OR, 3.73). The characteristics of surface features, basal border, and layer involvement could be valuable HFUS clues in the discrimination of AK, BD, and iSCC. Conclusion High-frequency ultrasound is valuable for the differentiation of AK, BD, and iSCC, which may allow dynamic and noninvasive monitoring in the spectrum of cSCC.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

A 33 years’ old male complained of excessive salivation with frequent swallowing and spitting, which resulted in communication disturbance, reduced quality of life, and social embarrassment for 19 years. He had been diagnosed as sialorrhea and submandibular gland hyperfunction by stomatologist, then had unilateral submandibular gland resection 13 years ago, but the symptom relief was not satisfactory. After that, he had been treated with glycopyrrolate for less than a year, which was withdrawn because of the short duration of symptomatic control after each tablet take-in and intolerable side effects. With the wish to receive a new treatment with long term effectiveness, low re-operation risk and normal preserved saliva secretion function, the patient was subject to MWA for the right submandibular gland. After systematic clinical evaluation, US-guided percutaneous MWA was successfully performed with an uneventful post-operative course. The volume of the right submandibular gland and ablated area were measured precisely by an ablation planning software system with automatic volume measurement function based on three-dimensional reconstruction of the pre-operative and post-operative enhanced magnetic resonance imaging (MRI) raw data. Finally, the ablated volume was calculated as 62.2% of the whole right submandibular gland. The patient was discharged 1 day after the operation, with symptoms relieved significantly, the mean value of whole saliva flow rate (SFR) decreased from 11 ml to 7.5 ml per 15 minutes. During the follow up by phone three months after operation, the patient reported that the treatment effect was satisfactory, whereas the SFR value became stable as 7 ml per 15 minutes, drooling frequency and drooling severity (DFDS) score decreased from 6 to 5, drooling impact scale (DIS) score decreased from 43 to 26. US-guided percutaneous MWA of submandibular gland seems to be an alternative, minimal invasive, and effective treatment for refractory sialorrhea. We described a patient with refractory sialorrhea treated successfully with ultrasound (US) guided percutaneous microwave ablation (MWA).

Pseudoaneurysm (PSA) formation is the most common arterial complication of endovascular procedures requiring arterial puncture. The present study reported a case of a 72-year-old male patient with iatrogenic femoral artery PSA treated with contrast-enhanced ultrasound (CEUS)-guided thrombin injection. Conventional ultrasound (US) and CEUS were used to diagnose, guide treatment, and evaluate the treatment efficacy. In the case, the PSA was successfully occluded with 1000 IU of thrombin. During the follow-up after 48 hours of thrombin injection, US found that the PSA had complete thrombosis without arterial supply. No complications occurrence in the course of the treatment. CEUS-guided thrombin injection for the treatment of PSA was effective and safety and the associated literatures were also reviewed.

Titanium–oxo clusters (TOCs), as a new class of molecular functional materials, have become one of the key research areas due to their novel structures and fascinating properties. Herein, two new tartrate-stabilized TOCs with sulfonate chromophore ligands, Ti4(C4H2O6)(AS)2(OiPr)10 (1) and Ti4(C4H2O6)(ATS)2(OiPr)10 (2) (C4H2O6 = tartrate, AS = aniline-2-sulfonate, and ATS = 4-aminotoluene-3-sulfonate), have been synthesized and characterized by elemental analysis, Fourier transform infrared spectroscopy, UV-vis diffuse reflection spectroscopy, thermogravimetric analysis, powder X-ray diffraction analysis, and single crystal X-ray diffraction. Their structural analyses indicate that the crystals are a class of small TOCs containing only four titanium atoms in the asymmetric unit, which form a centrosymmetric planar square {Ti4} core chelated by a bridging hexadentate tartrate ligand in trans orientation. Both TOCs show UV-vis absorption up to 600 nm with band gaps of 3.16 eV (for 1) and 2.95 eV (for 2), respectively. The photocurrent response and the photocatalytic activity for degradation of organic dye methylene blue (MB) have also been examined. Furthermore, the charge transfer from the sulfonate chromophore ligand to the {Ti4} core (LCCT) was evaluated using density functional theory calculations.

Background Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% of patients) is associated with loss of MGMT expression (MGMT−) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT-mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly(ADP-ribose) polymerase (PARP). Methods MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O6-methylguanine (O6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ. Results We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT-expressing GBM. Conclusion This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT-unmethylated GBM.

Over the last several hundred years, donkeys have adapted to high-altitude conditions on the Tibetan Plateau. Interestingly, the kiang, a closely related equid species, also inhabits this region. Previous reports have demonstrated the importance of specific genes and adaptive introgression in divergent lineages for adaptation to hypoxic conditions on the Tibetan Plateau. Here, we assessed whether donkeys and kiangs adapted to the Tibetan Plateau via the same or different biological pathways and whether adaptive introgression has occurred. We assembled a de novo genome from a kiang individual and analyzed the genomes of five kiangs and 93 donkeys (including 24 from the Tibetan Plateau). Our analyses suggested the existence of a strong hard selective sweep at the EPAS1 locus in kiangs. In Tibetan donkeys, however, another gene, i.e., EGLN1, was likely involved in their adaptation to high altitude. In addition, admixture analysis found no evidence for interspecific gene flow between kiangs and Tibetan donkeys. Our findings indicate that despite the short evolutionary time scale since the arrival of donkeys on the Tibetan Plateau, as well as the existence of a closely related species already adapted to hypoxia, Tibetan donkeys did not acquire adaptation via admixture but instead evolved adaptations via a different biological pathway.

The purpose of this study was to develop, validate and test a prediction model for discriminating malignant from benign breast lesions using conventional ultrasound (US), US elastography of strain elastography and contrast-enhanced ultrasound (CEUS). The study included 454 patients with breast imaging-reporting and data system (BI-RADS) category 4 breast lesions identified on histologic examinations. Firstly, 228 breast lesions (cohort 1) were analyzed by logistic regression analysis to identify the risk factors, and a breast malignancy prediction model was created. Secondly, the prediction model was validated in cohort 2 (84 patients) and tested in cohort 3 (142 patients) by using analysis of the area under the receiver operating characteristic curve (AUC). Univariate regression indicated that age ≥40 y, taller than wide shape on US, early hyperenhancement on CEUS and enlargement of enhancement area on CEUS were independent risk factors for breast malignancy (all p0.05). The logistic regression equation was established as follows: p = 1/1+Exp∑[-5.066 + 3.125 x (if age ≥40 y) + 1.943 x (if taller than wide shape) + 1.479 x (if early hyperenhancement) + 4.167 x (if enlargement of enhancement area). The prediction model showed good discrimination performance with an AUC of 0.967 in cohort 1, 0.948 in cohort 2 and 0.920 in cohort 3. By using the prediction model to selectively downgrade category 4a lesions, the re-rated BI-RADS yield an AUC of 0.880 (95% confidence interval [CI], 0.794-0.965) in cohort 2 and 0.870 (95% CI, 0.801-0.939) in cohort 3. The specificity increased from 0.0% (0/35) to 80.0% (28/35) without loss of sensitivity (from 100.0% to 95.9%, p = 0.153) in cohort 2. Similarly, the specificity increased from 0.0% (0/58) to 77.6% (45/58) without loss of sensitivity (from 100.0% to 96.4%, p = 0.081) in cohort 3. Multimodal US showed good diagnostic performance in predicting breast malignancy of BI-RADS category 4 lesions. Although the loss of sensitivity was existing, the addition of multimodal US to US BI-RADS could improve the specificity in BI-RADS category 4 lesions, which reduced unnecessary biopsies.

AIM: To investigate the influence of unilateral congenital ptosis on the development of the eye and vision in children. METHODS: In this prospective observational study, 41 patients with unilateral congenital ptosis were enrolled (age range 3-15y). The blepharoptosis was divided into 3 subgroups according to the margin reflex distance-1 (MRD-1), including mild group (MRD-1≥2 mm), moderate group (0≤MRD-1

Background: With the rapid aging of global population, the number of elderly patients with gastric cancer is increasing. This study aimed to evaluate short- and long-term outcomes after laparoscopi...

BACKGROUND Minimal-fat angiomyolipoma (mf-AML) is often misdiagnosed as renal cell carcinoma before surgery. AIM To analyze the magnetic resonance imaging (MRI) features of mf-AML and the causes of misdiagnosis by MRI before operation. METHODS A retrospective analysis was performed on ten patients with mf-AML confirmed by surgical pathology, all of whom underwent preoperative MRI examination to analyze the morphological characteristics and MRI signals of the tumor. RESULTS MRI revealed a circular-like mass in 4/10 (40%) patients, an oval mass in 6/10 patients (60%), a mass with a capsule in 9/10 patients (90%), and a mass with a lipid component in 7/10 patients (70%). The diameter of the masses in all ten patients was from 11 to 47 mm; the diameter was between 11 mm and 40 mm in 8/10 (80%) patients and between 40 mm and 47 mm in 2/10 (20%) patients. CONCLUSION An oval morphological characteristic is strong evidence for the diagnosis of mf-AML, while a capsule and lipids are atypical manifestations of mf-AML.

Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.

Objective: To investigate the mid-term local treatment efficiency of ultrasound-guided percutaneous microwave ablation (MWA) for uterine fibroids (UFs) and the associated influencing factors. Methods: From July 2020 to October 2021, a total of 28 patients with 52 UFs who had undergone ultrasound-guided MWA were retrospectively included in this study. Pre-treatment clinical characteristics, conventional ultrasound and contrast-enhanced ultrasound (CEUS) features were analyzed to explore their correlation with volume reduction ratios (VRRs) of sufficient ablation (i.e. a VRR of at least 50% at the 3 month follow-up). The patients were assessed at 1-, 3-, 6 month follow-up after MWA treatment and the assessment included VRR, adverse events, uterine fibroid symptom (UFS) and quality of life (QoL) scores, and clinical symptoms. Results: The procedures of percutaneous MWA for UFs were tolerated well and no major complications occurred in all patients. At the 1-, 3-, 6 month follow-up, the median VRRs of UFs were 30.1%, 46.9%, and 65.8%, respectively. At the 3 month follow-up, 44.4% of fibroids obtained sufficient ablation while the remaining 55.6% obtained partial ablation (i.e. a VRR of Conclusion: Ultrasound-guided MWA is an effective and safe method to treat patients with UFs. Non-enhancing area during the early phase on pretreatment CEUS is associated with mid-term local treatment efficiency, which might be used to predict treatment outcome. Advances in knowledge: Non-enhancing area during the early phase on pretreatment CEUS is an important factor associated with mid-term local treatment efficiency. This is the first study finding that CEUS feature can be used as a marker for the prediction of mid-term local treatment response.

DNA methylation, an epigenetic mark, is proposed to regulate plant anthocyanin biosynthesis. It well known that light induces anthocyanin accumulation, with bagging treatments commonly used to investigate light-controlled anthocyanin biosynthesis. We studied the DNA methylome landscape during pear skin coloration under various conditions (fruits re-exposed to sunlight after bag removal). The DNA methylation level in gene body/TE and its flanking sequence was generally similar between debagged and bagged treatments, however differentially methylated regions (DMRs) were re-modelled after light-exposure. Both DNA demethylase homologs and the RNA-directed DNA methylation (RdDM) pathways contributed to this re-distribution. A total of 310 DEGs were DMR-associated during light-induced anthocyanin biosynthesis between debagged and bagged treatments. The hypomethylated mCHH context was seen within the promoter of PyUFGT, together with other anthocyanin biosynthesis genes (PyPAL, PyDFR and PyANS). This enhanced transcriptional activation and promoted anthocyanin accumulation after light re-exposure. Unlike previous reports on bud sports, we did not detect DMRs within the MYB10 promoter. Instead, we observed the genome-wide re-distribution of methylation patterns, suggesting different mechanisms underlying methylation patterns of differentially accumulated anthocyanins caused by either bud mutation or environment change. We investigate the dynamic landscape of genome-scale DNA methylation, which is the combined effect of DNA demethylation and RdDM pathway, in the process of light-induced fruit colour formation in pear. This process is regulated by methylation changes on promoter regions of several DEGs. These results provide a DMR-associated DEGs set and new insight into the mechanism of DNA methylation involved in light-induced anthocyanin biosynthesis.

Repetitive transcranial magnetic stimulation (rTMS) has been used in the clinical treatment of Parkinson's disease (PD). Most of rTMS studies on PD used high-frequency stimulation; however, excessive nonvoluntary movement may represent abnormally cortical excitability, which is likely to be suppressed by low-frequency rTMS. Decreased neural activity in the basal ganglia on functional magnetic resonance imaging (fMRI) is a characteristic of PD. In the present study, we found that low-frequency (1 Hz) rTMS targeting individual finger-tapping activation elevated the amplitude of local neural activity (percentage amplitude fluctuation, PerAF) in the putamen as well as the functional connectivity (FC) of the stimulation target and basal ganglia in healthy participants. These results provide evidence for our hypothesis that low-frequency rTMS over the individual task activation site can modulate deep brain functions, and that FC might serve as a bridge transmitting the impact of rTMS to the deep brain regions. It suggested that a precisely localized individual task activation site can act as a target for low-frequency rTMS when it is used as a therapeutic tool for PD.

INTRODUCTION: Abdominal wall endometriosis (AWE) is a relatively uncommon condition associated with diagnostic and therapeutic difficulties among all the extra pelvic endometriosis. The main therapies include surgery and oral contraceptive administration. Percutaneous cryoablation and high intensity focused ultrasound (HIFU) are also proven to be valid alternatives. Microwave ablation (MWA) as one of the thermal ablation methods has not been applied in the treatment of AWE yet. Herein the feasibility of ultrasound (US) –guided MWA for AWE was explored and treatment response evaluation was carried out using contrast-enhanced imaging. METHODS: Three consecutive patients who underwent US-guided MWA for AWE with typical symptoms were included in this retrospective study. US, magnetic resonance imaging (MRI), laboratory tests, and US-guided core-needle biopsy were conducted for pre-treatment assessment and ruling out malignancy. The interventional procedure was carried out under local anesthesia with MWA and the output power was 60w. Post-treatment contrast-enhanced ultrasound (CEUS) was performed to evaluate the instant treatment response. The follow-up intervals were 1 month, 6 months, and 12 months after treatment. The clinical symptoms and condition of AWE lesions were recorded in each follow-up. RESULTS: The MWA procedure was completed in all the patients with no blood perfusion inside each lesion by instant CEUS after treatment. The mean ablation time was 687 seconds (s) for a single patient (ranged from 660s to 742s). Clinical symptoms were relieved evidently at the end of the follow-up. The pain according to the visual analogue scale (VAS) decreased from 4–6 before treatment to 0–2 after treatment. Mild to moderate complications included slightly abdominal pain and fat liquefaction occurred. In terms of technical outcomes, the volume of all six lesions reduced in different degrees at the end of follow-up (ranged: 16.6% to 100%). CONCLUSION: US-guided MWA may be a feasible and promising approach for symptomatic AWE.

Biliary cystadenocarcinoma (BCAC) is an extremely rare intrahepatic cystic tumor. Patients usually present with nonspecific symptoms such as abdominal pain, abdominal distention, and abdominal mass. This tumor occurs most commonly in the left hemiliver and is thought to mainly develop from a benign biliary cystadenoma (BCA). At present, the disease is mainly diagnosed by ultrasound, CT, MR, and other imaging methods, and the main treatment is radical surgical resection. We reported a 75-year-old female with an unresectable huge BCAC (i.e., 161×145×122 mm in three orthogonal directions) and poor general condition (40 in Karnofsky Performance Status, KPS) who received sequential thermal ablation (i.e., cryoablation and microwave ablation) in combination with sclerotherapy using lauromacrogol. The diagnosis of intrahepatic BCAC was confirmed pathologically. Preablation grayscale US showed the BCAC with a clear boundary, regular shape, and cystic-solid mixed echogenicity, which appeared as a huge multilocular cystic lesions with thick internal sepatations. Preablation contrast-enhanced ultrasound (CEUS) showed honeycomb-like hyper-enhancement of the thick internal sepatations and cystic wall in the arterial and portal phase, and sustained enhancement of the thick internal sepatations and cystic wall in the late phase. 6-month postablation CEUS showed non-enhancement in most parts of the lesion in the arterial phase and 6-month postablation MRI showed the volume reduction ratio (VRR) was about 70%. The abdominal pain and abdominal distension were relieved remarkably, and her quality of life was greatly improved (70 in KPS). In conclusion, sequential thermal ablation in combination with sclerotherapy provides a successful translative therapy for this unresectable huge BCAC with a poor general condition, which makes subsequent curative surgery or ablation possible.

The pea protein isolate nanoparticles/octenyl succinic anhydride linear dextrin (PPINs/OSA-LD) composite particles were fabricated by heating at acidic condition. Heating treatment not only made OSA-LD dissolve, but also promoted the hydrophobic interactions between PPINs and OSA-LD. With the increase of OSA-LD content, the average diameter of composite particles decreased due to the avoidance of hydrophobic aggregation between PPINs during heating, and the composite particles became more compact and regular. The high internal phase emulsions (HIPEs) stabilized by composite particles exhibited smaller droplet size, higher viscosity and modulus attributing to the formation of denser interfacial layer. The results of low field nuclear magnetic resonance proved that the HIPEs stabilized by composite particles showed more uniform distribution of water and oil. This work provided a facile method to fabricate composite particles, which had excellent capacity to stabilize the HIPEs.

The sound transmission across plenum windows installed with rigid non-resonant cylindrical scatterer arrays was investigated in detail using scale-down model measurements carried out inside a fully anechoic chamber. The arrays have manifested to some extent the acoustical behaviors of virtual sonic crystals. The maximum cross section blockage ratio was 0.6. The effects of plenum window gap, array configuration, and scatterer diameter on the sound transmission characteristics were also examined. Results indicate that the window cavity longitudinal modes and the gap modes control the sound transmission characteristics at low frequencies. The upper bound of this frequency range increases with decreasing gap width. Within this frequency range, the scatterers have negligible effect on the sound transmission. At higher frequencies, the array configurations with scatterer(s) attached to the window walls result in stronger sound reduction. There are relatively higher sound transmission loss improvements around the frequencies where a full bandgap is observed. There are wide bandgaps in various lattice directions, and the present results suggest that they play a role in the broadband improvement of sound reduction.

MXenes, a new class of two-dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W1.33 C i-MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in-plane ordered (W2/3 Y1/3 )2 AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33 C i-MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33 C i-MXene possesses a strong predominance of near-infrared (NIR) absorbance. The constructed ultrathin W1.33 C nanosheets feature excellent photothermal-conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal-imaging properties and photothermal-ablation performance of W1.33 C-BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33 C-BSA nanosheets-induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i-MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.

Background: This study aimed to assess the relationship between dyslipidemia (DL) risk and health-related physical fitness (HPF) and evaluated the prognostic value of HPF for risk of DL. Methods: A total of 776 university staff members were recruited, of which 407 were females, and 369 males. Blood samples and HPF tests were collected from all participants after 12 h fasting. Results: The prevalence of DL was 41.77% and 51.49% in female and male university staff members, respectively, and there was no significant difference between genders (χ2 = 2.687, p = 0.101). According to the logistic regression analysis, age, male sex, GLU, hypertension, BMI, BF, WHtR, and LAP were significant risk factors for DL (p < 0.05), VCI and, SAR were significant protective factors for DL (p < 0.05), and SMI, GS, and VG were not significantly associated with the risk of DL. The area under the receiver-operating characteristic (ROC) curve (AUC) analysis indicated that, LAP (AUC: 0.730, 95CI%: 0.697–0.762), WHtR (AUC: 0.626, 95CI%: 0.590–0.660), and BMI (AUC: 0.599, 95CI%: 0.563–0.634) are valid predictors of DL, and LAP and WHtR perform better than BMI (Z = 8.074, p < 0.001) in predicting DL in male and female university staff members. Conclusion: The risk of DL is significantly related to body composition, cardiorespiratory fitness, and flexibility. LAP and WHtR perform better than BMI in predicting risk of DL in male and female university staff members.

Background: Adaptive resistance is one of the major hinderances for unresectable hepatocellular carcinoma (HCC) treated with lenvatinib and anti-programmed cell death protein 1 (anti-PD-1) therapy. Physical activity is known to have anti-cancer effects, including immunomodulatory actions, influencing patients’ outcomes. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC.Methods: The physical activity levels of patients with unresectable HCC treated with combination therapy using lenvatinib plus anti-PD-1 antibodies were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS), analyzed using the Kaplan-Meier method with a log-rank test. Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). Factors associated with survival and ORR were analyzed using regression analyses. A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter. Results: Fifty-nine patients with unresectable HCC were categorized to active (n=28) or sedentary (n=31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI, 0.060-0.799) and PFS (HR = 0.158, 95% CI, 0.044-0.562) and higher ORR (OR = 4.571, 95% CI, 1.482-14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy. Conclusions: Regular physical activity was associated with improved outcomes in patients receiving combined lenvatinib plus anti-PD-1 therapy for unresectable HCC. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

Alfalfa expresses significantly distinct sets of genes in response to infection by different rhizobia strains at the below-species level (i.e., biotype or strain). However, differences in the transcriptomic profiles of two alfalfa cultivars nodulated by a single rhizobium strain have been largely unexamined. In this study, the comparative RNA-seq analysis of two alfalfa cultivars, Medicago sativa cv. Gannong No. 3 and Gannong No. 9 inoculated with one Sinorhizobium meliloti strain LL2, with varying in symbiotic performance, was conducted, followed by a hub gene interaction network construction based on weighted gene co-expression network analysis (WGCNA). The G9-LL2 symbiotic system showed better nodule-formation, nitrogen-fixing, and growth characteristics than the G3-LL2 system. Compared with the uninoculated control (CK), the LL2-inoculated G9 plants (10053) produced more differentially expressed genes (DEGs) than the LL2-inoculated G3 plants (7112). A group of 227 (2623 shared) genes displayed completely distinguished expression in G9 (6.63 < log2(FC) < 15.45) and G3 (‒3.05 < log2(FC) < 12.05), which are primarily involved in encoding nodule-specific cysteine-rich peptides (NCRs), nodulin, and leghemoglobin. Although genes with predicted roles in nitrogen metabolism were primarily upregulated, and almost all of those in ubiquitin-mediated proteolysis and plant-pathogen interaction were suppressed, interestingly, a consistently higher expression level measured by log2(FC) was observed in G9 plants. Hub gene interaction networks showed that the NCRs, late nodulin, and genes related to plant immunity (TIR-NBS-LRR, defensin, thioredoxin, thionine, and polygalacturonase) regulated other genes at the source node positions. After the successful initiation of nodulation in both alfalfa cultivars G3 and G9 by S. meliloti strain LL2, G9 achieved preferable outcomes of rhizobia-alfalfa symbiosis by equilibrating the antagonism and compatibility of plant immunity. It elevated PTI and suppressed defense and ETI, as well as enhancing nitrogen fixation and utilization efficiency by inducing the expression of genes encoding NCRs, nodulin, and leghemoglobin. Hub genes predominantly underlying the highly specific rhizobia-alfalfa symbiosis, positively governed by NCRs and fine-tuned immune antagonism, comprise NCRs, late nodulin, and TIR-NBS-LRR. These findings provide insights into the genetic mechanisms underlying the modification and efficient utilization of semi-compatible and incompatible rhizobia resources.

Background To construct the lncRNA-miRNA-mRNA axis based on the study of molecular oncology, to explore the role and mechanism of this axis in the occurrence and development of liver cancer, so as to provide a new channel for the treatment of liver cancer. Methods Using public online databases to establish lncRNA-miRNA-mRNA ceRNA regulation network, after which using QPCR and other experimental techniques to verify that this axis is established and the mechanism of participating in the development of liver cancer. Results It can be concluded from database mining that the expressions of hsa-miR-182-5p and ADH4 are negatively correlated in hepatocellular carcinoma, and LINC01018 is also negatively correlated hsa-miR-182-5p-ADH4, indicating that LINC01018, hsa-miR-182-5p and ADH4 are strongly correlated. Constitute the regulatory axis to participate in the occurrence and development tendency of tumors. LINC01018 regulates ADH4 to inhibit LIHC cell growth by inhibiting hsa-miR-182-5p, providing a feasible theoretical basis for the treatment of HCC.The regulatory axis may also regulate the occurrence and development tendency in liver cancer by adjusting the expression levels of key proteins and phosphorylation proteins in GO and KEGG signaling pathways. Conclusions In this study, it was found that LINC01018/hsa-miR-182-5p/ADH4 ceRNA regulatory axis exists in the human body, and this axis has the possibility of becoming an immune checkpoint inhibitor for liver cancer, which is regarded as a new entry point in the diagnosis and therapy of liver cancer.

Objectives To compare the imaging findings of Bowen's disease (BD) between ultrasound biomicroscopy (UBM) and conventional high-frequency ultrasound (HFUS). Methods A total of 29 pathologically proven BD lesions in 28 patients were retrospectively enrolled in the study, and all were after surgery. All the lesions were imaged with both UBM and HFUS. The imaging features on HFUS and UBM were analyzed and compared. The diagnostic results of ultrasound for BD were referenced with pathology results. Results All the 29 (100%) BD lesions appeared hypoechogenicity, solid component, and superficial hyperechoic layer (ie, keratinization) on both UBM and HFUS. The typical imaging feature of BD lesions, that was, infiltration depth confined to the epidermis, was visualized in 25 (86.2%, 25/29) lesions on UBM whereas 15 (51.7%, 15/29) on HFUS (P = .002). A "wave sign," which corresponds to the surface keratinization of BD lesion, was visualized in 17 (58.6%, 17/29) of BD lesions on UBM whereas 6 (20.7%, 6/29) on HFUS (P = .001). UBM and HFUS correctly diagnosed 25 (86.2%, 25/29) and 15 (51.7%, 15/29) BD lesions, respectively (P = .002). Conclusions Bowen's disease has some typical imaging features on US. The "wave sign" of the superficial hyperechoic layer and the clear borderline between the tumor in epidermis and the slightly hyperechoic dermis layer are better depicted by UBM in comparison with HFUS, which leads to a more accurate diagnosis of BD. UBM has potential to be used as a diagnostic tool for characterization of BD on account of its high resolution.

Purpose:Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy.Experimental Design:Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (n = 14) and validation set (n = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP–DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in vivo glioma models.Results:EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP–DNA trapping, which augmented the cytotoxicity. EGFR amplification–associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in nonamplified models.Conclusions:EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.

Fatigue driving is one of the main factors which affect the safety of drivers and passengers in mountain freeway. To improve the driving safety, the application of fatigue driving detection system is a crucial measure. Accuracy, speed and robustness are key performances of fatigue detection system. However, most researches pay attention to one of them, instead of taking care of them all. It has limitation in practical application. This paper proposes a novel three-layered framework, named Real-time and Robust Detection System. Specifically, the framework includes three modules, called facial feature extraction, eyes regions extraction and fatigue detection. In the facial feature extraction module, the paper designs a deep cascaded convolutional neural network to detect the face and locate eye key points. Then, a face tracking sub-module is constructed to increase the speed of the algorithm, and a face validation submodule is applied to improve the stability of detection. Furthermore, to ensure the orderly operation of each sub-module, we designed a recognition loop based on the finite state machine. It can extract facial feature of the driver. In the second module, eyes regions of the driver were captured according to the geometric feature of face and eyes. In the fatigue detection module, the ellipse fitting method is applied to obtain the shape of driver's pupils. According to the relationship between the long and short axes of the ellipse, eyes state (opening or closed) can be decided. Lastly, the PERCLOS, which is defined by calculating the number of closed eyes in a period, is used to determine whether fatigue driving or not. The experimental results show that the comprehensive accuracy of fatigue detection is 95.87%. The average algorithm rate is 32.29 ms/f in an image of 640×480 pixels. The research results can serve the design of a new generation of driver fatigue detection system to mountain freeway.

Thyroid nodules have a high prevalence and a small percentage is malignant. Many non-invasive methods have been developed with the help of the Internet of Things to improve the detection rate of malignant nodules. These methods can be roughly categorized into two classes: radiomics based and deep learning based approaches. In general, convolutional neural networks based deep learning methods have achieved promising performance in many medical image analysis and classification applications; however, no existing comparison has been done between radiomics based and deep learning based approaches. Therefore, in this paper, we aim to compare the performance of radiomics and deep learning based methods for the classification of thyroid nodules from ultrasound images. On one hand, we developed a radiomics based method, which consists of extracting high throughput 302-dimensional statistical features from pre-processed images. Then dimension reduction was performed using mutual information and linear discriminant analysis respectively to achieve the final classification. On the other hand, a deep learning based method was also developed and tested by pre-training a VGG16 model with fine-tuning. Ultrasound images including 3120 images (1841 benign nodules and 1393 malignant nodules) from 1040 cases were retrospectively collected. The dataset was divided into 80% training and 20% testing data. The highest accuracies yielded on the testing data for radiomics and deep learning based methods were 66.81% and 74.69%, respectively. A comparison result demonstrated that the deep learning based method can achieve a better performance than using radiomics.

Background Tranexamic acid (TXA) has been demonstrated to reduce blood loss following primary total knee and hip arthroplasty. This study aimed to compare the efficacy and safety of oral and intravenous tranexamic acid for primary total knee and hip arthroplasty. Methods The PubMed, Embase, and Cochrane Library databases were searched for relevant studies published before June 20, 2019. Studies clearly reporting a comparison of oral and intravenous TXA were selected, and total blood loss (TBL), the decline in hemoglobin (DHB), deep vein thrombosis (DVT), intramuscular venous thrombosis (IVT), the length of hospital stay, and the transfusion rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects or random-effects model. Results Ten studies involving 1140 (oral 557; intravenous 583) patients were included in this meta-analysis. There was no significant difference in terms of total blood loss, the decline in hemoglobin, the length of hospital stay, the incidence of DVT or IVT, or the transfusion rate between the oral and intravenous groups, and five studies reported that oral TXA was associated with a lower cost. Conclusion Our research suggests that compared with intravenous use of TXA, the oral approach has similar clinical outcomes and is less expensive for total joint replacement patients.

PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.Significance:These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.

Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B,, extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.

Background Pistachio (Pistacia vera), one of the most important commercial nut crops worldwide, is highly adaptable to abiotic stresses and is tolerant to drought and salt stresses. Results Here, we provide a draft de novo genome of pistachio as well as large-scale genome resequencing. Comparative genomic analyses reveal stress adaptation of pistachio is likely attributable to the expanded cytochrome P450 and chitinase gene families. Particularly, a comparative transcriptomic analysis shows that the jasmonic acid (JA) biosynthetic pathway plays an important role in salt tolerance in pistachio. Moreover, we resequence 93 cultivars and 14 wild P. vera genomes and 35 closely related wild Pistacia genomes, to provide insights into population structure, genetic diversity, and domestication. We find that frequent genetic admixture occurred among the different wild Pistacia species. Comparative population genomic analyses reveal that pistachio was domesticated about 8000 years ago and suggest that key genes for domestication related to tree and seed size experienced artificial selection. Conclusions Our study provides insight into genetic underpinning of local adaptation and domestication of pistachio. The Pistacia genome sequences should facilitate future studies to understand the genetic basis of agronomically and environmentally related traits of desert crops. Electronic supplementary material The online version of this article (10.1186/s13059-019-1686-3) contains supplementary material, which is available to authorized users.

The sterility of hormone-sensitive lipase (HSL) knockout mice clearly shows the link between lipid metabolism and spermatogenesis. However, which substrate or product of this multifunctional lipase affects spermatogenesis is unclear. We found that an HSL protein with a His-tag at the N-terminus preserved the normal hydrolase activity of cholesteryl ester (CE) but the triglyceride lipase (TG) activity significantly decreased in vitro. Therefore, mice with this functionally incomplete HSL (His-HSL) were produced on a background of HSL deficiency (HSL-/- h). As a result, HSL-/- h testis has an 8.65-fold higher CE activity than wild-type testis but a twofold higher TG activity than wild-type testis. To compare His-HSL and wild-type HSL in vitro and in vivo, we confirmed that the His-tag significantly suppressed HSL TG activity. From our results, we believe that TG activity was affected by the His-tag insertion, but CE activity was not influenced. Furthermore, the His-tag protected HSL from binding to the inhibitor BAY. From our study, TG activity and BAY binding sites were affected by N-terminal His-tag insertion.

Objective To analyze the safety and efficacy of indocyanine green (ICG) fluorescence real-time imaging technology and digital ultrasound guidance technology for laparoscopic liver resection (LLR) of HCC at special location. Methods Twenty-four patients with hepatocellular carcinoma at special location were enrolled and equally divided into two groups: ICG fluorescent group received intravenous indocyanine green injection 2-3 days before operation, and then did fluorescent laparoscopic liver resection, while the normal control group were given general laparoscopic liver resection; meanwhile, the intraoperative and postoperative indexes including operative time, intraoperative bleeding, complications and length of hospital stay were analyzed to judge the clinical feasibility. Results Except 1 case treated with laparoscopic radiofrequency ablation because of the old age and illness factors and 1 case for conversion to laparotomy, all the rest were treated by LLR with ICG real-time images combined guidance of ultrasound in ICG fluorescent group, and all the patients but one who underwent conversion to laparotomy received general laparoscopic resection in the normal control group. There was no statistical difference between the two groups in terms of operative time [(215.0±35.8)min vs. (208.0±18.6)min, P=0.554]. As compared with the normal control group, the intraoperative bleeding volume significantly reduced [(255.0±19.4)ml vs. (230.0±17.5)ml, P=0.0032], and the hospital stay significantly shortened [(8.9±1.2)d vs. (10.6±1.6)d, P=0.0076], but there was no statistical differences between the two groups in R0 cutting edge and complications (P=0.308; P=0.173). Conclusion Laparoscopic liver resection using ICG fluorescence real-time imaging combined the digital imaging technology under ultrasound guidance is a safe and effective treatment approach for HCC at the special position, being worthy of further promotion clinically. DOI: 10.11855/j.issn.0577-7402.2019.04.12