Omicron variant infection worsen the prognosis of haemodialysis (HD) patients.

BACKGROUND: Haemodialysis (HD) patients are predisposed to physical ailments, and their occurrence of coronavirus disease 2019 (COVID-19) could potentially lead to a more unfavourable prognosis. However, the impact of SARS-CoV-2 (Omicron variant) infection on the prognosis of HD patients remains unclear. This study aimed to explore the impact of Omicron variant infection on the prognosis of HD patients. METHODS: Eligible participants were patients undergoing maintenance HD treatment during a large-scale outbreak of COVID-19 (Omicron variant) in Shanghai, China, from April 7 to May 30, 2022. According to SARS-CoV-2 infection status of participants, the HD patients were divided into two groups: a COVID-19 group and a non-COVID-19 group. The primary outcome assessed was in-hospital mortality, and secondary outcomes encompassed the incidence of severe cases, admission to intensive care, length of hospital stay, and blood indices. Statistical analysis was conducted by comparative analysis and multiple logistic regression. RESULTS: This study recruited 588 HD patients, including 199 cases in the COVID-19 group and 389 in the non-COVID-19 group. In the COVID-19 group, the mortality rate was 8.45% (17/199), whereas in the non-COVID-19 group, the rate was 3.34% (13/389) (p < 0.05). Compared with the non-COVID-19 group, the COVID-19 group had a risk ratio (RR) with 95% confidence interval (CI) of 2.56 (1.27-5.15) for mortality, and the absolute risk difference (ARD) with 95% CI of 5.20% (1.34%-9.06%). Multiple logistic regression confirmed Omicron variant as a risk factor for mortality among HD patients. Additionally, the COVID-19 group had a higher proportion of severe cases, intensive care admission, hypocalcaemia and hyperphosphatemia and longer hospitalization duration, compared to the non-COVID-19 group (p < 0.05). CONCLUSIONS: Omicron variant infection was associated with increased mortality risk in HD patients, and Omicron infection worsen the prognosis of HD patients. Enhancing immune protection against SARS-CoV-2 is crucial for HD patients during the ongoing COVID-19 pandemic.

Elucidation of the anti-fibrotic diseases mechanism of chelerythrine by integrative approach of network pharmacology and experimental verification.

In the present study, we conducted an integrative approach of network pharmacology and experimental validation study to elucidate the underlying mechanisms of Chelerythrine (CLT), in treating fibrotic diseases (FD), which are disorders characterised by excessive accumulation of extracellular matrix. 27 common targets of CLT against FD were analysed, and these common targets were used to construct the PPI network. The results of GO and KEGG enrichment analyses suggested that CLT exerted pharmacological effects on FD by regulating mTOR signalling pathway, AKT-PI3K pathway and apoptosis signalling pathway. Finally, molecular docking confirmed a strong binding affinity between CLT and the core target proteins. CLT has inhibitory effects on the proliferation and migration of L929 cells, CLT could promote cell apoptosis. CLT decreased levels of the Bcl-2, p-AKT/AKT, p-mTOR/mTOR and p-PI3K/PI3K, meanwhile increased levels of the Bax. Taken together, these results indicate that CLT may be a potential drug for anti-fibrotic diseases therapy.

FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis.

BACKGROUND: The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. METHODS: We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. RESULTS: We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. CONCLUSION: We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Reno-protective Effects of Empagliflozin in High Fat Diet Induced Obesity-Related Glomerulopathy by Regulation of Gut-Kidney Axis.

BACKGROUND: The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose co-transporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in obese individuals and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. METHODS: We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with Empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. RESULTS: ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared to NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multi-tissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05). CONCLUSION: The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG.

Morphological characterization and distribution of antennal sensilla of Spodoptera frugiperda (Lepidoptera: Noctuidae) using scanning electron microscopy.

The fall armyworm (FAW), Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), is a globally significant agricultural pest, causing severe damage to corn production in China. Chemical odor-based trapping is a major approach for FAW control, making it essential to understand the FAW antennal sensillum types to enhance development of effective chemical odor attractants. In this study, we comprehensively examined the antennal sensilla types of FAW, identifying eight types and two subtypes, including Böhm's bristles, sensilla trichoidea, sensilla chaetica (I and II), sensilla coeloconica, sensilla styloconica, sensilla squamiformia (I and II), sensilla auricillica, and sensilla basiconica. Sensilla chaetica II, and sensilla squamiformia II are reported for the first time for FAW in this study. Detailed low-voltage field emission scanning electron microscope (LVSEM) images and descriptions are provided for each sensillum type. This study provides the morphological information to aid in conducting antennal sensillum neurophysiological tests on FAW. RESEARCH HIGHLIGHTS: The types of sensilla of fall armyworm were examined, identifying eight types and two subtypes, including Böhm's bristles, sensilla trichoidea, sensilla chaetica (I and II), sensilla coeloconica, sensilla styloconica, sensilla squamiformia (I and II), sensilla auricillica, and sensilla basiconica. Detailed low-voltage field emission scanning electron microscope images and descriptions were provided for each sensillum type.

HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway.

Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.

Covalent versus noncovalent attachments of [FeFe]­hydrogenase models onto carbon nanotubes for aqueous hydrogen evolution reaction.

In an effort to develop the biomimetic chemistry of [FeFe]­hydrogenases for catalytic hydrogen evolution reaction (HER) in aqueous environment, we herein report the integrations of diiron dithiolate complexes into carbon nanotubes (CNTs) through three different strategies and compare the electrochemical HER performances of the as-resulted 2Fe2S/CNT hybrids in neutral aqueous medium. That is, three new diiron dithiolate complexes [{(µ-SCH2)2N(C6H4CH2C(O)R)}Fe2(CO)6] (R = N-oxylphthalimide (1), NHCH2pyrene (2), and NHCH2Ph (3)) were prepared and could be further grafted covalently to CNTs via an amide bond (this 2Fe2S/CNT hybrid is labeled as H1) as well as immobilized noncovalently to CNTs via π-π stacking interaction (H2) or via simple physisorption (H3). Meanwhile, the molecular structures of 1-3 are determined by elemental analysis and spectroscopic as well as crystallographic techniques, whereas the structures and morphologies of H1-H3 are characterized by various spectroscopies and scanning electronic microscopy. Further, the electrocatalytic HER activity trend of H1 > H2 ≈ H3 is observed in 0.1 M phosphate buffer solution (pH = 7) through different electrochemical measurements, whereas the degradation processes of H1-H3 lead to their electrocatalytic deactivation in the long-term electrolysis as proposed by post operando analysis. Thus, this work is significant to extend the potential application of carbon electrode materials engineered with diiron molecular complexes as heterogeneous HER electrocatalysts for water splitting to hydrogen.

Differential responses of soil bacteria, fungi and protists to root exudates and temperature.

The impact of climate warming on soil microbes has been well documented, with studies revealing its effects on diversity, community structure and network dynamics. However, the consistency of soil microbial community assembly, particularly in response to diverse plant root exudates under varying temperature conditions, remains an unresolved issue. To address this issue, we employed a growth chamber to integrate temperature and root exudates in a controlled experiment to examine the response of soil bacteria, fungi, and protists. Our findings revealed that temperature independently regulated microbial diversity, with distinct patterns observed among bacteria, fungi, and protists. Both root exudates and temperature significantly influenced microbial community composition, yet interpretations of these factors varied among prokaryotes and eukaryotes. In addition to phototrophic bacteria and protists, as well as protistan consumers, root exudates determined to varying degrees the enrichment of other microbial functional guilds at specific temperatures. The effects of temperature and root exudates on microbial co-occurrence patterns were interdependent; root exudates primarily simplified the network at low and high temperatures, while responses to temperature varied between single and mixed exudate treatments. Moreover, temperature altered the composition of keystone species within the microbial network, while root exudates led to a decrease in their number. These results emphasize the substantial impact of plant root exudates on soil microbial community responses to temperature, underscoring the necessity for future climate change research to incorporate additional environmental variables.

Transcutaneous Electrical Spinal Cord Stimulation Increased Target-Specific Muscle Strength and Locomotion in Chronic Spinal Cord Injury.

BACKGROUND: The recovery of locomotion is greatly prioritized, and neuromodulation has been emerging as a promising approach in recent times. STUDY DESIGN: Single-subject research design. SETTINGS: A laboratory at The Hong Kong Polytechnic University. OBJECTIVES: To investigate the effects of augmenting activity-based therapy (ABT) to transcutaneous electrical spinal cord stimulation (TSCS) on enhancing specific lower limb muscle strength and improving locomotor ability in an individual with chronic incomplete spinal cord injury (iSCI). METHODS: An individual with iSCI underwent two phases of treatment, ABT alone followed by combined ABT+TSCS, each for a period of 10 weeks. The TSCS stimulated T10-T11 and T12-L1 segments with a frequency of 30 Hz at an intensity between 105 mA and 130 mA. Manual muscle testing, 6 min walk test (6MWT), and surface electromyography (EMG) responses of specific lower limb muscles were measured. Additionally, spasticity and sensorimotor examinations were conducted every two weeks, while pain tolerance was recorded after each treatment session. RESULTS: After the ABT+TSCS treatment, there was an increase in overall muscle strength grading (from 1.8 ± 0.3 to 2.2 ± 0.6 out of 5.0). The 6MWT showed a greater increase in walking distance (3.5 m to 10 m) after combined treatment than ABT alone. In addition, the EMG response of the anterior rectus femoris, biceps femoris, medial gastrocnemius, and tibialis anterior after ABT+TSCS increased more than after ABT alone. The spasticity grade was reduced (from 0.8 ± 0.7 to 0.5 ± 0.6) whereas the average lower limb motor score increased from 17 to 23 points. No adverse effects were reported. CONCLUSIONS: ABT+TSCS increased the target-specific lower limb muscle strength and walking ability more than ABT alone in an individual with chronic iSCI.

An ultrasensitive electrochemical/colorimetric dual-mode self-powered biosensing platform for lung cancer marker detection by multiple-signal amplification strategy.

BACKGROUND: In recent years, miRNAs have emerged as potentially valuable tumor markers, and their sensitive and accurate detection is crucial for early screening and diagnosis of tumors. However, the analysis of miRNAs faces significant challenges due to their short sequence, susceptibility to degradation, high similarity, low expression level in cells, and stringent requirements for in vitro research environments. Therefore, the development of sensitive and efficient new methods for the detection of tumor markers is crucial for the early intervention of related tumors. RESULTS: An ultrasensitive electrochemical/colorimetric dual-mode self-powered biosensor platform is established to detect microRNA-21 (miR-21) via a multi-signal amplification strategy. Gold nanoparticles (AuNPs) and VS4 nanosheets self-assembled 3D nanorods (VS4-Ns-Nrs) are prepared for constructing a superior performance enzyme biofuel cell (EBFC). The double-signal amplification strategy of Y-shaped DNA nanostructure and catalytic hairpin assembly (CHA) is adopted to further improve enhance the strength and specificity of the output signal. In addition, a capacitor is matched with EBFC to generate an instantaneous current that is amplified several times, and the output detection signal is improved once more. At the same time, electrochemical and colorimetric methods are used for dual-mode strategy to achieve the accuracy of detection. The linear range of detection is from 0.001 pg/mL to 1000 pg/mL, with a relatively low limit of detection (LOD) of 0.16 fg/mL (S/N = 3). SIGNIFICANCE: The established method enables accurate and sensitive detection of markers in patients with lung cancer, providing technical support and data reference for precise identification. It is anticipated to offer a sensitive and practical new technology and approach for early diagnosis, clinical treatment, and drug screening of cancer and other related major diseases.

Exploring the therapeutic potential of Nelumbo nucifera leaf extract against amyloid-beta-induced toxicity in the Caenorhabditis elegans model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) represents a critical global health challenge with limited therapeutic options, prompting the exploration of alternative strategies. A key pathology in AD involves amyloid beta (Aß) aggregation, and targeting both Aß aggregation and oxidative stress is crucial for effective intervention. Natural compounds from medicinal and food sources have emerged as potential preventive and therapeutic agents, with Nelumbo nucifera leaf extract (NLE) showing promising properties. Methods: In this study, we utilized transgenic Caenorhabditis elegans (C. elegans) models to investigate the potential of NLE in countering AD and to elucidate the underlying mechanisms. Various assays were employed to assess paralysis rates, food-searching capabilities, Aß aggregate accumulation, oxidative stress, lifespan under stress conditions, and the expression of stress-resistance-related proteins. Additionally, autophagy induction was evaluated by measuring P62 levels and the formation of LGG-1+ structures, with RNAi-mediated inhibition of autophagy-related genes to confirm the mechanisms involved. Results: The results demonstrated that NLE significantly reduced paralysis rates in CL4176 and CL2006 worms while enhancing food-searching capabilities in CL2355 worms. NLE also attenuated Aß aggregate accumulation and mitigated Aß-induced oxidative stress in C. elegans. Furthermore, NLE extended the lifespan of worms under oxidative and thermal stress conditions, while concurrently increasing the expression of stress-resistance-related proteins, including SOD-3, GST-4, HSP-4, and HSP-6. Moreover, NLE induced autophagy in C. elegans, as evidenced by reduced P62 levels in BC12921 worms and the formation of LGG-1+ structures in DA2123 worms. The RNAi-mediated inhibition of autophagy-related genes, such as bec-1 and vps-34, negated the protective effects of NLE against Aß-induced paralysis and aggregate accumulation. Discussion: These findings suggest that NLE ameliorates Aß-induced toxicity by activating autophagy in C. elegans. The study underscores the potential of NLE as a promising candidate for further investigation in AD management, offering multifaceted approaches to mitigate AD-related pathology and stress-related challenges.

Utilizing Single-Branched Stent in Combination With Fenestration or Chimney for Endovascular Repair of Aortic Arch Lesions With Aberrant Subclavian Artery.

OBJECTIVE: The study was to figure out the feasibility, efficacy, and safety of a single-branched stent graft, namely Castor, in combination with fenestration or chimney in the context of aortic arch lesions presenting with aberrant subclavian artery (ASA) and/or Kommerell's diverticulum (KD). METHODS: All consecutive patients with aortic arch lesions and ASA and/or KD receiving Castor from June 2018 to June 2023 were investigated. RESULTS: Incorporating 18 patients, the study encompassed 11 cases with KD, 3 cases with dysphagia; 2 cases of right-sided aortic arch with left-sided aberrant left subclavian artery (ALSA), and 16 cases of left-sided aortic arch with right-sided aberrant right subclavian artery (ARSA). The mean operation time was 132±23 minutes. The mean measured proximal aortic diameter was 30.9±1.6 mm, and proximal diameter of Castor stent was 34 (32, 34.5) mm, with oversize of 9.1±1.6%; the mean measured branch diameter was 8.8±0.97 mm, and branch diameter of Castor stent was 10 (8, 10) mm, with oversize of 0.86±0.57 mm. Technical success rate was 100%, and no in-hospital mortality, no stroke, and no endoleak were identified. One (5.6%) case with spinal cord ischemia and one (5.6%) case with poor healing of operative site were identified. During the follow-up period, no aortic-related death or secondary intervention was recorded. The maximal aortic diameter was significantly reduced at the sixth postoperative month (padj=0.031); KD diameter was significantly reduced at the third (padj=0.001) and sixth (padj<0.001) postoperative month. CONCLUSION: Totally endovascular repair of aortic arch lesions with ASA and KD via Castor stent in combination with fenestration or chimney is feasible, effective, and safe, which can achieve an encouraging medium-term outcome and provide excellent remodeling at the lesions. CLINICAL IMPACT: Single branched stent in combination with fenestration or chimney achieved a sufficient proximal landing zone and provided an encouraging medium-term outcome in this retrospective review of 18 patients receiving endovascular treatment of pathological aortic arch with aberrant subclavian artery and/or Kommerell's diverticulum. The authors suggest this time-saving and efficient technique to establish systematic experience for the treatment in this kind of patients.

Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V.

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (Mpro) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir's efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of Mpro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) Mpro, P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances Mpro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug-protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

Intubation at Birth Is Associated with Death after Pulmonary Hemorrhage in Very Low Birth Weight Infants.

OBJECTIVE: This retrospective cohort study was performed to clarify the association between intubation in the delivery room and the mortality after pulmonary hemorrhage in very low birth weight infants (VLBWIs) during hospitalization. METHODS: The study participants were screened from the VLBWIs admitted to the neonatal intensive care unit (NICU) of the Children's Hospital Affiliated to Nanjing Medical University from 31 July 2019 to 31 July 2022. The newborns who ultimately were included were those infants who survived until pulmonary hemorrhage was diagnosed. These subjects were divided into the intubation-at-birth group (n = 29) and the non-intubation-at-birth group (n = 35), retrospectively. RESULTS: Univariate analysis found that the intubation group had a higher mortality and shorter hospital stay than the non-intubation group (p < 0.05) (for mortality: 25/29 (86.21%) in intubation group versus 14/35 (40.00%) in non-intubation group). By multivariate analysis, the result further showed that intubation in the delivery room was related to shorter survival time and higher risk of death (adjusted hazard ratio: 2.341, 95% confidence interval: 1.094-5.009). CONCLUSIONS: Intubation at birth suggested a higher mortality in the VLBWIs when pulmonary hemorrhage occurred in the NICU.

Percutaneous transhepatic cholangioscopy-assisted biliary polypectomy for local palliative treatment of intraductal papillary neoplasm of the bile duct.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a premalignant biliary-type epithelial neoplasm with intraductal papillary or villous growth. Currently reported local palliative therapeutic modalities, including endoscopic nasobiliary drainage, stenting and biliary curettage, endoscopic biliary polypectomy, percutaneous biliary drainage, laser ablation, argon plasma coagulation, photodynamic therapy, and radiofrequency ablation to relieve mechanical obstruction are limited with weaknesses and disadvantages. We have applied percutaneous transhepatic cholangioscopy (PTCS)-assisted biliary polypectomy (PTCS-BP) technique for the management of IPNB including mucin-hypersecreting cast-like and polypoid type tumors since 2010. AIM: To assess the technical feasibility, efficacy, and safety of PTCS-BP for local palliative treatment of IPNB. METHODS: Patients with mucin-hypersecreting cast-like or polypoid type IPNB and receiving PTCS-BP between September 2010 and December 2019 were included. PTCS-BP was performed by using a half-moon type snare with a soft stainless-steel wire, and the tumor was snared and resected with electrocautery. The primary outcome was its feasibility, indicated by technical success. The secondary outcomes were efficacy, including therapeutic success, curative resection, and clinical success, and safety. RESULTS: Five patients (four with mucin-hypersecreting cast-like type and one with polypoid type IPNB) were included. Low- and high-grade intraepithelial neoplasia (HGIN) and recurrent IPNB with invasive carcinoma were observed in one, two, and two patients, respectively. Repeated cholangitis and/or obstructive jaundice were presented in all four patients with mucin-hypersecreting cast-like type IPNB. All five patients achieved technical success of PTCS-BP. Four patients (three with mucin-hypersecreting cast-like type and one with polypoid type IPNB) obtained therapeutic success; one with mucin-hypersecreting cast-like type tumors in the intrahepatic small bile duct and HGIN had residual tumors. All four patients with mucin-hypersecreting IPNB achieved clinical success. The patient with polypoid type IPNB achieved curative resection. There were no PTCS-BP-related serious adverse events. CONCLUSION: PTCS-BP appears to be feasible, efficacious, and safe for local palliative treatment of both mucin-hypersecreting cast-like and polypoid type IPNB.

Percent duration of heart rate acceleration within the respiratory cycle: a novel approach to assess heart rate asymmetry.

Accelerations and decelerations of heart rate are nonsymmetrical in the magnitude and number of beat-to-beat changes. The asymmetric features of heart rate variability are related to respiratory durations. To explore the link between respiration and heart rate asymmetry (HRA), we evaluated 14 seated, healthy young adults who breathed with nine combinations of inspiration duration (TI) and expiration duration (TE), chosen respectively from 2, 4, and 6 s. A 5-min R-R interval (RRI) time series was obtained from each study period to construct an averaged pattern waveform relative to the respiratory cycle. We observed that the time interval between inspiration onset and RRI minimum progressively lengthened as TI and TE increased. The time interval between expiration onset and RRI maximum also lengthened when TE increased but shortened when TI increased. Consequently, TI and TE had different effects on the acceleration time (AT; from RRI maximum to RRI minimum) and deceleration time (DT; from RRI minimum to RRI maximum). The percentage of AT within the respiratory cycle showed a strong correlation with traditional Guzik's (r = 0.862, P < 0.001) and Porta's (r = 0.878, P < 0.001) indexes of HRA assessed in a Poincaré plot analysis. These findings suggest that, in addition to considering the magnitude and number of beat-to-beat changes, HRA can also be assessed based on another aspect: the duration of consecutive changes. The stepwise link between the duration of heart rate change and respiratory duration provides insight into the mechanisms connecting respiration to HRA.NEW & NOTEWORTHY In healthy adults who regulated their breathing across nine combinations of inspiration and expiration durations, we used averaged pattern waveform technique to quantify the durations of heart rate acceleration and deceleration within the respiratory cycle. The percent duration of acceleration showed a strong correlation with traditional heart rate asymmetry indexes, which evaluate the magnitude and number of beat-to-beat changes. This new approach opens a window to explore the asymmetric features of heart rate variability.

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Investigation of 3D vessel reconstruction under Doppler imaging with phantoms: Towards reconstruction of the Circle of Willis.

BACKGROUND: Stroke is the second leading cause of death across the globe. Early screening and risk detection could provide early intervention and possibly prevent its incidence. Imaging modalities, including 1D-Transcranial Doppler Ultrasound (1D-TCD) or Transcranial Color-code sonography (TCCS), could only provide low spatial resolution or 2D image information, respectively. Notably, 3D imaging modalities including CT have high radiation exposure, whereas MRI is expensive and cannot be adopted in patients with implanted devices. This study proposes an alternative imaging solution for reconstructing 3D Doppler ultrasound geared towards providing a screening tool for the 3D vessel structure of the brain. METHODS: The system comprises an ultrasound phased array attached to a servo motor, which can rotate 180˚ at a speed of 2˚/s. We extracted the color Doppler ROI from the image before reconstructing it into a 3D view using a customized pixel-based algorithm. Different vascular diameters, flow velocity, and depth were tested using a vascular phantom with a pumped flow to confirm the system for imaging blood flow. These variables were set to mimic the vessel diameter, flow speed, and depth of the Circle of Willis (CoW) during a transcranial screening. RESULTS AND CONCLUSIONS: The lower values of absolute error and ratio were found in the larger vascular channels, and vessel diameter overrepresentation was observed. Under different flow velocities, such diameter overrepresentation in the reconstructed flow did not change much; however, it did change with different depths. Meanwhile, the setting of the velocity scale and the color gain affected the dimension of reconstructed objectives. Moreover, we presented a 3D image of CoW from a subject to demonstrate its potential. The findings of this work can provide a good reference for further studies on the reconstruction of the CoW or other blood vessels using Doppler imaging.