A new mode for the diagnosis of angioimmunoblastic T-cell lymphoma.

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.

[Clinical Significance of Genetic and Molecular Changes in Primary Myeloid Sarcoma].

OBJECTIVE: To investigate the clinical significance of genetic and molecular changes in primary myeloid sarcoma (MS). METHODS: Fourteen patients with primary MS were selected in Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, The First People's Hospital of Lianyungang from September 2010 to December 2021. AML1-ETO fusion, PML-RARα fusion and CBFß breakage were detected by fluorescence in situ hybridization (FISH), and the mutations of NPM1, CEBPA, FLT3, RUNX1, ASXL1, KIT and TP53 genes were detected by new generation sequencing (NGS). RESULTS: Among 14 patients, the MS occurred in bone, breast, epididymis, lung, chest wall, cervix, small intestine, ovary, lymph nodes and central nervous system. The tumor cells expressed MPO (13 cases), CD34 (7 cases), CD43 (8 cases), CD68 (7 cases), CD99 (8 cases) and CD117 (6 cases). Cytogenetic abnormalities were observed in 4 cases, including 3 cases of AML1-ETO fusion and 1 case of CBFß breakage, while no PML-RARα fusion was detected. There were no significant differences in overall survival (OS) and leukemia-free survival (LFS) between patients with and without AML1-ETO fusion/CBFß breakage (both P >0.05). Among the 14 patients, the number of NPM1, CEBPA, FLT3-ITD, RUNX1, ASXL1, KIT and TP53 gene mutations was 5, 3, 5, 3, 2, 2, 1, respectively, of which 7 cases had at least one mutation in FLT3-ITD, RUNX1, ASXL1 and TP53 gene. The OS and LFS of patients with FLT3-ITD, RUNX1, ASXL1 or TP53 mutation were shorter than those without mutations (both P <0.01). CONCLUSION: The genetic and molecular abnormalities of primary MS can be detected by FISH and NGS techniques. FLT3-ITD, RUNX1, ASXL1 or TP53 mutation indicates a worse prognosis, but further clinical studies are needed to confirm it.

Preparation of PEG/P(U-AM-ChCl) composite hydrogels using ternary DES light polymerization and their properties.

Deep eutectic solvents (DES) were prepared using urea (U) and acrylamide (AM) as hydrogen bond donors (HBD) and choline chloride (ChCl) as hydrogen bond acceptor (HBA), and polyethylene glycol (PEG) was selected as a filler and uniformly dispersed in DES to prepare PEG/P(U-AM-ChCl) composite hydrogels by light polymerization. The composite hydrogels were characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The effects of the content of PEG on the swelling properties, mechanical properties and fatigue resistance of the composite hydrogels were investigated. The results showed that the compressive strength and fatigue strength of the composite hydrogels were gradually enhanced with the increase of the PEG content in the composite hydrogels, in which the maximum compressive strength of the hydrogels with 1 wt% PEG added was increased by 1.86 times. The composite hydrogel had excellent swelling properties, and the equilibrium swelling degree of the hydrogel with 1 wt% PEG added reached 10.15. Meanwhile, the PEG/P(U-AM-ChCl) composite hydrogel had excellent self-healing properties, and the self-healing rate of the composite hydrogel with a PFG content of 1 wt% could reach 91.93% after 48 hours of healing. This study provides a convenient and efficient method to prepare composite hydrogels with superior swelling properties and self-healing properties.

Trailing-edge fringes enable robust aerodynamic force production and noise suppression in an owl wing model.

As one of the unique owl-wing morphologies, trailing-edge (TE) fringes are believed to play a critical role in the silent flight of owls and have been widely investigated using idealized single/tandem airfoils. However, the effect of TE fringes and associated mechanisms on the aeroacoustics of owl wings, which feature curved leading edges, wavy TEs, and several feather slots at the wingtips, have not yet been addressed. In this study, we constructed two 3D owl wing models, one with and one without TE fringes, based on the geometric characteristics of a real owl wing. Large-eddy simulations and the Ffowcs Williams‒Hawkings analogy were combined to resolve the aeroacoustic characteristics of the wing models. Comparisons of the computed aerodynamic forces and far-field acoustic pressure levels demonstrate that the fringes on owl wings can robustly suppress aerodynamic noise while sustaining aerodynamic performance comparable to that of a clean wing. By visualizing the near-field flow dynamics in terms of flow and vortex structures as well as flow fluctuations, the mechanisms of TE fringes in owl wing models are revealed. First, the TE fringes on owl wings are reconfirmed to robustly suppress flow fluctuations near the TE by breaking up large TE vortices. Second, the fringes are observed to effectively suppress the shedding of wingtip vortices by mitigating the flow interaction between feathers (feather-slot interaction). These complementary mechanisms synergize to enhance the robustness and effectiveness of the TE fringe effects in owl wing models, in terms of aerodynamic force production and noise suppression. This study thus deepens our understanding of the role of TE fringes in real owl flight gliding and points to the validity and feasibility of employing owl-inspired TE fringes in practical applications of low-noise fluid machinery.

Genome-Wide Identification and Expression Analysis of the TCP Gene Family Related to Developmental and Abiotic Stress in Ginger.

Ginger (Zingiber officinale Roscoe), a widely consumed edible and medicinal plant, possesses significant nutritional and economic value. Abiotic stresses such as drought and low temperatures can impact the growth and development of ginger. The plant-specific transcription factor Teosinte branched1/cycloidea/proliferating cell factor (TCP) has progressively been identified in various plants for its role in regulating plant growth and development as well as conferring resistance to abiotic stresses. However, limited information on the TCP family is available in ginger. In this study, we identified 20 TCP members in the ginger genome, which were randomly distributed across 9 chromosomes. Based on phylogenetic analysis, these ginger TCP were classified into two subfamilies: Class I (PCF) and Class II (CIN, CYC/TB). The classification of the identified ginger TCPs was supported by a multi-species phylogenetic tree and motif structure analysis, suggesting that the amplification of the ginger TCP gene family occurred prior to the differentiation of angiosperms. The promoter region of ginger TCP genes was found to contain numerous cis-acting elements associated with plant growth, development, and abiotic stress response. Among these elements, the stress response element, anaerobic induction, and MYB binding site play a dominant role in drought responsiveness. Additionally, expression pattern analysis revealed variations in the expression of ginger TCP gene among different tissues and in response to diverse abiotic stresses (drought, low temperature, heat, and salt). Our research offers a thorough examination of TCP members within the ginger plant. This analysis greatly contributes to the understanding of how TCP genes regulate tissue development and response to stress, opening up new avenues for further exploration in this field.

Exploring the Heat Shock Transcription Factor (HSF) Gene Family in Ginger: A Genome-Wide Investigation on Evolution, Expression Profiling, and Response to Developmental and Abiotic Stresses.

Ginger is a valuable crop known for its nutritional, seasoning, and health benefits. However, abiotic stresses, such as high temperature and drought, can adversely affect its growth and development. Heat shock transcription factors (HSFs) have been recognized as crucial elements for enhancing heat and drought resistance in plants. Nevertheless, no previous study has investigated the HSF gene family in ginger. In this research, a total of 25 ZoHSF members were identified in the ginger genome, which were unevenly distributed across ten chromosomes. The ZoHSF members were divided into three groups (HSFA, HSFB, and HSFC) based on their gene structure, protein motifs, and phylogenetic relationships with Arabidopsis. Interestingly, we found more collinear gene pairs between ZoHSF and HSF genes from monocots, such as rice, wheat, and banana, than dicots like Arabidopsis thaliana. Additionally, we identified 12 ZoHSF genes that likely arose from duplication events. Promoter analysis revealed that the hormone response elements (MEJA-responsiveness and abscisic acid responsiveness) were dominant among the various cis-elements related to the abiotic stress response in ZoHSF promoters. Expression pattern analysis confirmed differential expression of ZoHSF members across different tissues, with most showing responsiveness to heat and drought stress. This study lays the foundation for further investigations into the functional role of ZoHSFs in regulating abiotic stress responses in ginger.

The Relationship Between Fear of COVID-19 and Psychological Distress in Tour Guides: The Mediating Role of Job Insecurity and the Moderating Role of Psychological Resilience.

Purpose: The COVID-19 has greatly affected the tourism industry in China, leading to an increase in psychological distress among tour guides. This study explores the mechanisms by which tour guides' fear of the COVID-19 affects psychological distress, using job insecurity as a mediating variable and psychological resilience as a moderating variable. Patients and Methods: From August 11 to 30, 2022, 447 Chinese tour guides were invited online to fill in a questionnaire, and SPSS and Mplus tools were used for statistical analysis and hypothesis testing to conduct an empirical analysis of the relationship between COVID-19 fear and psychological distress. Results: A total of 417 questionnaires (effective rate was 93.3%) were collected, among which female (n = 243) and male (41.7%) (n =174). The age concentration of participants was 46.5% between 26 and 35 years old, 9.1% under 25 years old, and 9.8% over 46 years old. Guides' fear of COVID-19 positively and significantly influenced psychological distress (ß= 0.3051), and the relationship between fear of COVID-19 and psychological distress was mediated by job insecurity (ß=0.196, 95% CI = 0.141, 0.255). In addition, psychological resilience significantly moderated the pathway from fear of COVID-19 to job insecurity and from fear of COVID-19 to guided psychological distress (ß= 0.1371; ß=0.116). Conclusion: The diversion of fear of COVID-19 and job insecurity can alleviate the psychological distress of tour guides; strengthening their own psychological construction also helps to alleviate the effects of fear of COVID-19 on job insecurity and psychological distress. The findings of the study can provide theoretical support for the prevention and counseling of psychological problems of tourism employees in public health crises.

Can red tourism lead to spiritual transformation? Evidence from tourists visiting the Red Army Long March Xiangjiang Battle Memorial Park.

The mechanism of spiritual transformation in red tourism plays a key role in facilitating the inheritance of red culture. A survey of 385 tourists of Chinese nationality was conducted to explore the path of red tourism's influence on tourists' spiritual transformation. Based on the stimulus-organism-response theory, this paper explores tourists' environmental perceptions of red tourism activities as special external stimuli, introduces a positive emotion factor, and constructs a path model of red tourism for tourists' positive emotions based on educational function and cultural identity, which ultimately leads to their spiritual transformation. The results of the empirical tests using structural equation modelling indicated that environmental perceptions had a significantly positive effect on the stimulation of positive emotions, while positive emotions had an indirect effect on spiritual transformation. The research results enhance people's understanding of the spiritual transformation brought by red tourism and provide management significance for red tourism planning.

Rapid preparation of N-CNTs/P(AA-co-AM) composite hydrogel via frontal polymerization and its mechanical and conductive properties.

Deep eutectic solvent (DES) was prepared by using acrylic acid (AA) and acrylamide (AM) as hydrogen bonding donors (HBD) and choline chloride (ChCl) as hydrogen bonding receptors (HBA). Nitrogen-doped carbon nanotubes (N-CNTs) were dispersed in DES as fillers, and N-CNTs/P(AA-co-AM) composite hydrogels were prepared by FP. The interaction mode between the hydrogel and N-CNTs was characterized by Fourier infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The mechanical properties, pH response and electrical conductivity of the composite hydrogels were studied. The results showed that the mechanical properties of the hydrogel were significantly enhanced with the increase of N-CNT content. The tensile strength and compressive strength of the FP4 composite hydrogel reached 5.42 MPa and 4.29 MPa, respectively. Due to the dissociation of carboxyl groups in AA in an alkaline environment the composite hydrogel showed excellent pH response performance. The conductivity of the hydrogel was also found to be improved with the content of N-CNTs. When the content of N-CNTs is 1.0 wt%, the conductivity of the hydrogel was 4.2 times higher than that of the hydrogel without N-CNTs, and connecting it to a circuit can make an LED lamp emit bright light. In this study, a simple and green method was proposed to prepare composite hydrogels with excellent mechanical properties and electrical conductivity by FP of DES in less than 5 min.

African swine fever virus M1249L protein antagonizes type I interferon production via suppressing phosphorylation of TBK1 and degrading IRF3.

Cyclic GMP-AMP synthase (cGAS) is a major DNA sensor. The recognition of cytosolic DNA by cGAS triggers a robust innate immune response that restricts the replication of diverse viral pathogens through the type I interferon (IFN) and nuclear factor-κB (NF-κB) pathways. African swine fever virus (ASFV) is a large and complex DNA virus reported to strongly inhibit the cGAS-STING signaling pathway. Herein, 12 ASFV structural proteins were screened to determine their effects on the cGAS-STING pathway. Ectopic expression of the ASFV caspid protein M1249L significantly inhibited the IFN-ß promoter activity induced by the cGAS-STING pathway in a dose-dependent manner. And it could also downregulate the levels of IFN-ß and several interferon-stimulating genes (ISGs) induced by cGAS-STING and 2'3'-cGAMP. Moreover, ASFV M1249L also suppressed phosphorylation of TBK1 by cGAS and STING overexpression. Further study showed that M1249L co-localized and interacted with interferon regulatory factor 3 (IRF3), which led to induce IRF3 degradation by lysosomal pathway. Taken together, our study revealed a novel strategy utilized by ASFV for cGAS-STING-related immune evasion.

Genetic characterization and evolutionary analysis of canine parvovirus in Tangshan, China.

Canine parvovirus (CPV) is a major enteric virus of carnivores worldwide that poses a considerable threat to dogs. In this study, we investigated the genetic variation of CPV in Tangshan, China, and the relationships between CPV disease and the vaccination status, age, and gender of dogs. Seventy-seven fecal samples from dogs in Tangshan that tested positive for CPV were obtained for analysis. Twenty-two full-length VP2 gene sequences were successfully amplified. The 22 strains included 17 CPV-2c variants, four new CPV-2a variants, and one new CPV-2b variant. Phylogenetic analysis showed that all of the CPV-2c strains clustered together and were closely related to CPV-2c strains from Asia but distantly related to CPV-2c strains from Europe. Further amino acid sequence analysis showed that, relative to CPV-2c strains from Europe, most of the CPV-2c stains in this study had A5G, F267Y, Y324I, and Q370R mutations. These findings provide a more comprehensive understanding of the variants of CPV circulating in China.

Multiple indeterminate domain (IDD)-DELLA1 complexes participate in gibberellin feedback regulation in peach.

KEY MESSAGE: Peach encodes 14 INDETERMINATE DOMAIN (IDD) transcription factors. PpIDD4, -12 and -13 mediated PpDELLA1 binding to the PpGA20ox1 promoter. Each of these three PpIDD-DELLA1 complexes activated transcription of PpGA20ox1. PpTPR1 and -4 interrupted the interaction of PpIDDs with PpDELLA1. The plant growth regulator gibberellin (GA) plays an important role in the rapid growth of annual shoots in peach. Our previous study showed that the peach cultivar 'FenHuaShouXingTao' (FHSXT), a gibberellic acid receptor (gid1) mutant, accumulates active GAs in annual shoot tips. This mutant enhances GA feedback regulation in peach. The results of this study suggested that the PpIDD-DELLA1 complex is the underlying mechanism of GA feedback regulation in peach. Fourteen IDD genes were identified in peach, and three PpIDDs (PpIDD4, -12 and -13, all from group IV) interacted with PpDELLA1, an important component in GA signaling pathway. Truncation, segmentation and site mutation of the promoter of PpGA20ox1 (a GA biosynthesis gene) showed that all three PpIDD proteins recognized the core motif TTGTC. PpIDD4 and -13 mainly bind to site 3, while PpIDD12 binds to site 5 of the PpGA20ox1 promoter. All three PpIDD-DELLA1 complexes activated the PpGA20ox1 promoter-LUC fusion. These data suggested that PpIDDs bridge PpDELLA1 and the promoter of PpGA20ox1, which then activated the transcription of PpGA20ox1. In addition, PpTPR1 and -4 disrupted the interaction of PpIDDs with PpDELLA1. Our research will be helpful for understanding and possibly modifying the regulation of annual shoot growth and GA biosynthesis.

Isolation and phylogenetic analysis of strains of feline calicivirus in Beijing, China.

Feline calicivirus (FCV) is a contagious cat pathogen that causes oral ulceration and/or upper respiratory disease. In this study, we collected 61 samples from a pet hospital in Beijing and used PCR or RT-PCR to detect FCV and feline herpesvirus 1 (FHV-1). Approximately 44.3% (27/61) of the samples were FCV positive, and 23.0% (14/61) were coinfected with FCV and FHV-1. FCV was isolated from 15 samples. One isolate was from a cat with virulent systemic disease (VSD) signs, and 14 isolates were from cats with stomatitis or upper respiratory diseases. The range of genome sequence identity among these isolates was 76.1-100.0%. Four of the isolates were considered to be of the same strain, with sequence identity ranging from 99.5 to 99.7%, and two isolates, BJ-280 and BJ-288, had completely identical sequences. The genomic sequence identity ranged from 76.0 to 88.5% between the 15 isolates and several reference strains, including the F4 and F9 vaccine strains. These results demonstrate that many FCV strains are co-circulating in Beijing. Due to the diversity of FCV in Beijing, it is necessary to monitor the current prevalence of the virus. This study provides more information for the development of effective measures to control FCV.

Co-located angularly offset fiber Bragg grating pair for temperature-compensated unambiguous 3D shape sensing.

A 10 mm-long three-dimensional shape sensor in a single-mode fiber is described and demonstrated experimentally. The sensor is based on a pair of fiber Bragg gratings inscribed at the same location along the fiber axis but offset along different radial directions away from the fiber center. Each offset grating generates cladding mode resonances over a ${\sim}{20}\;{\rm{nm}}$-wide spectral bandwidth, and the two gratings are also offset in period so that their transmission spectra are separated by 40 nm, and thus non-overlapping and fully distinguishable. Directional bending sensitivity results from the differential amplitude response of the cladding mode resonances from the two gratings, depending on the relative orientation of the bend with the azimuthal direction of the grating offsets. It is further demonstrated that both axial deformation and temperature have no influence on the shape measurement as they both only cause a global wavelength shift of the spectra without amplitude change. The experimental results demonstrate that the shape orientation of an object can be unambiguously determined for bend directions covering the full 360° range around the fiber axis with sensitivities of the order of ${{1}}\;{\rm{dB/}}{{\rm{m}}^{- 1}}$ and small curvatures between 0 and ${{1}}\;{{\rm{m}}^{- 1}}$.

Temperature-compensated fiber directional-bend sensor based on a sandwiched MMF-PMPCF structure.

An optical fiber directional-bend sensor based on an inline Mach-Zehnder interferometer is proposed and demonstrated. The device consists of a piece of a multimode fiber (MMF) splicing with a polarization-maintaining photonic crystal fiber (PMPCF) and sandwiched by lead in/out single-mode fibers (SMFs). Owing to the larger diameter of the MMF, some high-order modes in fiber are efficiently coupled and transmitted through the PMPCF, and finally interfere with each other in the output SMFs. The experimental results show that a well-defined interference fringe envelope can be obtained in the transmitted spectrum and, when the fiber is bent, both the intensity and the fringe visibility of the interference pattern are changed with the bending curvature. Meanwhile, the bend sensitivities are varied with different bending directions, and the maximum sensitivity is achieved up to -8.33dB/m-1 within the bend range from 0 to 1.7m-1. The proposed device also demonstrates a very low-intensity cross-talk of environment temperature.

African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3.

African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-ß (IFN-ß) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.

Epidemiological and phylogenetic analysis of canine kobuviruses in Tangshan, China.

Canine kobuviruses (CaKoV) have been found in healthy and diarrheic dogs as well as asymptomatic wild carnivores in various countries. In order to investigate the prevalence and evolution of CaKoV in Tangshan, China, 82 dog fecal samples from pet hospitals in Tangshan were subjected to RT-PCR targeting a segment of the 3D gene of CaKoV. Using this method, we identified CaKoV in 14 samples (17.07%, 14/82). Of the CaKoV-positive samples, 78.57% (11/14) and 50% (7/14) were positive for canine parvovirus and canine coronavirus, respectively. The nucleotide sequences of the 14 strains 96.6%-100% identical to each other and 77.6%-99.2% identical to representative sequences from the NCBI GenBank database. We also amplified the 14 VP1 gene sequences and found that they were 93.3%-99.6% identical to each other and 73.3%-97.8% identical to representative sequences from the NCBI GenBank database. Phylogenetic analysis revealed that the 14 CaKoV strains from Tangshan are closely related to those identified in China and Thailand and display less similarity to those found in Africa, the United States, and Europe. Our data suggest that CaKoV circulated in young pet dogs in Tangshan and displays a high co-infection rate with CCoV and CPV. However, the relationship between the three viruses and their roles in the host requires further investigation.

Correlation of Cerebral White Matter Lesions with Carotid Intraplaque Neovascularization assessed by Contrast-enhanced Ultrasound.

PURPOSE: Carotid atherosclerotic plaque is closely associated with cerebral white matter lesions (WMLs), while intraplaque neovascularization (IPN) contributes significantly to arterial remodeling and plaque vulnerability. In this study, we aim to evaluate the correlation of carotid IPN with cerebral WMLs. METHODS: The presence of IPN and WMLs were assessed by contrast-enhanced ultrasound (CEUS) and MRI respectively. IPN was evaluated utilizing semi-quantification visual grading scale and WMLs was divided according to Fazekas grading scale. We investigated the baseline data, Fazekas grades, and IPN grades among 269 participants. We explored the influences of each variable on Fazekas grades using ordinal logistic regression and evaluated the relationship between IPN grades and WMLs Fazekas grades. RESULTS: Increased age (OR: 1.06, P<0.001), hypertension (OR: 2.17, P=0.002), cerebral infarction (OR: 1.74, P=0.046), and elevated carotid IPN grading were significantly associated with aggravated Fazekas grades (grade 2 or 3). To be specific, people having grade 3, 2, and 1 carotid IPN were 25.84 (P<0.001), 10.64 (P<0.001), and 5.96 (P=0.010) times as likely to have elevated Fazekas grades compared with those who having grade 0 carotid IPN. CONCLUSION: Increased carotid IPN is independently correlated with aggravated cerebral WMLs.

A multi-functionalized nanocomposite constructed by gold nanorod core with triple-layer coating to combat multidrug resistant colorectal cancer.

Multi-drug resistance (MDR) remains the main culprit for the low survival rate of advanced colorectal cancer (CRC). Photothermal-therapy (PPT) is effective to kill MDR tumor cells, but fails to completely eradicate tumors. In this study, we prepared a nanocomposite based on gold nanorod core with triple layer coating (GNRs/mSiO2/PHIS/TPGS/DOX) to combat multidrug resistant (MDR) colorectal cancer via multi-strategies. We first synthesized the mesoporous silica-coated gold nanorods (GNRs/mSiO2), and loaded with antitumor drug doxorubicin (DOX) to realize a combination of chemo- and photothermal-therapy. To reverse DOX resistance, pH responsive poly-histidine (PHIS) was conjugated on GNRs/mSiO2 to increase drug intracellular accumulation via efficient endo/lysosome escape; d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) was then assembled on the surface of the particles to realize drug intracellular retention by inhibition P-glycoprotein. The results showed that the nanocomposite exhibited a highly efficient photothermal conversion in the NIR region, a pH and NIR triggered drug release profile and an increment of DOX intracellular accumulation and cytotoxicity on MDR SW620/Ad300 cells. Most importantly, the nanocomposite showed the most potent antitumor efficacy without obvious systemic toxicity comparing to other control groups with either chemo- or photothermal therapy alone on SW620/Ad300 tumor bearing mice. Altogether, the successful preparation of the nanocomposite and its potent efficacy might provide evidence for the future design and develop of nano-therapeutic system in the treatment of MDR colorectal cancer.

Structural basis for client recognition and activity of Hsp40 chaperones.

Hsp70 and Hsp40 chaperones work synergistically in a wide range of biological processes including protein synthesis, membrane translocation, and folding. We used nuclear magnetic resonance spectroscopy to determine the solution structure and dynamic features of an Hsp40 in complex with an unfolded client protein. Atomic structures of the various binding sites in the client complexed to the binding domains of the Hsp40 reveal the recognition pattern. Hsp40 engages the client in a highly dynamic fashion using a multivalent binding mechanism that alters the folding properties of the client. Different Hsp40 family members have different numbers of client-binding sites with distinct sequence selectivity, providing additional mechanisms for activity regulation and function modification. Hsp70 binding to Hsp40 displaces the unfolded client. The activity of Hsp40 is altered in its complex with Hsp70, further regulating client binding and release.