Although evidence has indicated that the presence of catch bond-like crosslinking proteins can significantly alter the viscoelastic response of bio-polymer networks, a detailed mechanistic ...understanding is still lacking. Here we report a computational investigation to examine how catch- or slip-bond kinetics of crosslinking molecules affects the time-dependent behavior of realistic F-actin and collagen networks. Specifically, it was found that, under oscillating shear, the rate of cross-linkers getting ruptured and then reformed reaches the maximum at intermediate driving frequency, eventually leading to a locally peaked bulk loss modulus of the network. Interestingly, when a pre-stress was applied the position of such peak shifted to higher frequencies for networks with slip bond cross-linkers. In comparison, the peaked loss modulus of actin network constructed by catch bond-like crosslinking molecules was reached at a lower driving frequency because of the stabilization effect of pre-stress on such cross-linkers. Similarly, the appearance of catch bond cross-linkers was also found to greatly alter the hysteresis of networks under staircase of sinusoidal shear excitations, all in good agreement with experimental observations. Finally, we showed that stress relaxation in slip-bond collagen networks becomes faster under increasing imposed strain, in direct contrast to networks constructed by catch bond crosslinking proteins where the characteristic timescale for stress decay grows with the strain. By elucidating the mechanism by which crosslink kinetics profoundly affects the bulk behavior of biopolymer networks, our study provides useful insights for the development of future biomaterials and understanding the physical role of cytoskeleton in various cellular processes.
Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy ...(nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).
Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596).
A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28, with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).
NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.
•The CMISG1701 trial assessed the safety and efficacy of nCRT versus nCT followed by MIE for locally advanced bulky ESCC.•The nCRT followed by MIE strategy could not improve survival significantly compared with the nCT strategy.•The best strategy of neoadjuvant therapy for locally advanced bulky ESCC remains a pending issue.
•The overaged samples have the lowest tensile strength among the three aging states, but their fatigue strength is the highest.•Planar slip dislocations are less likely to annihilate by cross slip at ...the UA state, thus contributing to better work-hardening ability, resulting in better strength and plasticity.•Wave slip dislocations at the OA state are frequently annihilated on the second phase, so that the number of dislocations reaching and gathering at GBs is relatively low, which reduces the damage at GBs.
The high-cycle fatigue (HCF) behaviors of wrought Al alloys are vitally important for their industrial application. To optimize the fatigue property of the wrought Al alloy, the effects of aging conditions on the fatigue properties of 7N01, 7075 and 2024 Al alloys were studied. The results show that the overaged samples have the lowest tensile strength among the three aging states, but their fatigue strength is the highest. Further investigations on the dislocation morphologies indicates that the dislocations are easy to accumulate and annihilate at the second phase boundaries for the overaged state, which reduces the fatigue damage degree at the grain boundaries. Besides, the discontinuous distribution of the grain boundary precipitates and the increased width of the precipitate-free zone also contributed to the improved fatigue property of the overaged state. Those results should be significantly important for the optimization of their fatigue properties and the industrial application of wrought Al alloys.
Chronotherapy is no longer a novel concept in cancer treatment after approximately 20 years of development. Many clinical trials have provided strong supporting evidence that chronomodulated ...treatment yields better results than a traditional dosage regimen. This study aimed to evaluate the adverse reactions, effect on immune functions, and therapeutic efficacy of chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) combined with intensity-modulated radiation therapy (IMRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 148 patients with biopsy-diagnosed untreated stage III-IVb NPC were randomly assigned to undergo two cycles of chronomodulated infusion (study group) or flat intermittent infusion (control group) of DDP (100 mg/m2 on day 1, 21 days/cycle) synchronized with radical radiotherapy. Patients in the study group received chronomodulated infusion, with peak delivery of DDP at 16:00 pm. Patients in the control group received a routine constant rate of infusion. Both groups were treated with the same radiotherapy techniques. Over a median follow-up of 20 months, the study group had better outcomes for adverse effects and immune functions compared with the control group. During the phase of concurrent chemoradiotherapy, the incidence of nausea, vomiting, and oral mucositis in the study and control groups was 66.7% and 79.5% (p < 0.05), 47.9% and 71.2% (p < 0.05), and 73.9% and 87.7% (p < 0.05), respectively. There was no significant difference in 2-year overall survival, progression-free survival, and distant metastasis-free survival between the two groups (p > 0.05). Chronochemotherapy significantly reduced the incidence of adverse reactions and enhanced the tolerance for treatment without affecting survival. It is worth mentioning that reduced destruction of immune function is a novel area of exploration in chronotherapy research.
Cancers may arise from rare self-renewing tumor-initiating cells (T-IC). However, how T-IC self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure. Because miRNAs ...can regulate cell-fate decisions, we compared miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-BT-IC from 1° breast cancers.
let-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with
let-7-lentivirus reduced proliferation, mammosphere formation, and the proportion of undifferentiated cells in vitro and tumor formation and metastasis in NOD/SCID mice, while antagonizing
let-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased
let-7 paralleled reduced H-RAS and HMGA2, known
let-7 targets. Silencing
H-RAS in a BT-IC-enriched cell line reduced self renewal but had no effect on differentiation, while silencing
HMGA2 enhanced differentiation but did not affect self renewal. Therefore
let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target.
Frequent dusty weather has led to an increasing interest in dust aerosols, which were observed by lidar as nonspherical particles. To solve the problem of large errors in the previous inversion ...results of nonspherical aerosol particle size distribution (APSD), an inversion model of nonspherical APSD is proposed in this article. This inversion model is made up of three steps. First, the discrete dipole approximation (DDA) method was used instead of the Lorenz-Mie (Mie) theory to compute the optical properties of nonspherical particles. Second, the traditional generalized cross-validation (GCV) method was replaced by a hybrid algorithm and combined with Tikhonov's regularization. The hybrid algorithm combines a particle swarm optimization (PSO) with a genetic algorithm (GA). The problem of the instability of the Lagrange multiplier values is solved. Third, a multi wavelength polarization lidar and an aerodynamic particle sizer (APS) were used to detect dust aerosols in Yinchuan. The nonspherical property of the dust aerosol was verified by the depolarization ratio of the 532-nm polarization channel. Overall, the simulation shows that the hybrid algorithm gives more accurate results and that the real part of the complex refractive index has a greater effect on the nonspherical APSD than the imaginary part of the complex refractive index. There is a clear inverse relationship between the variation of dust aerosol quantities at high altitudes and near the ground. Calculations from the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model revealed the reason for this phenomenon. The model shows that dust aerosol number changes were influenced by updrafts from Russian and Afghan regions and Shaanxi.
In addition to hecogenin
3-O-β-
d-glucopyranosyl(1 → 4)-β-
d-galactopyranoside
, two new steroidal saponins were isolated from the aerial parts of
Tribulus terrestris L. On the basis of chemical and ...spectroscopic evidence, especially 2D NMR spectroscopic techniques, the structures of the new saponins were established as
26-O-β-
d-glucopyranosyl
-3-O-
{β-
d-xylopyranosyl(1 → 3)}{β-
d-galactopyranosyl(1 → 2)}-β-
d-glucopyranosyl (1 → 4)-β-
d-glucopyranosyl-5α-furost-20(22)-en-12-one-3β,26-diol
and
26-O-β-
d-glucopyranosyl
-3-O-rm{β-
d-xylopyranosyl(1 → 3){β-
d-galactopyranosyl(1 → 2)}-β-
d-glucopyranosyl (1 → 4)-β-
d-glucopyranosyl-5α-furostan-12-one-3β,22,26-triol
.
Rifamycin-derived drugs, including rifampin, rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, ...the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are found to mediate, respectively, a unique C-O bond formation in rifamycin L and an atypical P450 ester-to-ether transformation from rifamycin L to B. Both reactions showcase interesting chemistries for these two widespread and well-studied enzyme families.
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