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Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease.

Chlorinated organic compounds are emerging pollutants of widespread concern because of their toxicity, bioaccumulation, persistence, and lack of adequate regulatory measures. Their abiotic transformation, facilitated by iron-bearing minerals, is critical to their natural dissipation in soils and sediments. However, further exploration is needed to understand their underlying mechanisms and potential engineering applications under different redox conditions. This paper reviews the abiotic transformation behaviors and mechanisms of chlorinated organics at the active surface of iron-bearing minerals under anoxic and oxic conditions and summarizes the strategies for enhancing the abiotic transformation efficiency of chlorinated organics. The abiotic transformation rate under oxic conditions can be a few orders of magnitude higher than that under anoxic conditions. Under anoxic conditions, chlorinated organics undergo reductive dechlorination through reductive elimination, hydrogenolysis, dehydrohalogenation, and nucleophilic substitution. A close relationship between the abiotic transformation of chlorinated organics and the production of hydroxyl radicals by iron-bearing minerals under oxic conditions was discovered. Synthetic active iron-bearing minerals, carbonaceous materials, and biological synergy can facilitate abiotic dechlorination under anoxic conditions. Meanwhile, the regulation of redox conditions, the introduction of ligands, and the utilization of coexisting anions are proposed to enhance oxidative degradation. This study is expected to improve the comprehension of the abiotic degradation of chlorinated organics mediated by iron-bearing minerals and provide the theoretical foundation for developing new approaches aimed at addressing chlorinated organic pollution.

Lanthanide-containing luminescent hydrogels have shown potential for sensing and imaging applications. Nonetheless, integrating lanthanide ions or complexes into the polymer matrix often results in the poor stability and mechanical strength of the hydrogels. This work presents an innovative approach to fabricating luminescent hydrogels with three dynamic cross-links: imine bond, boronate ester bond, and metal–ligand coordination. Europium(III) (Eu3+) ions are incorporated into a dual-cross-linked matrix composed of phenylboronic acid-polyethylenimine-modified gelatin (PPG) and alginate dialdehyde (ADA) through a combined treatment involving freeze-drying-swelling (FDS) and freeze–thawing (FT) processes. The FDS process facilitates the formation of additional europium-carboxylate cross-links within the polymeric network to enhance its luminescence and stability, while the FT process strengthens the network physically. The impact of the FDS-FT cycle number on the microstructures and properties of PPG/ADA-Eu3+hydrogels is thoroughly investigated, and their potential for monitoring bacterial growth and detecting copper(II) ions is also demonstrated.

Capacitive touchscreens have become the primary human-machine interface for personal devices such as smartphones and tablets. In this article, we present GhostTouch, the first active contactless attack against capacitive touchscreens. GhostTouch uses electromagnetic interference (EMI) to inject fake touch points into a touchscreen without the requirement to physically touch it. By tuning the parameters of the electromagnetic signal and adjusting the antenna, we can inject two types of basic touch events, taps and swipes, into targeted locations of the touchscreen and control them to manipulate the underlying device. We successfully launch theGhostTouch attacks on nine smartphone models. We can inject targeted taps continuously with a standard deviation of as low as $14.6 \times 19.2$14.6×19.2 pixels from the target area, and a distance of up to $\text{40}\; {\text mm}$40mm. We show the real-world impact of the GhostTouch attacks in a few proof-of-concept scenarios, including pressing the button, answering an eavesdropping phone call, and swiping up to unlock. Finally, we propose touchscreen reinforcement and attack detection mechanisms to mitigate the threat of GhostTouch attack.

Across systems, higher-order interactions between components govern emergent dynamics. Here we tested whether contextual threat memory retrieval in mice relies on higher-order interactions between dorsal CA1 hippocampal neurons requiring learning-induced dendritic spine plasticity. We compared population-level Ca2+transients as wild-type mice (with intact learning-induced spine plasticity and memory) and amnestic mice (TgCRND8 mice with high levels of amyloid-β and deficits in learning-induced spine plasticity and memory) were tested for memory. Using machine-learning classifiers with different capacities to use input data with complex interactions, our findings indicate complex neuronal interactions in the memory representation of wild-type, but not amnestic, mice. Moreover, a peptide that partially restored learning-induced spine plasticity also restored the statistical complexity of the memory representation and memory behavior in Tg mice. These findings provide a previously missing bridge between levels of analysis in memory research, linking receptors, spines, higher-order neuronal dynamics and behavior.

To transmit high power very-low-frequency signals with low harmonic content, the high-frequency cascaded H-bridge multilevel inverter (HF-MLI) usually has large number of levels and uses the selective harmonic elimination (SHE) technique for modulation. However, when the number of levels exceeds 25, the conventional SHE switching angle computation methods have a problem since the computed switching angles tend to be located at 0 and π/2, which makes the harmonic suppression effect worse. To realize a good harmonic suppression effect for HF-MLIs with a large number of levels, an interior-point-method-based switching angle computation method is proposed in this paper. With the aid of the interior point method (IPM), the constraints of switching angles are combined with the harmonic function in the objective function through a penalty function. The iteration is divided into the inner loop and the outer loop. The switching angles are computed in the inner loop and the weight of the penalty function is updated in the outer loop. The penalty function can keep the switching angles away from constraints. When compared with conventional methods, the proposed method has a higher accuracy, a shorter execution time and better harmonic suppression effect when computing the switching angles of MLIs with more than 25 levels. The harmonics from 9 to 19th-order of the proposed method are suppressed to less than 0.1%, which is experimentally verified on a single-phase 49-level HF-MLI.

Although the environmentally friendly waterborne epoxy (WEP) coatings exhibit high adhesion to substrates, the abundant hydrophilic groups in those coatings always bring about poor anticorrosion performance. Herein, a nonionic WEP emulsifier with the lipophilic–hydrophilic–lipophilic (L-H-L) structure has been successfully prepared to enhance the anticorrosion performance of the WEP coating. After the hydrophilic chains formed between polyethylene glycol (PEG) and hexahydrophthalic anhydride (HHPA) are terminated by epoxy resin (E51), the WEP emulsifier with the L-H-L structure can be obtained, which is then used for preparing the WEP emulsion with regular shape, small particle size, uniform distribution, and high stability by the phase inversion method. The WEP coatings of uniform thickness (110 ± 15 μm) without anticorrosion fillers can be prepared by spraying. The results of electrochemical impedance spectroscopy (EIS) show that the WEP-PEG2000-10% coating exhibits high anticorrosion performance with the low-frequency impedance value as high as 7.47 × 109ohm·cm2after being immersed in 3.5 wt % NaCl solution for 60 days. Actually, the L-H-L structure effectively reduces the free hydrophilic groups in the WEP coating, thus significantly improving the anticorrosion performance. This study provides new insight on developing novel inherent WEP coating with high anticorrosion performance.

C21H21MnN6O6S, monoclinic, P21/c(no. 14), a= 13.093(3) Å, b= 23.810(5) Å, c= 7.9852(17) Å, β= 106.882(4)°, V= 2,382.1(9) Å3, Z= 4, Rgt(F) = 0.0498, wRref(F2) = 0.1299, T= 296(2) K.

•Outcomes in patients who developed septic shock after allo-HSCT were poor.•Gram-negative bacilli accounted for 61.5% of the positive isolates.•Escherichia coliwas the dominant isolated pathogen.•Patients with late-onset septic shock had a significantly worse outcome.•Of patients with sepsis-induced coagulopathy, the 28-day mortality rate was 88.1%.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most important curative method for intermediate- and high-risk adult acute myeloid leukemia (AML) patients. We aimed to identify the clinical outcomes of haploidentical related donor (HID) peripheral blood stem cell transplantation (PBSCT) who receiving peripheral blood (G-PB) harvest, and the patients receiving bone marrow (BM) plus G-PB harvest (BM + PB) as grafts were enrolled as control. The engraftments of neutrophil and platelet in G-PB group were both faster than those in BM + PB group. The cumulative incidences of grade II–IV acute graft-versus-host disease (aGVHD), and moderate to severe chronic GVHD (cGVHD) were all comparable between G-PB and BM + PB groups. The cumulative incidence of relapse and non-relapse mortality at 3 years after HID HSCT was 12.6% versus 13.7% (p= 0.899) and 3.6% versus 7.3% (p= 0.295), respectively, in G-PB and BM + PB group. While the probabilities of GVHD-free/relapse-free survival, leukemia-free survival, and overall survival at 3 years after HID HSCT were 60.6% versus 53.4% (p= 0.333), 83.8% versus 79.0% (p= 0.603), and were 87.3% versus 82.9% (p= 0.670), respectively. We confirmed the safety and efficacy of HID PBSCT in intermediate- and high-risk AML patients in a large cohort.

This study aimed to compare the pharmacokinetics and bioavailability of 2 formulations: a fixed‐dose combination tablet containing allisartan isoproxil (AI) and indapamide sustained‐release (SR), and a monotherapy combination of AI and indapamide SR, in healthy Chinese subjects. A monocentric, open‐label, single‐dose, randomized, 2‐way crossover study design was implemented. A total of 38 healthy male and female volunteers were equally divided into 2 treatment sequences. The analysis of plasma concentrations was conducted using a nonstereospecific liquid chromatography/tandem mass spectrometric method. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. For the fixed‐dose combination and monotherapy combination, the mean values of EXP3174 (metabolite of AI) Cmax, AUC0‒t, and AUC0‐∞were 987 and 999 ng/mL, 8059 and 7749 ng/mL h, and 8332 and 8007 ng/mL h, respectively. The corresponding values for indapamide were 27 and 32 ng/mL, 1002 and 1105 ng/mL h, and 1080 and 1172 ng/mL h. No serious adverse events were reported during the study. The combination tablet containing 240 mg of AI and 1.5 mg of indapamide SR met the bioequivalence standards. Additionally, both formulations were tolerated and had good safety profiles in the research.

The security of capacitive touchscreens is crucial since they have become the primary human-machine interface on smart devices. This paper presents Marionette, the first wired attack that creates ghost touches on capacitive touchscreens via charging cables and can manipulate the victim's devices with undesired consequences, e.g., establishing malicious Bluetooth connections. Our study provides a new threat vector against touchscreens that only requires connecting to a malicious charging port, which could be a public charging station, and is effective across various USB data blockers and power adapters. Despite the fact that smartphones employ abundant noise reduction and voltage management techniques, we manage to inject carefully crafted signals that can induce ghost touches within a chosen range. The underlying principle is to inject common-mode noises over the power line to avoid being effectively filtered yet affecting the touch measurement mechanism and synchronize the malicious noise with the screen measurement scanning cycles to place the ghost touches at target locations. We achieve three types of attacks, i.e., injection, alteration, and Denial-of-Service, and the evaluation of 12 commercial electronics, 6 power adapters, and 13 charging cables demonstrate the feasibility of Marionette.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33–215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8–24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9–140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p< 0.001) and platelet engraftment (75.8% versus 32.3%, p< 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p= 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

Prophylactic/preemptive donor lymphocyte infusion (p/pDLI) and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia (RRAL), but real-world data remain scarce. We conducted a multicenter, population-based analysis of 932 consecutive patients. The three-year leukemia-free survival (LFS) rates were 56% for patients receiving both p/pDLI and intensified myeloablative conditioning (MAC) (intenseMAC) and 30% for those who received neither therapy per landmark analysis. Multivariable analyses were run separately for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality. IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL, while there was no impact of intenseMAC observed in AML. p/pDLI achieved superior outcomes in both matched-sibling donor (MSD) and haploidentical donor transplantation, while intenseMAC only influenced MSD outcomes. Data suggest that RRAL patients receiving “total therapy” by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS, with p/pDLI being safer with a more extensive impact relative to intenseMAC. Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.

The aromaticity of π-conjugated compounds has long been a confusing issue. Based on a recently emerged two-dimensional (2D) superatomic-molecule theory, a unified rule was built to decipher the aromaticity of cyclic superatomic molecules of π-conjugated compounds from the chemical bonding perspective. Herein, a series of planar [n]helicenes and [n]circulenes, composed of benzene, thiophene, or furfuran, are systemically studied and seen as superatomic molecules ◊On-2◊F2or ◊On, where superatoms ◊F and ◊O denote π-conjugated units with 5 and 4 π electrons, respectively. The ascertained superatomic Lewis structures intuitively display aromaticity with each basic unit meeting the superatomic sextet rule of benzene, similar to classical valence bond theory, which is favored by the synthesized complex π-conjugated compounds comprising different numbers and kinds of subrings. The evolutionary trend of ring currents and chemical bonding suggests a local ribbon-like aromaticity in these π-conjugated compounds. Moreover, nonplanar helical π-conjugated compounds have the potential to evolve into spring-like periodic materials with excellent physical properties.

Improving the drug loading and delivery efficiency of biodegradable nanomaterials used for targeting prostate cancer (PCa) remains a challenging task. To accomplish this task, herein, a new surface molecularly imprinted polymer (ZIF-8/DOX-HA@MIP) was designed and constructed with a hyaluronic acid (HA)-modified zeolitic imidazolate framework-8 (ZIF-8) metal–organic framework loaded with doxorubicin (DOX) as a substrate and a responsive molecularly imprinted polymer film as a shell. Owing to the large surface area of ZIF-8, DOX was successfully loaded into the ZIF-8/DOX-HA@MIP with a high drug loading efficiency (more than 88%). In vitro cell experiments have shown that the strengthened targeting ability of ZIF-8/DOX-HA@MIP to PCa cells was realized through the synergistic effect of HA and the molecularly imprinted membrane. Under the condition of simulated tumor microenvironment solution, Zn species were released and the particle size of ZIF-8/DOX-HA@MIP decreased gradually by the synergistic effect of hyaluronidase, pH, and glutathione, showing excellent biodegradability. In vivo antitumor research indicated the excellent antitumor activity and biocompatibility of ZIF-8/DOX-HA@MIP. The multifunctional ZIF-8/DOX-HA@MIP constructed herein provides a novel impetus for the development of targeted drug delivery in PCa treatment and a new strategy for treating other tumors.

ABSTRACTIntervertebral disc degeneration (IVDD), a widely known contributor to low back pain (LBP), has been proved to be a global health challenging conundrum. Hesperidin (hesperetin-7-O-rutinoside, HRD) is a flavanone glycoside that belongs to the subgroup of citrus flavonoids with therapeutic effect on various diseases due to its anti-inflammatory, antioxidant properties. However, the effect of HRD on IVDD remains elusive. The human nucleus pulposus tissues were harvested for isolating human nucleus pulposus (HNP) cells to verify the expression of Nrf2. The biological effect of HRD on HNP cells were assessed in vitro, and the in vivo therapeutic effects of HRD were assessed in mice. Firstly, we found that the expression of Nrf2 was decreased with the progression of degeneration in degenerated human nucleus pulposus tissue. Subsequently, we confirmed that HRD could mitigate oxidative stress-induced ferroptosis in nucleus pulposus cells via enhancing the expression of Nrf2 axis and suppressing the NF-κB pathway to protect intervertebral disc from degeneration in vitro. Finally, the therapeutic effects of HRD were confirmed in vivo. The current study proved for the first time that HRD may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-κB pathway. The evidence will provide a possible basis for future targeted treatment for IVDD

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.

•Our model is the first to predict heart failure mortality following allogeneic hematopoietic stem cell transplantation.•The BLIPS score demonstrated high discrimination and calibration power.•The model can provide early identification of patients with heart failure, with a higher 2-month mortality rate.