Rational design of novel diaryl ether-linked benzimidazole derivatives as potent and selective BACE1 inhibitors.

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC50 values of 0.05-2.71 µM. The aryloxy-phenyl analogs 20j showed the EC50 value as low as 0.07 µM in the enzyme assay, whereas, the benzyloxyphenyl dervative 24b was comparatively less effective in the enzyme assay. But interestingly the latter was more effective in the cell assay (EC50 value 1.2 µM). While comparing synthesized derivatives in the cell assay using PC12-APPSW cell, compound 27f appeared as the most potent BACE1 inhibitor having EC50 value 0.7 µM. This scaffold also showed high selectivity over BACE2 enzyme and cathepsin D. Furthermore, the research findings were bolstered through the incorporation of molecular docking, molecular dynamics, and DFT studies. We firmly believe that these discoveries will pave the way for the development of a novel class of small-molecule selective BACE1 inhibitors.

IL-23 induces CLEC5A+ IL-17A+ neutrophils and elicit skin inflammation associated with psoriatic arthritis.

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23RGFP reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1+CD11b+Ly6G+ population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R+MDL1+ cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.

Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Development of pyramided lines carrying brown planthopper resistance genes in the genetic background of Indica Group rice (Oryza sativa L.) variety 'IR64'.

The development of resistant rice (Oryza sativa L.) varieties is a key strategy for the eco-friendly control of brown planthopper (BPH: Nilaparvata lugens Stål). However, BPH outbreaks occur frequently owing to the evolution of virulent strains in the field and the rapid breakdown of monogenic resistance to BPH. Therefore, to enhance BPH resistance and gauge the effectiveness of gene pyramiding against strongly virulent BPH, we developed pyramided lines (PYLs) in the genetic background of 'IR64' carrying BPH resistance genes. We developed six IR64-PYLs (BPH3 + BPH17, BPH32 + BPH17, BPH32 + BPH20, BPH3 + BPH17-ptb, BPH20 + BPH3, and BPH17-ptb + BPH32) through marker-assisted selection. To assess the resistance of the IR64-PYLs, we conducted antibiosis test, honeydew test, and modified seedbox screening test (MSST) using strongly virulent BPH populations. The level of BPH resistance increased in all six IR64-PYLs compared to both 'IR64' and the corresponding NILs in MSST. Among them, IR64-BPH3 + BPH17 and IR64-BPH32 + BPH17 exhibited the highest resistance to BPH. However, the resistance level of most IR64-PYLs was not significantly higher than that of the corresponding NILs in antibiosis test. Thus, these PYLs could serve as a valuable resource for breeding programs aimed at improving resistance to virulent strains of BPH and enhancing their durability.

Development and characterization of near-isogenic lines for brown planthopper resistance genes in the genetic background of japonica rice 'Sagabiyori'.

The brown planthopper (BPH: Nilaparvata lugens Stål) is one of the most destructive insects in rice production. The use of host plant resistance has potential to reduce damage caused by BPH. The heat tolerance japonica rice 'Sagabiyori', with superior grain quality and high soluble starch in the stem, is highly susceptible to damage by BPH. Here, to enhance its BPH resistance, we developed seven near-isogenic lines (NILs) carrying BPH2, BPH17-ptb, BPH32, BPH3, BPH17, BPH20, and BPH21 through marker-assisted selection and evaluated resistance to two BPH populations. Most lines were more resistant to the Hadano-1966 BPH population than Sagabiyori but were less effective against the highly virulent Koshi-2013 population. Nevertheless, in antixenosis tests, Koshi-2013 settled less on all NILs than on Sagabiyori. In addition, adult mortality and the percentage of fresh weight loss of lines carrying BPH17 and BPH3 indicated that these lines have higher resistance to Koshi-2013 than Sagabiyori. Current study revealed that BPH resistance of Sagabiyori became stronger by transferring BPH3 and BPH17 genes. Thus, BPH3 and BPH17 might be valuable for breeding programs to enhance BPH resistance of high grain quality rice varieties with heat tolerance.

Financial incentives for sanitation take-up: A randomized control trial in rural Vietnam.

This study assesses the impact of financial incentives on hygienic latrine ownership by poor/near-poor households in Vietnam. Rural communes were randomly assigned to a control group and three treatment arm groups: (T1) a rebate for households that installed a hygienic latrine; (T2) a financial reward for commune governments if the proportion of hygienic latrines in their commune increased by 30 percentage points; (T3) both a household rebate and a commune reward. We find a strong and positive effect from the household rebate (treatment arms 1 and 3) but an insignificant effect from the commune reward (treatment arm 2) on household ownership of a septic tank latrine. Our analysis provides suggestive evidence that microcredit is a channel through which a rebate encourages the installation of septic tank latrines. We also find that treatment arm 3 increases people's knowledge regarding sanitation and the availability of water and soap for handwashing within households.

Vitamin D3 and its Potential to Ameliorate Chemical and Radiation-Induced Skin Injury During Cancer Therapy.

Skin injury and dermatitis are common complications following chemotherapy and radiation administration for cancer treatment. Symptomatic relief of these complications is limited to slow-acting therapies and often results in holding or modifying cancer therapy that may impact patient outcomes. The off-label use of oral high dose vitamin D3 has demonstrated rapid clinical improvement in skin inflammation and swelling in both chemotherapy and radiation-induced injury. Furthermore, vitamin D3 has been shown to downregulate pro-inflammatory pathways and cytokines, including NFkB, and CCL2, as well as CCL20, which are not only involved in tissue injury, but may confer resistance to cancer treatment. In this paper, we discuss 2 patients with acute radiation dermatitis and acute radiation recall dermatitis following chemotherapy who received 50 000 - 100 000 IU of oral high dose vitamin D3 with improvement in their symptoms. These findings may indicate the potential use of vitamin D as a therapeutic intervention and future target for studying skin healing following chemotherapy and/ or radiation-induced cutaneous toxicity.

MELEP: A Novel Predictive Measure of Transferability in Multi-label ECG Diagnosis.

In practical electrocardiography (ECG) interpretation, the scarcity of well-annotated data is a common challenge. Transfer learning techniques are valuable in such situations, yet the assessment of transferability has received limited attention. To tackle this issue, we introduce MELEP, which stands for Muti-label Expected Log of Empirical Predictions, a measure designed to estimate the effectiveness of knowledge transfer from a pre-trained model to a downstream multi-label ECG diagnosis task. MELEP is generic, working with new target data with different label sets, and computationally efficient, requiring only a single forward pass through the pre-trained model. To the best of our knowledge, MELEP is the first transferability metric specifically designed for multi-label ECG classification problems. Our experiments show that MELEP can predict the performance of pre-trained convolutional and recurrent deep neural networks, on small and imbalanced ECG data. Specifically, we observed strong correlation coefficients (with absolute values exceeding 0.6 in most cases) between MELEP and the actual average F1 scores of the fine-tuned models. Our work highlights the potential of MELEP to expedite the selection of suitable pre-trained models for ECG diagnosis tasks, saving time and effort that would otherwise be spent on fine-tuning these models.

Lead (II) ions enable the ion-specific effects of monovalent anions on the molecular structure and interactions at silica/aqueous interfaces.

HYPOTHESIS: The adsorption of heavy metal ions such as Pb(II) onto negatively charged minerals such as silica is expected to alter the structure and the interactions at the silica/aqueous interfaces. Besides the solution pH, the inner-sphere sorption of Pb(II) is expected to regulate the surface charge/potential, hypothesized to control the actions of monovalent anions in the aqueous environment. These complex pictures can be probed directly using surface-sensitive sum-frequency generation (SFG) spectroscopy. EXPERIMENTS: The pH-dependent water structure within the double layer at silica/aqueous interfaces under the influence of different ions was examined using SFG. The recorded SFG spectra were deconvoluted into the Stern layer (SL) and diffuse layer (DL) using the maximum entropy method in conjunction with the electrical double-layer theory. FINDINGS: Standalone monovalent sodium salts do not exhibit ion-specific effects on the silica/aqueous interfaces. However, the mixture of Pb(II) species and each of these salts display profound ion-specific effects on the structure of silica/aqueous interfaces, indicating the role of Pb(II) as an enabler of the ion-specificity of the investigated monovalent anions. The interesting effect arises from a complex interplay between the physical processes (i.e., electrostatic interactions, screening effects, etc.) and chemical processes such as the hydrolysis of Pb(II) ions, ion complexation, protonation and deprotonation of the surface silanol group.

Optimizing neurointerventional procedures: an algorithm for embolization coil detection and automated collimation to enable dose reduction.

Purpose: Monitoring radiation dose and time parameters during radiological interventions is crucial, especially in neurointerventional procedures, such as aneurysm treatment with embolization coils. The algorithm presented detects the presence of these embolization coils in medical images. It establishes a bounding box as a reference for automated collimation, with the primary objective being to enhance the efficiency and safety of neurointerventional procedures by actively optimizing image quality while minimizing patient dose. Methods: Two distinct methodologies are evaluated in our study. The first involves deep learning, employing the Faster R-CNN model with a ResNet-50 FPN as a backbone and a RetinaNet model. The second method utilizes a classical blob detection approach, serving as a benchmark for comparison. Results: We performed a fivefold cross-validation, and our top-performing model achieved mean mAP@75 of 0.84 across all folds on validation data and mean mAP@75 of 0.94 on independent test data. Since we use an upscaled bounding box, achieving 100% overlap between ground truth and prediction is not necessary. To highlight the real-world applications of our algorithm, we conducted a simulation featuring a coil constructed from an alloy wire, effectively showcasing the implementation of automatic collimation. This resulted in a notable reduction in the dose area product, signifying the reduction of stochastic risks for both patients and medical staff by minimizing scatter radiation. Additionally, our algorithm assists in avoiding extreme brightness or darkness in X-ray angiography images during narrow collimation, ultimately streamlining the collimation process for physicians. Conclusion: To our knowledge, this marks the initial attempt at an approach successfully detecting embolization coils, showcasing the extended applications of integrating detection results into the X-ray angiography system. The method we present has the potential for broader application, allowing its extension to detect other medical objects utilized in interventional procedures.

Two-dimensional Janus Si2OX (X = S, Se, Te) monolayers as auxetic semiconductors: theoretical prediction.

The auxetic materials have exotic mechanical properties compared to conventional materials, such as higher indentation resistance, more superior sound absorption performance. Although the auxetic behavior has also been observed in two-dimensional (2D) nanomaterials, to date there has not been much research on auxetic materials in the vertical asymmetric Janus 2D layered structures. In this paper, we explore the mechanical, electronic, and transport characteristics of Janus Si2OX (X = S, Se, Te) monolayers by first-principle calculations. Except for the Si2OTe monolayer, both Si2OS and Si2OSe are found to be stable. Most importantly, both Si2OS and Si2OSe monolayers are predicted to be auxetic semiconductors with a large negative Poisson's ratio. The auxetic behavior is clearly observed in the Janus Si2OS monolayer with an extremely large negative Poisson's ratio of -0.234 in the x axis. At the equilibrium state, both Si2OS and Si2OSe materials exhibit indirect semiconducting characteristics and their band gaps can be easily altered by the mechanical strain. More interestingly, the indirect-direct bandgap phase transitions are observed in both Si2OS and Si2OSe monolayers when the biaxial strains are introduced. Further, the studied Janus structures also exhibit remarkably high electron mobility, particularly along the x direction. Our findings demonstrate that Si2OS and Si2OSe monolayers are new auxetic materials with asymmetric structures and show their great promise in electronic and nanomechanical applications.

Theoretical prediction of electronic properties and contact barriers in a metal/semiconductor NbS2/Janus MoSSe van der Waals heterostructure.

The emergence of van der Waals (vdW) heterostructures, which consist of vertically stacked two-dimensional (2D) materials held together by weak vdW interactions, has introduced an innovative avenue for tailoring nanoelectronic devices. In this study, we have theoretically designed a metal/semiconductor heterostructure composed of NbS2 and Janus MoSSe, and conducted a thorough investigation of its electronic properties and the formation of contact barriers through first-principles calculations. The effects of stacking configurations and the influence of external electric fields in enhancing the tunability of the NbS2/Janus MoSSe heterostructure are also explored. Our findings demonstrate that the NbS2/MoSSe heterostructure is not only structurally and thermally stable but also exfoliable, making it a promising candidate for experimental realization. In its ground state, this heterostructure exhibits p-type Schottky contacts characterized by small Schottky barriers and low tunneling barrier resistance, showing its considerable potential for utilization in electronic devices. Additionally, our findings reveal that the electronic properties, contact barriers and contact types of the NbS2/MoSSe heterostructure can be tuned by applying electric fields. A negative electric field leads to a conversion from a p-type Schottky contact to an n-type Schottky contact, whereas a positive electric field gives rise to a transformation from a Schottky into an ohmic contact. These insights offer valuable theoretical guidance for the practical utilization of the NbS2/MoSSe heterostructure in the development of next-generation electronic and optoelectronic devices.

Alkali to alkaline earth metals: a DFT study of monolayer TiSi2N4 for metal ion batteries.

A significant problem in the area of rechargeable alkali ion battery technologies is the exploration of anode materials with overall high specific capacities and superior physical properties. By using first-principles calculations, we have determined that monolayer TiSi2N4 is precisely such a potential anode candidate. Its demonstrated dynamic, thermal, mechanical, and energetic stabilities make it feasible for experimental realization. An important benefit of the electrode conductivity is that the electronic structure reveals that the pristine system experiences a change from a semiconductor to a metal throughout the entire alkali adsorption process. What's more interesting is that monolayer TiSi2N4 can support up to double-sided 3-layer ad-atoms, resulting in extremely high theoretical capacities for Li, Na, Mg, and K of 1004, 854, 492 and 531 mA h g-1 and low average open-circuit voltages of 0.55, 0.25, 0.55, and -1.3 V, respectively. Alkali diffusion on the surface has been demonstrated to occur extremely quickly, with migration energy barriers for Li, Na, Mg, and K as low as 0.25, 0.14, 0.10, and 0.07 eV, respectively. The results reveal that the migration barrier energy is the lowest for Li and Mg from path-2 and Na and K from path-1. Overall, these findings suggest that monolayer TiSi2N4 is a suitable anode candidate for use in high-performance and low-cost metal-ion batteries.

Achieving ultra-low contact barriers in MX2/SiH (M = Nb, Ta; X = S, Se) metal-semiconductor heterostructures: first-principles prediction.

Minimizing the contact barriers at the interface, forming between two different two-dimensional metals and semiconductors, is essential for designing high-performance optoelectronic devices. In this work, we design different types of metal-semiconductor heterostructures by combining 2D metallic MX2 (M = Nb, Hf; X = S, Se) and 2D semiconductor SiH and investigate systematically their electronic properties and contact characteristics using first principles calculations. We find that all the MX2/SiH (M = Nb, Ta; X = S, Se) heterostructures are energetically stable, suggesting that they could potentially be synthesized in the future. Furthermore, the generation of the MX2/SiH metal-semiconductor heterostructures leads to the formation of the Schottky contact with ultra-low Schottky barriers of a few tens of meV. This finding suggests that all the 2D MX2 (M = Nb, Ta; X = S, Se) metals act as effective electrical contact 2D materials to contact with the SiH semiconductor, enabling electronic devices with high charge injection efficiency. Furthermore, the tunneling resistivity of all the MX2/SiH (M = Nb, Ta; X = S, Se) MSHs is low, confirming that they exhibit high electron injection efficiency. Our findings underscore fundamental insights for the design of high-performance multifunctional Schottky devices based on the metal-semiconductor MX2/SiH heterostructures with ultra-low contact barriers and high electron injection efficiency.

Checklist of the genus Ridsdalea (Rubiaceae, Gardenieae) in Vietnam with description of the new species R.backanensis.

The paper provides an identification key and an annotated list of all six species of the genus Ridsdalea J.T.Pereira & K.M.Wong (Rubiaceae, Gardenieae) recorded in the flora of Vietnam, along with data on their valid names, synonyms, types, and distribution. A new species, R.backanensis, discovered in the limestone area of Bac Kan Province (northern Vietnam), is described and illustrated. Detailed data on its characters, ecology, distribution, phenology, preliminary IUCN conservation status, and taxonomical notes are given. The newly discovered species is potentially interesting for cultivation as an ornamental tree that may be effectively used in garden and urban green architecture.

Extracting lignin from sugarcane bagasse for methylene blue and hexavalent chromium adsorption in textile wastewater: a facile, green, and sustainable approach.

This study presents the process of extracting lignin from sugarcane bagasse collected in the Mekong Delta, Vietnam by the alkali method. NaOH has been used as an effective, environmentally friendly chemical to enhance the extraction process. The obtained lignin was applied for methylene blue (MB) and hexavalent chromium (Cr(vi)) removal. Factors influencing lignin extraction and adsorption processes of MB and Cr(vi) were investigated, showcasing the sustainable reusability of lignin extracted from sugarcane bagasse. Lignin characterization was also carried out by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) techniques. The results showed that the extracted lignin content reached 38.61% under optimal conditions (NaOH concentration of 10%, reaction temperature of 90 °C and reaction time of 90 min). The adsorption efficiency and capacity of lignin reached 90.90% and 9.09 mg g-1 for MB and 80.10% and 28.04 mg g-1 for Cr(vi), respectively, under optimum adsorption conditions (pH, adsorption time, initial methylene blue concentration, and used lignin content). The adsorption process obeyed Langmuir adsorption and was principally physical adsorption. These findings prove sugarcane bagasse based lignin as a cheap and efficient adsorbent for MB and Cr(vi) removal, which contributes to the utilization of the abundant agricultural by-product for wastewater treatment.

PFAS removal from landfill leachate by ozone foam fractionation: System optimization and adsorption quantification.

Landfills are the primary endpoint for the disposal of PFAS-laden waste, which subsequently releases PFAS to the surrounding environments through landfill leachate. Ozone foam fractionation emerges as a promising technology for PFAS removal to address the issue. This study aims to (i) assess the effectiveness of the ozone foam fractionation system to remove PFAS from landfill leachate, and (ii) quantify equilibrium PFAS adsorption onto the gas-water interface of ozone bubbles, followed by a comparison with air foam fractionation. The results show that ozone foam fractionation is effective for PFAS removal from landfill leachate, with more than 90 % long-chain PFAS removed. The identified operating conditions provide valuable insights for industrial applications, guiding the optimization of ozone flow rates (1 L/min), dosing (43 mg/L) and minimizing foamate production (4 % wettability). The equilibrium modelling reveals that the surface excess of air bubbles exceeds that of ozone bubbles by 20-40 % at a corresponding PFAS concentration. However, the overall removal of PFAS from landfill leachate by ozone foam fractionation remains substantial. Notably, ozone foam fractionation generates foamate volumes 2 - 4 times less, resulting in significant cost savings for the final disposal of waste products and reduced site storage requirements.

First-principles investigations of the controllable electronic properties and contact types of type II MoTe2/MoS2 van der Waals heterostructures.

Two-dimensional (2D) van der Waals (vdW) heterostructures are considered as promising candidates for realizing multifunctional applications, including photodetectors, field effect transistors and solar cells. In this work, we performed first-principles calculations to design a 2D vdW MoTe2/MoS2 heterostructure and investigate its electronic properties, contact types and the impact of an electric field and in-plane biaxial strain. We find that the MoTe2/MoS2 heterostructure is predicted to be structurally, thermally and mechanically stable. It is obvious that the weak vdW interactions are mainly dominated at the interface of the MoTe2/MoS2 heterostructure and thus it can be synthesized in recent experiments by the transfer method or chemical vapor deposition. The construction of the vdW MoTe2/MoS2 heterostructure forms a staggered type II band alignment, effectively separating the electrons and holes at the interface and thereby extending the carrier lifetime. Interestingly, the electronic properties and contact types of the type II vdW MoTe2/MoS2 heterostructure can be tailored under the application of external conditions, including an electric field and in-plane biaxial strain. The semiconductor-semimetal-metal transition and type II-type I conversion can be achieved in the vdW MoTe2/MoS2 heterostructure. Our findings underscore the potential of the vdW MoTe2/MoS2 heterostructure for the design and fabrication of multifunctional applications, including electronics and optoelectronics.