Exploring the therapeutic potential of DV-B-120 as an inhibitor of dengue virus infection.

Dengue fever, an infectious disease prevalent in subtropical and tropical regions, currently lacks effective small-molecule drugs as treatment. In this study, we used a fluorescence peptide cleavage assay to screen seven compounds to assess their inhibition of the dengue virus (DENV) NS2B-NS3 protease. DV-B-120 demonstrated superior inhibition of NS2B-NS3 protease activity and lower toxicity compared to ARDP0006. The selectivity index of DV-B-120 was higher than that of ARDP0006. In vivo assessments of the antiviral efficacy of DV-B-120 against DENV replication demonstrated delayed mortality of suckling mice treated with the compound, with 60-80% protection against life-threatening effects, compared to the outcomes of DENV-infected mice treated with saline. The lower clinical scores of DENV-infected mice treated with DV-B-120 indicated a reduction in acute-progressive illness symptoms, underscoring the potential therapeutic impact of DV-B-120. Investigations of DV-B-120's ability to restore the antiviral type I IFN response in the brain tissue of DENV-infected ICR suckling mice demonstrated its capacity to stimulate IFN and antiviral IFN-stimulated gene expression. DV-B-120 not only significantly delayed DENV-2-induced mortality and illness symptoms but also reduced viral numbers in the brain, ultimately restoring the innate antiviral response. These findings strongly suggest that DV-B-120 holds promise as a therapeutic agent against DENV infection and highlight its potential contribution in addressing the current lack of effective treatments for this infectious disease.IMPORTANCEThe prevalence of dengue virus (DENV) infection in tropical and subtropical regions is escalating due to factors like climate change and mosquito vector expansion. With over 300 million annual infections and potentially fatal outcomes, the urgent need for effective treatments is evident. While the approved Dengvaxia vaccine has variable efficacy, there are currently no antiviral drugs for DENV. This study explores seven compounds targeting the NS2B-NS3 protease, a crucial protein in DENV replication. These compounds exhibit inhibitory effects on DENV-2 NS2B-NS3, holding promise for disrupting viral replication and preventing severe manifestations. However, further research, including animal testing, is imperative to assess therapeutic efficacy and potential toxicity. Developing safe and potent treatments for DENV infection is critical in addressing the rising global health threat posed by this virus.

Teriparatide as an Effective Nonsurgical Treatment for a Patient with Basicervical Peritrochanteric Fracture Nonunion-A Case Report.

The nonunion rate of surgically treated basicervical peritrochanteric fractures has been reported to be as high as 9%. Due to the high 1-year mortality rate following revision surgery, finding an effective nonsurgical treatment option is of interest. Over the last decade, numerous reports have been published that have suggested teriparatide as an effective treatment for certain types of fracture nonunion. However, the literature focused on teriparatide treatment for proximal femoral fracture nonunion is scanty. A 70-year-old man suffering from a left hip basicervical peritrochanteric fracture received cephalomedullary nail fixation. Nine months after the surgery, the patient still complained of left hip pain referring to the medial thigh with an antalgic limping gait. No sign of healing was noted for more than a consecutive 3 months of follow-up. Fracture nonunion was diagnosed and further confirmed by the computed tomography (CT). The patient preferred nonsurgical treatment after thorough discussion. He then received 4 months of subcutaneous teriparatide injections, 20 mcg daily. After less than 4 months of teriparatide treatment, a follow-up CT confirmed fracture union and the patient's pain subsided. The patient also tolerated independent ambulation afterward. Teriparatide has been reported to be an effective treatment for certain types of fracture nonunion. Our case goes a step further to expand its possible application for basicervical peritrochanteric fracture nonunion. However, further larger scale studies are needed to confirm its efficacy.

Fast Photoresponsive Phototransistor Memory Using Star-Shaped Conjugated Rod-Coil Molecules as a Floating Gate.

With the explosive growth in data generation, photomemory capable of multibit data storage is highly desired to enhance the capacity of storage media. To improve the performance of phototransistor memory, an organic-molecule-based electret with an elaborate nanostructure is of great importance because it can enable multibit data storage in a memory device with high stability. In this study, a series of star-shaped rod-coil molecules consisting of perylenediimide (PDI) and biobased solanesol were synthesized in two-armed (PDI-Sol2), four-armed (PDI-Sol4), and six-armed (PDI-Sol6) architectures. Their molecular architecture-morphology relationships were investigated, and phototransistor memory was fabricated and characterized to evaluate the structure-performance relationship of these rod-coil molecules. Accordingly, the memory devices were enabled by photowriting with panchromatic light (405-650 nm) and electrical erasing using a gate bias. The PDI-Sol4-based memory device showed high memory ratios of 10 000 over 10 000 s and a rapid multilevel photoresponse of 50 ms. This achievement is related to the favorable energy-level alignment, isolated nanostructure, and face-on orientation of PDI-Sol4, which eliminated the charge tunneling barrier. The results of this study provide a new strategy for tailoring nanostructures in organic-molecule-based electrets by using a star-shaped rod-coil architecture for high-performance phototransistor memory.

Cryo-EM structure of the nucleosome core particle containing Giardia lamblia histones.

Giardia lamblia is a pathogenic unicellular eukaryotic parasite that causes giardiasis. Its genome encodes the canonical histones H2A, H2B, H3, and H4, which share low amino acid sequence identity with their human orthologues. We determined the structure of the G. lamblia nucleosome core particle (NCP) at 3.6 Å resolution by cryo-electron microscopy. G. lamblia histones form a characteristic NCP, in which the visible 125 base-pair region of the DNA is wrapped in a left-handed supercoil. The acidic patch on the G. lamblia octamer is deeper, due to an insertion extending the H2B α1 helix and L1 loop, and thus cannot bind the LANA acidic patch binding peptide. The DNA and histone regions near the DNA entry-exit sites could not be assigned, suggesting that these regions are asymmetrically flexible in the G. lamblia NCP. Characterization by thermal unfolding in solution revealed that both the H2A-H2B and DNA association with the G. lamblia H3-H4 were weaker than those for human H3-H4. These results demonstrate the uniformity of the histone octamer as the organizing platform for eukaryotic chromatin, but also illustrate the unrecognized capability for large scale sequence variations that enable the adaptability of histone octamer surfaces and confer internal stability.

Structural basis of nucleosomal histone H4 lysine 20 methylation by SET8 methyltransferase.

SET8 is solely responsible for histone H4 lysine-20 (H4K20) monomethylation, which preferentially occurs in nucleosomal H4. However, the underlying mechanism by which SET8 specifically promotes the H4K20 monomethylation in the nucleosome has not been elucidated. Here, we report the cryo-EM structures of the human SET8-nucleosome complexes with histone H3 and the centromeric H3 variant, CENP-A. Surprisingly, we found that the overall cryo-EM structures of the SET8-nucleosome complexes are substantially different from the previous crystal structure models. In the complexes with H3 and CENP-A nucleosomes, SET8 specifically binds the nucleosomal acidic patch via an arginine anchor, composed of the Arg188 and Arg192 residues. Mutational analyses revealed that the interaction between the SET8 arginine anchor and the nucleosomal acidic patch plays an essential role in the H4K20 monomethylation activity. These results provide the groundwork for understanding the mechanism by which SET8 specifically accomplishes the H4K20 monomethylation in the nucleosome.

Medial joint space width and convergence angle change with time after medial opening-wedge high tibial osteotomy.

BACKGROUND: Although the medial joint space width (MJSW) is commonly used for radiographic evaluation of knee osteoarthritis, the changes in knee joint space width (JSW) during weight bearing after medial opening-wedge high tibial osteotomy (MOWHTO) remain unclear. This study aimed to depict how medial and lateral JSWs and convergence angles change gradually after MOWHTO. METHODS: We retrospectively followed up 81 MOWHTO cases for over 45 months on average. Pre- and postoperative mechanical axes were recorded. The JSWs and convergence angles were measured preoperatively, immediately postoperatively, and 3-6, 9-12, and 21-24 months postoperatively. Patient-reported outcomes were measured using a visual analogue scale (VAS). RESULTS: The mean mechanical femoral-tibial angle improved from 8.1° varus to 2.4° valgus. At the aforementioned times, the respective mean values of MJSW were 2.6, 3.5, 3.8, 4.0, and 4.2 mm; mean convergence angles were 4.8°, 2.9°, 2.2°, 2.1°, and 1.9°; and the mean VAS scores were 7.2, 7.8, 4.8, 1.4, and 1.3. The MJSW continued to increase significantly in the first year postoperatively and then plateaued for a minimum of 2 years follow up after MOWHTO. The convergence angle decreased significantly in the first 6 months postoperatively and was then maintained. CONCLUSIONS: The MJSW, convergence angle, and VAS scores continued to improve through weight bearing during the first year after MOWHTO and were maintained for at least 2 years. Thus, JSW measurement may be an easy and representative way of radiographically monitoring the effect of MOWHTO.

Cryo-EM Structures of Centromeric Tri-nucleosomes Containing a Central CENP-A Nucleosome.

The histone H3 variant CENP-A is a crucial epigenetic marker for centromere specification. CENP-A forms a characteristic nucleosome and dictates the higher-order configuration of centromeric chromatin. However, little is known about how the CENP-A nucleosome affects the architecture of centromeric chromatin. In this study, we reconstituted tri-nucleosomes mimicking a centromeric nucleosome arrangement containing the CENP-A nucleosome, and determined their 3D structures by cryoelectron microscopy. The H3-CENP-A-H3 tri-nucleosomes adopt an untwisted architecture, with an outward-facing linker DNA path between nucleosomes. This is distinct from the H3-H3-H3 tri-nucleosome architecture, with an inward-facing DNA path. Intriguingly, the untwisted architecture may allow the CENP-A nucleosome to be exposed to the solvent in the condensed chromatin model. These results provide a structural basis for understanding the 3D configuration of CENP-A-containing chromatin, and may explain how centromeric proteins can specifically target the CENP-A nucleosomes buried in robust amounts of H3 nucleosomes in centromeres.

Terahertz volatile gas sensing by using polymer microporous membranes.

A compact, inexpensive, low loss, highly sensitive gas sensor is important for various biomedical and industrial applications. However, current gas sensors still have an inadequate study in terahertz (THz) frequency range. In this study, simple multilayer-stacked microporous polymer membranes are experimentally validated in the THz regime for organic vapor sensing under ambient atmosphere and room temperature. The hydrophilic porous polymer structure provides a large surface area to adsorb polar vapors, and exhibits excellent discrimination in different types of organic vapors based on distinct dipole moments. Various concentrations of volatile vapors can also be successfully distinguished by detecting the limits of low ppm concentrations. Furthermore, the microporous structural gas sensor has a reasonable response time in repeat usage. This study would provide new perspectives on toxic gas sensing and exhaled breath detection applications in the THz spectral frequency.

Hierarchical structures consisting of SiO2 nanorods and p-GaN microdomes for efficiently harvesting solar energy for InGaN quantum well photovoltaic cells.

We experimentally and theoretically demonstrated the hierarchical structure of SiO(2) nanorod arrays/p-GaN microdomes as a light harvesting scheme for InGaN-based multiple quantum well solar cells. The combination of nano- and micro-structures leads to increased internal multiple reflection and provides an intermediate refractive index between air and GaN. Cells with the hierarchical structure exhibit improved short-circuit current densities and fill factors, rendering a 1.47 fold efficiency enhancement as compared to planar cells.

Blockade of JAK2 activity suppressed accumulation of ß-catenin in leukemic cells.

The Wnt/ß-catenin pathway has been implicated in leukemogenesis. We found ß-catenin abnormally accumulated in both human acute T cell leukemia Jurkat cells and human erythroleukemia HEL cells. ß-Catenin can be significantly down-regulated by the Janus kinase 2 specific inhibitor AG490 in these two cells. AG490 also reduces the luciferase activity of a reporter plasmid driven by LEF/ß-catenin promoter. Similar results were observed in HEL cells infected with lentivirus containing shRNA against JAK2 gene. After treatment with 50 µM AG490 or shRNA, the mRNA expression levels of ß-catenin, APC, Axin, ß-Trcp, GSK3α, and GSK3ß were up-regulated within 12-16 h. However, only the protein levels of GSK3ß and ß-Trcp were found to have increased relative to untreated cells. Knockdown experiments revealed that the AG490-induced inhibition of ß-catenin can be attenuated by shRNA targeting ß-TrCP. Taken together; these results suggest that ß-Trcp plays a key role in the cross-talk between JAK/STAT and Wnt/ß-catenin signaling in leukemia cells.