A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Empowering women as enablers in public health: A quantitative-qualitative systematic review of the gender-transformative approach.

Women are expected to take on multiple roles as caregivers and health care providers, but they are still often perceived as victims or beneficiaries rather than enablers. We aimed to explore women's empowerment and gender equality in public health systems and identify proactive enablers that can be incorporated into projects. A systematic review of peer-reviewed literature as well as text analysis were conducted to examine changes in perceptions of women's roles in public health projects. The authors conducted a quantitative analysis of the collected article titles, which revealed a shift in research from identifying risk factors to exploring women's autonomy in health promotion. However, our qualitative review of the articles showed that previous gender-related projects used a gender-sensitive approach that perpetuated the view of women as victims or beneficiaries rather than enablers. The concept of proactive enablers in all aspects of project planning and implementation ensures that women's roles are fully recognized and valued.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

Interfacial-Water-Modulated Photoluminescence of Single-Layer WS2 on Mica.

Because of their bandgap tunability and strong light-matter interactions, two-dimensional (2D) semiconductors are considered promising candidates for next-generation optoelectronic devices. However, their photophysical properties are greatly affected by their surrounding environment because of their 2D nature. In this work, we report that the photoluminescence (PL) of single-layer WS2 is substantially affected by interfacial water that is inevitably present between it and the supporting mica substrates. Using PL spectroscopy and wide-field imaging, we show that the emission signals from A excitons and their negative trions decreased at distinctively different rates with increasing excitation power, which could be attributed to the more efficient annihilation between excitons than between trions. By gas-controlled PL imaging, we also prove that the interfacial water converted the trions into excitons by depleting native negative charges through an oxygen reduction reaction, which rendered the excited WS2 more susceptible to nonradiative decay via exciton-exciton annihilation. Understanding the role of nanoscopic water in complex low-dimensional materials will eventually contribute to devising their novel functions and related devices.

"My body is the evidence, assess my health": Women's disposable sanitary pads social health movement in Korea.

Researcher focused on the sanitary pads health movement in Korea from the feminist health perspective. The methodology was based on web content/statement analysis. Statements were collected and analyzed from government, women NGOs, online petitions, news articles, and reports gathered for three years from March 2017 to September 2020. The disposable sanitary pads health movement was triggered by the Korean Women's Environmental Network KWEN unveiled that it detected carcinogenic substances in its harmful substance detection tests with Professor Kim in March 2017. Women who were silenced for a long time could finally argue for their health rights in the Korean society.

Use of High-Resolution Ultrasound in Characterizing the Surface Topography of a Breast Implant.

Background and Objectives: With the emergence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), it has become necessary to identify the implant shell type patients have received. Therefore, an immediate, reliable method for identifying a breast implant shell type is essential. Evidence-based research and applying a real-world technique that identifies the surface topographic information of the inserted breast implants, without surgery, has become of paramount importance for breast implant physicians. Methods and Materials: A review of the medical records of 1901 patients who received 3802 breast implants and subsequently received an ultrasound-assisted examination was performed. All patients received not only a breast cancer examination but also a high-resolution ultrasonography (HRUS) assisted examination of the device at a single center between 31 August 2017 and 31 December 2022. Results: Most patients had breast implants within 10 years (77.7%) of the examination. Of the 3802 implants screened, 2034 (53.5%) were identified with macro-textured shell topography in ultrasonography. A macrotextured shell type implant was used in 53.5% of cases and a smooth type in 42.7% of cases. Seventy-three (1.9%) breast implant shell types could not be identified due to ruptures. However, 250 breast implant shell types could be identified despite rupture cases (6.5%). Conclusions: HRUS was found to be a useful and reliable image modality for identifying various surface shell types of breast implants. The shell type information would be helpful to patients who lack information about their breast implants and are concerned about BIA-ALCL.

L-Type Calcium Channel Blocker Enhances Cellular Delivery and Gene Silencing Potency of Cell-Penetrating Asymmetric siRNAs.

The efficient delivery of small interfering RNAs (siRNAs) to the target cells is critical for the pharmaceutical success of RNA interference (RNAi) drugs. One of the possible strategies to improve siRNA delivery is to identify auxiliary molecules that augment their cellular uptake. Herein, we performed a chemical library screening in an effort to discover small molecules that enhance the potency of cholesterol-conjugated, cell-penetrating asymmetric siRNAs (cp-asiRNAs). Interestingly, three compounds identified from the screen share a common dihydropyridine (DHP) core and function as L-type calcium channel blockers (CCBs). Using confocal microscopy and quantitative analysis of small RNAs, we demonstrated that the L-type CCBs increased the endocytic cellular uptake of cp-asiRNAs. Furthermore, these small molecules substantially improved the potency of cp-asiRNAs, not only in vitro but also in vivo on rat skin. Collectively, our study provides an alternative pharmacological approach for the identification of small molecules that potentiate the effects of therapeutic siRNAs.

Nanoclay-Polyamine Composite Hydrogel for Topical Delivery of Nitric Oxide Gas via Innate Gelation Characteristics of Laponite.

Because nitric oxide (NO) gas is an endogenously produced signaling molecule related to numerous physiological functions, manystudies have been conducted to develop NO delivery systems for potential biomedical applications. However, NO is a reactive radical gas molecule that has a very short life-time and readily transforms into nitrogen oxide species via reaction with oxygen species. Therefore, it is necessary to develop an NO delivery carrier that allows local release of the NO gas at the site of application. In this study, Laponite (LP) nanoclay was used to fabricate an NO delivery carrier through the formation of Laponite-polyamine (LP-PAn) composites. The Laponite clay and pentaethylenehexamine (PEHA) formed a macromolecular structure by electrostatic interaction and the nitric oxide donor, N-diazeniumdiolate (NONOates), was synthesized into the LP-PAn composite. We investigated the conformation of the LP-PAn composite structure and the NO donor formation by ζ potential, X-ray diffraction, and UV-vis and Fourier transform infrared (FT-IR) spectroscopies and also by analyzing the NO release profile. Additionally, we confirmed the applicability in biomedical applications via a cell viability and in vitro endothelial cell tube formation assay.

Real-time effect of electron beam on MoS2 field-effect transistors.

Irradiation of MoS2 field-effect transistors (FETs) fabricated on Si/SiO2 substrates with electron beams (e-beams) below 30 keV creates electron-hole pairs (EHP) in the SiO2, which increase the interface trap density (Nit ) and change the current path in the channel, resulting in performance changes. In situ measurements of the electrical characteristics of the FET performed using a nano-probe system mounted inside a scanning electron microscope show that e-beam irradiation enables both multilayer and monolayer MoS2 channels act as conductors. The e-beams mostly penetrate the channel owing to their large kinetic energy, while the EHPs formed in the SiO2 layer can contribute to the conductance by flowing into the MoS2 channel or inducing the gate bias effect. The analysis of the device parameters in the initial state and the vent-evacuation state after e-beam irradiation can clarify the effect of the interplay between the e-beam-induced EHPs and ambient adsorbates on the carrier behavior, which depends on the thickness of the MoS2 layer. DC and low frequency noise analysis reveals that the e-beam-induced EHPs increase Nit from 109-1010 to 1011 cm-2 eV-1 in both monolayer and multilayer devices, while the interfacial Coulomb scattering parameter αSC increases by three times in the monolayer and decreases to one-tenth of its original value in the multilayer. In other words, an MoS2 layer with a thickness of ∼30 nm is less sensitive to adsorbates by surface screening. Thus, the carrier mobility in the monolayer device decreases from 45.7 to 40 cm2 V-1 s-1, while in the 30 nm-thick multilayer device, it increases from 4.9 to 5.6 cm2 V-1 s-1. This is further evidenced by simulations of the distribution of interface traps and channel carriers in the MoS2 FET before and after e-beam irradiation, demonstrating that Coulomb scattering decreases as the effective channel moves away from the interface.

A Novel Zinc Chelator, 1H10, Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Zinc Toxicity and AMPK Activation.

Previous studies in our lab revealed that chemical zinc chelation or zinc transporter 3 (ZnT3) gene deletion suppresses the clinical features and neuropathological changes associated with experimental autoimmune encephalomyelitis (EAE). In addition, although protective functions are well documented for AMP-activated protein kinase (AMPK), paradoxically, disease-promoting effects have also been demonstrated for this enzyme. Recent studies have demonstrated that AMPK contributes to zinc-induced neurotoxicity and that 1H10, an inhibitor of AMPK, reduces zinc-induced neuronal death and protects against oxidative stress, excitotoxicity, and apoptosis. Here, we sought to evaluate the therapeutic efficacy of 1H10 against myelin oligodendrocyte glycoprotein 35-55-induced EAE. 1H10 (5 µg/kg) was intraperitoneally injected once per day for the entire experimental course. Histological evaluation was performed three weeks after the initial immunization. We found that 1H10 profoundly reduced the severity of the induced EAE and that there was a remarkable suppression of demyelination, microglial activation, and immune cell infiltration. 1H10 also remarkably inhibited EAE-associated blood-brain barrier (BBB) disruption, MMP-9 activation, and aberrant synaptic zinc patch formation. Furthermore, the present study showed that long-term treatment with 1H10 also reduced the clinical course of EAE. Therefore, the present study suggests that zinc chelation and AMPK inhibition with 1H10 may have great therapeutic potential for the treatment of multiple sclerosis.

Risk Factors of Clonorchis sinensis Human Infections in Endemic Areas, Haman-Gun, Republic of Korea: A Case-Control Study.

Clonorchis sinensis is the most common fish-borne intestinal parasite in Korea. The aim of the present investigation was to survey the status of C. sinensis infection and analyze associated risk factors in residents of Haman-gun, Gyeongsangnam-do. A total of 5,114 residents from 10 administrative towns/villages voluntarily agreed to participate in the study, which comprised fecal examination, a questionnaire survey for risk factors, ultrasonography, and enzymelinked immunosorbent assay for cancer biomarker detection in the blood. We detected C. sinensis eggs in 5.3% of the subjects. By region, Gunbuk-myeon had the highest number of residents with C. sinensis eggs. The infection rate and intensity were higher in male than in female residents. Based on the risk factor questionnaire, infection was highly associated with drinking, a history of C. sinensis infection, and the practice of eating of raw freshwater fish. Extension of the bile duct, infection intensity, and cancer biomarker detection significantly correlated with the presence of eggs in the study population. In conclusion, the development of feasible, long-term control policies and strategies for the elimination of C. sinensis in Korea is still required.

Novel colchicine derivatives enhance graft survival after transplantation via suppression of T-cell differentiation and activity.

Immunosuppressants are crucial in organ transplantation but their side effects are a trade-off for long-term use. Colchicine has been shown to be effective in various diseases, albeit with many side effects. To enhance the immunosuppressive effects of colchicine, in addition to minimizing its side effects, we attempted to synthesize new colchicine derivatives (KR compounds). In rat cardiac and pancreatic islet allograft, long-term graft survival was identified in KR compound-treated groups. The use of cyclosporine A (CsA) or colchicine inhibited the CD3+ and CD4+ T-cell proliferation, whereas KR compounds inhibited the CD8+ T cells as well as CD4+ T cells. KR compounds reduced the apoptosis, interleukin-2 receptor expression, and signal transducer and activator of transcription 3 phosphorylation more than CsA. These results indicate that KR compounds have a potential therapeutic value as novel agents for prevention of graft deterioration by allograft of rejection.

Zinc preconditioning protects against neuronal apoptosis through the mitogen-activated protein kinase-mediated induction of heat shock protein 70.

During brain ischemic preconditioning (PC), mild bursts of ischemia render neurons resistant to subsequent strong ischemic injuries. Previously, we reported that zinc plays a key role in PC-induced neuroprotection in vitro and in vivo. Zinc-triggered p75(NTR) induction transiently activates caspase-3, which cleaves poly(ADP-ribose) polymerase-1 (PARP-1). Subsequently, the PARP-1 over-activation-induced depletion of nicotinamide adenine dinucleotide (NAD(+))/adenosine triphosphate (ATP) after exposures to lethal doses of zinc or N-methyl-D-aspartate is significantly attenuated in cortical neuronal cultures. In the present study, zinc-mediated preconditioning (Zn PC) reduced apoptotic neuronal death that was caused by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), etoposide, or staurosporine in mouse cortical cells. We focused on heat shock protein 70 (HSP70) because NAD(+)/ATP depletion does not directly cause apoptosis, and HSP70 can inhibit the activation of caspase-9 or caspase-3 by preventing apoptosome formation or cytochrome C release. Zn PC-mediated HSP70 induction was required for neuroprotection against neuronal apoptosis, and geldanamycin-induced HSP70 induction sufficiently blocked neuronal apoptotic cell death. Furthermore, Zn PC-mediated HSP70 induction was blocked by chemical inhibitors of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase (MAPK) signaling, but not c-Jun N-terminal protein kinase. Similarly, neuroprotection by Zn PC against TPEN-induced apoptosis was almost completely reversed by the blockade of ERK or p38 MAPK signaling. Our findings suggest that the ERK- or p38 MAPK-mediated induction of HSP70 plays a key role in inhibiting caspase-3 activation during Zn PC.

Conceptualizing prenatal care: recent research and the application of Tae-Kyo, Korean traditional beliefs and practices.

The value of prenatal care has long been recognized by various cultures. The author's purpose in this article is to propose a framework to conceptualize prenatal care using the traditional Korean practice of prenatal care called Tae-Kyo, which means education for the fetus. The philosophy of Tae-Kyo shows the importance of children's development from the very beginning of life and indicates the moral and social responsibilities of pregnant women, family members, and communities in delivering healthy babies. This comprehensive view implies a framework for conceptualizing prenatal care that encompasses multidimensional aspects of prenatal care.

Retarded protein folding of the human Z-type α1-antitrypsin variant is suppressed by Cpr2p.

The human Z-type α1-antitrypsin variant has a strong tendency to accumulate folding intermediates due to extremely slow protein folding within the endoplasmic reticulum (ER) of hepatocytes. Human α1-antitrypsin has 17 peptidyl-prolyl bonds per molecule; thus, the effect of peptidyl-prolyl isomerases on Z-type α1-antitrypsin protein folding was analyzed in this study. The protein level of Cpr2p, a yeast ER peptidyl-prolyl isomerase, increased more than two-fold in Z-type α1-antitrypsin-expressing yeast cells compared to that in wild-type α1-antitrypsin-expressing cells. When CPR2 was deleted from the yeast genome, the cytotoxicity of Z-type α1-antitrypsin increased significantly. The interaction between Z-type α1-antitrypsin and Cpr2p was confirmed by co-immunoprecipitation. In vitro folding assays showed that Cpr2p facilitated Z-type α1-antitrypsin folding into the native state. Furthermore, Cpr2p overexpression significantly increased the extracellular secretion of Z-type α1-antitrypsin. Our results indicate that ER peptidyl-prolyl isomerases may rescue Z-type α1-antitrypsin molecules from retarded folding and eventually relieve clinical symptoms caused by this pathological α1-antitrypsin.

Consensus scoring approach to identify the inhibitors of AMP-activated protein kinase α2 with virtual screening.

Due to the involvement in the ischemic damage in the brain, 5'-adenosine monophosphate-activated protein kinase subunit α2 (AMPK2) serves as a promising target for the development of new medicines for stroke. Despite such a pharmaceutical importance, only a few small-molecule inhibitors have been reported so far. We aim in this study to identify a new class of AMPK2 inhibitors based on the structure-based virtual screening with docking simulations. To take advantage of and supplement the deficiencies of force field-based and empirical scoring functions, a consensus scoring method is employed to select the putative inhibitors by the combined use of AutoDock and FlexX programs. Prior to the virtual screening with docking simulations, both scoring functions are modified by implementing the molecular solvation free energy term to enhance the accuracy in estimating the protein-ligand binding affinity. As a consequence of the consensus virtual screening with the two modified scoring functions, we find seven structurally diverse AMPK2 inhibitors with micromolar inhibitory activity. Detailed binding mode analyses indicate that all these inhibitors can be stabilized in the ATP-binding pocket through the simultaneous establishment of the multiple hydrogen bonds and hydrophobic interactions. It is also found that a high inhibitory activity can be achieved by the reduction of desolvation cost for the inhibitor as well as by the strengthening of the enzyme-inhibitor interactions. Thus, the results of the present study demonstrate the outperformance of consensus scoring with the force field-based and empirical scoring functions that are modified to include the effects of ligand solvation on protein-ligand docking.

Blue-Emissive ZnSeTe Quantum Dots and Their Electroluminescent Devices.

Over the last two decades, quantum-dot light-emitting diodes (QLEDs), also known as quantum dot (QD) electroluminescent devices, have gained prominence in next-generation display technologies, positioning them as potential alternatives to organic light-emitting diodes. Nonetheless, challenges persist in enhancing key device performances such as efficiency and lifetime, while those of blue QLEDs lag behind compared with green and red counterparts. In this Perspective, we discuss key factors affecting the photoluminescence characteristics of environmentally benign blue-emissive ternary ZnSeTe QDs, including composition, core/shell heterostructure, and surface ligand. Notably, we highlight the recent progress in breakthrough strategies to enhance blue QLED performance, examining the effects of the ZnSeTe QD attribute and device architecture on device performance. This Perspective offers insights into integrated aspects of QD material and device structure in overcoming challenges toward a high-performance blue ZnSeTe QLED.

Biofabrication of nanocomposite-based scaffolds containing human bone extracellular matrix for the differentiation of skeletal stem and progenitor cells.

Autograft or metal implants are routinely used in skeletal repair. However, they fail to provide long-term clinical resolution, necessitating a functional biomimetic tissue engineering alternative. The use of native human bone tissue for synthesizing a biomimetic material ink for three-dimensional (3D) bioprinting of skeletal tissue is an attractive strategy for tissue regeneration. Thus, human bone extracellular matrix (bone-ECM) offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells (HBMSCs) to proliferate and differentiate along the osteogenic lineage. In this study, we engineered a novel material ink (LAB) by blending human bone-ECM (B) with nanoclay (L, Laponite®) and alginate (A) polymers using extrusion-based deposition. The inclusion of the nanofiller and polymeric material increased the rheology, printability, and drug retention properties and, critically, the preservation of HBMSCs viability upon printing. The composite of human bone-ECM-based 3D constructs containing vascular endothelial growth factor (VEGF) enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane (CAM) model. The inclusion of bone morphogenetic protein-2 (BMP-2) with the HBMSCs further enhanced vascularization and mineralization after only seven days. This study demonstrates the synergistic combination of nanoclay with biomimetic materials (alginate and bone-ECM) to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair. Supplementary Information: The online version contains supplementary material available at 10.1007/s42242-023-00265-z.

Tracking cellular uptake, intracellular trafficking and fate of nanoclay particles in human bone marrow stromal cells.

Clay nanoparticles, in particular synthetic smectites, have generated interest in the field of tissue engineering and regenerative medicine due to their utility as cross-linkers for polymers in biomaterial design and as protein release modifiers for growth factor delivery. In addition, recent studies have suggested a direct influence on the osteogenic differentiation of responsive stem and progenitor cell populations. Relatively little is known however about the mechanisms underlying nanoclay bioactivity and in particular the cellular processes involved in nanoclay-stem cell interactions. In this study we employed confocal microscopy, inductively coupled plasma mass spectrometry and transmission electron microscopy to track the interactions between clay nanoparticles and human bone marrow stromal cells (hBMSCs). In particular we studied nanoparticle cellular uptake mechanisms and uptake kinetics, intracellular trafficking pathways and the fate of endocytosed nanoclay. We found that nanoclay particles present on the cell surface as µm-sized aggregates, enter hBMSCs through clathrin-mediated endocytosis, and their uptake kinetics follow a linear increase with time during the first week of nanoclay addition. The endocytosed particles were observed within the endosomal/lysosomal compartments and we found evidence for both intracellular degradation of nanoclay and exocytosis as well as an increase in autophagosomal activity. Inhibitor studies indicated that endocytosis was required for nanoclay upregulation of alkaline phosphatase activity but a similar dependency was not observed for autophagy. This study into the nature of nanoclay-stem cell interactions, in particular the intracellular processing of nanosilicate, may provide insights into the mechanisms underlying nanoclay bioactivity and inform the successful utilisation of clay nanoparticles in biomaterial design.

Zwitterionic Inhaler with Synergistic Therapeutics for Reprogramming of M2 Macrophage to Pro-Inflammatory Phenotype.

Myriad lung diseases are life threatening and macrophages play a key role in both physiological and pathological processes. Macrophages have each pro-/anti-inflammatory phenotype, and each lung disease can be aggravated by over-polarized macrophage. Therefore, development of a method capable of mediating the macrophage phenotype is one of the solutions for lung disease treatment. For mediating the phenotype of macrophages, the pulmonary delivery system (PDS) is widely used due to its advantages, such as high efficiency and accessibility of the lungs. However, it has a low drug delivery efficiency ironically because of the perfect lung defense system consisting of the mucus layer and airway macrophages. In this study, zwitterion-functionalized poly(lactide-co-glycolide) (PLGA) inhalable microparticles (ZwPG) are synthesized to increase the efficiency of the PDS. The thin layer of zwitterions formed on PLGA surface has high nebulizing stability and show high anti-mucus adhesion and evasion of macrophages. As a reprogramming agent for macrophages, ZwPG containing dexamethasone (Dex) and pirfenidone (Pir) are treated to over-polarized M2 macrophages. As a result, a synergistic effect of Dex/Pir induces reprogramming of M2 macrophage to pro-inflammatory phenotypes.