Literature-based predictions of Mendelian disease therapies.

In the effort to treat Mendelian disorders, correcting the underlying molecular imbalance may be more effective than symptomatic treatment. Identifying treatments that might accomplish this goal requires extensive and up-to-date knowledge of molecular pathways-including drug-gene and gene-gene relationships. To address this challenge, we present "parsing modifiers via article annotations" (PARMESAN), a computational tool that searches PubMed and PubMed Central for information to assemble these relationships into a central knowledge base. PARMESAN then predicts putatively novel drug-gene relationships, assigning an evidence-based score to each prediction. We compare PARMESAN's drug-gene predictions to all of the drug-gene relationships displayed by the Drug-Gene Interaction Database (DGIdb) and show that higher-scoring relationship predictions are more likely to match the directionality (up- versus down-regulation) indicated by this database. PARMESAN had more than 200,000 drug predictions scoring above 8 (as one example cutoff), for more than 3,700 genes. Among these predicted relationships, 210 were registered in DGIdb and 201 (96%) had matching directionality. This publicly available tool provides an automated way to prioritize drug screens to target the most-promising drugs to test, thereby saving time and resources in the development of therapeutics for genetic disorders.

Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.

Nanostructured Molecular Packing of Polymer Films Formed on Water Surfaces.

In this study, we examined the nanostructured molecular packing and orientations of poly[[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)] (P(NDI2OD-T2)) films formed on water for the application of nanotechnology-based organic electronic devices. First, the nanoscale molecule-substrate interaction between the polymer and water was modulated by controlling the alkyl side chain length in NDI-based copolymers. Increasing alkyl side chain lengths induced a nanomorphological transition from face-on to edge-on orientation, confirmed by molecular dynamics simulations revealing nanostructural behavior. Second, the nanoscale intermolecular interactions of P(NDI2OD-T2) were controlled by varying the volume ratio of the high-boiling-point additive solvent in the binary solvent blends. As the additive solvent ratio increased, the nanostructured molecular orientation of the P(NDI2OD-T2) films on water changed remarkably from edge-on to bimodal with more face-on crystallites, thereby affecting charge transport. Our finding provides essential insights for precise nanoscale morphological control on water substrates, enabling the formation of high-performance polymer films for organic electronic devices.

Applicability of selected reaction monitoring for precise screening tests.

INTRODUCTION: The proactive identification of diseases through screening tests has long been endorsed as a means to preempt symptomatic onset. However, such screening endeavors are fraught with complications, such as diagnostic inaccuracies, procedural risks, and patient unease during examinations. These challenges are amplified when screenings for multiple diseases are administered concurrently. Selected Reaction Monitoring (SRM) offers a unique advantage, allowing for the high-throughput quantification of hundreds of analytes with minimal interferences. AREAS COVERED: Our research posits that SRM-based assays, traditionally tailored for single-disease biomarker profiling, can be repurposed for multi-disease screening. This innovative approach has the potential to substantially alleviate time, labor, and cost demands on healthcare systems and patients alike. Nonetheless, there are formidable methodological hurdles to overcome. These include difficulties in detecting low-abundance proteins and the risk of model overfitting due to the multiple functionalities of single proteins across different disease spectrums - issues especially pertinent in blood-based assays where detection sensitivity is constrained. As we move forward, technological strides in sample preparation, online extraction, throughput, and automation are expected to ameliorate these limitations. EXPERT OPINION: The maturation of mass spectrometry's integration into clinical laboratories appears imminent, positioning it as an invaluable asset for delivering highly sensitive, reproducible, and precise diagnostic results.

Strong, Chemically Stable, and Enzymatically On-Demand Detachable Hydrogel Adhesion Using Protein Crosslink.

Achieving strong adhesion between hydrogels and diverse materials is greatly significant for emerging technologies yet remains challenging. Existing methods using non-covalent bonds have limited pH and ion stability, while those using covalent bonds typically lack on-demand detachment capability, limiting their applications. In this study, a general strategy of covalent bond-based and detachable adhesion by incorporating amine-rich proteins in various hydrogels and inducing the interfacial crosslinking of the hydrogels using a protein-crosslinking agent is demonstrated. The protein crosslink offers topological adhesion and can reach a strong adhesion energy of ≈750 J m-2 . The chemistry of the adhesion is characterized and that the inclusion of proteins inside the hydrogels does not alter the hydrogels' properties is shown. The adhesion remains intact after treating the adhered hydrogels with various pH solutions and ions, even at an elevated temperature. The detachment is triggered by treating proteinase solution at the bonding front, causing the digestion of proteins, thus breaking up the interfacial crosslink network. In addition, that this approach can be used to adhere hydrogels to diverse dry surfaces, including glass, elastomers and plastics, is shown. The stable chemistry of protein crosslinks opens the door for various applications in a wide range of chemical environments.

Using electron energy-loss spectroscopy to measure nanoscale electronic and vibrational dynamics in a TEM.

Electron energy-loss spectroscopy (EELS) can measure similar information to x-ray, UV-Vis, and IR spectroscopies but with atomic resolution and increased scattering cross-sections. Recent advances in electron monochromators have expanded EELS capabilities from chemical identification to the realms of synchrotron-level core-loss measurements and to low-loss, 10-100 meV excitations, such as phonons, excitons, and valence structures. EELS measurements are easily correlated with electron diffraction and atomic-scale real-space imaging in a transmission electron microscope (TEM) to provide detailed local pictures of quasiparticle and bonding states. This perspective provides an overview of existing high-resolution EELS (HR-EELS) capabilities while also motivating the powerful next step in the field-ultrafast EELS in a TEM. Ultrafast EELS aims to combine atomic-level, element-specific, and correlated temporal measurements to better understand spatially specific excited-state phenomena. Ultrafast EELS measurements also add to the abilities of steady-state HR-EELS by being able to image the electromagnetic field and use electrons to excite photon-forbidden and momentum-specific transitions. We discuss the technical challenges ultrafast HR-EELS currently faces, as well as how integration with in situ and cryo measurements could expand the technique to new systems of interest, especially molecular and biological samples.

Capacitive Electrode-Based Electric Field Treatments on Redox-Toxic Iron Deposits in Transgenic AD Mouse Models: The Electroceutical Targeting of Alzheimer's Disease Feasibility Study.

Iron accumulation in the brain accelerates Alzheimer's disease progression. To cure iron toxicity, we assessed the therapeutic effects of noncontact transcranial electric field stimulation to the brain on toxic iron deposits in either the Aß fibril structure or the Aß plaque in a mouse model of Alzheimer's disease (AD) as a pilot study. A capacitive electrode-based alternating electric field (AEF) was applied to a suspension of magnetite (Fe3O4) to measure field-sensitized reactive oxygen species (ROS) generation. The increase in ROS generation compared to the untreated control was both exposure-time and AEF-frequency dependent. The frequency-specific exposure of AEF to 0.7-1.4 V/cm on a magnetite-bound Aß-fibril or a transgenic Alzheimer's disease (AD) mouse model revealed the degradation of the Aß fibril or the removal of the Aß-plaque burden and ferrous magnetite compared to the untreated control. The results of the behavioral tests show an improvement in impaired cognitive function following AEF treatment on the AD mouse model. Tissue clearing and 3D-imaging analysis revealed no induced damage to the neuronal structures of normal brain tissue following AEF treatment. In conclusion, our results suggest that the effective degradation of magnetite-bound amyloid fibrils or plaques in the AD brain by the electro-Fenton effect from electric field-sensitized magnetite offers a potential electroceutical treatment option for AD.

Measurement of the NOx reduction effect on food wastewater during waste incineration.

Incineration is the most effective method for reducing the increasing waste volume. However, as the pollutants generated during incineration may cause secondary pollution, blocking them in advance is necessary. During incineration, prevention facilities are operated to reduce the amount of pollutants. Conventional selective non-catalytic reduction (SNCR) reduces nitrogen oxides (NOx) by injecting ammonia and urea as reducing agents. In this study, the NOx reduction effect on food wastewater (FW) was examined. In addition, the removal efficiency was compared at different concentrations of urea mixed with FW. When different concentrations of urea were injected in SNCR facilities A, B and C, NOx removal efficiencies of up to 75% were observed; with FW injection only, removal efficiency was 56%; and when both urea and FW were injected, removal efficiency was up to 79%. Although FW showed a lower NOx removal efficiency than urea, injecting both increased the efficiency. In addition, when air pollutant emissions and the incinerator temperature were analysed, we found that they could be managed without exceeding the allowed limits. However, for the injection and incineration of reducing agents, the characteristics of the incineration facility and reducing agents must be considered.

The role of SHMT2 in modulating lipid metabolism in hepatocytes via glycine-mediated mTOR activation.

Serine hydroxymethyltransferase 2 (SHMT2) converts serine into glycine in the mitochondrial matrix, transferring a methyl group to tetrahydrofolate. SHMT2 plays an important role in the maintenance of one-carbon metabolism. Previously, we found a negative correlation between the serine concentration and the progression of fatty liver disease (FLD). However, little is known about the role of SHMT2 in hepatic lipid metabolism. We established SHMT2 knockdown (KD) mouse primary hepatocytes using RNA interference to investigate the role of SHMT2 in lipid metabolism. SHMT2 KD hepatocytes showed decreased lipid accumulation with reduced glycine levels compared to the scramble cells, which was restored upon reintroducing SHMT2. SHMT2 KD hepatocytes showed downregulation of the mTOR/PPARÉ£ pathway with decreased gene expression related to lipogenesis and fatty acid uptake. Pharmacological activation of mTOR or PPARÉ£ overexpression blocked the inhibitory effect of SHMT2 KD on lipid accumulation. We also showed that glycine activated mTOR/PPARÉ£ signaling and identified glycine as a mediator of SHMT2-responsive lipid accumulation in hepatocytes. In conclusion, silencing SHMT2 in hepatocytes ameliorates lipid accumulation via the glycine-mediated mTOR/PPARÉ£ pathway. Our findings underscore the possibility of SHMT2 as a therapeutic target of FLD.

Enhanced thermoelectric performance of defect engineered monolayer graphene.

We propose a method of improving the thermoelectric properties of graphene using defect engineering through plasma irradiation and atomic layer deposition (ALD). We intentionally created atomic blemishes in graphene by oxygen plasma treatment and subsequently healed the atomistically defective places using Pt-ALD. After healing, the thermal conductivity of the initially defective graphene increased slightly, while the electrical conductivity and the square of the Seebeck coefficient increased pronouncedly. The thermoelectric figure of merit of the Pt-ALD treated graphene was measured to be over 4.8 times higher than the values reported in the literature. We expect that our study could provide a useful guideline for the development of graphene-based thermoelectric devices.

Improved gliotransmission by increasing intracellular Ca2+ via TRPV1 on multi-walled carbon nanotube platforms.

BACKGROUND: Astrocyte is a key regulator of neuronal activity and excitatory/inhibitory balance via gliotransmission. Recently, gliotransmission has been identified as a novel target for neurological diseases. However, using the properties of nanomaterials to modulate gliotransmission has not been uncovered. RESULTS: We prepared non-invasive CNT platforms for cells with different nanotopography and properties such as hydrophilicity and conductivity. Using CNT platforms, we investigated the effect of CNT on astrocyte functions participating in synaptic transmission by releasing gliotransmitters. Astrocytes on CNT platforms showed improved cell adhesion and proliferation with upregulated integrin and GFAP expression. In addition, intracellular GABA and glutamate in astrocytes were augmented on CNT platforms. We also demonstrated that gliotransmitters in brain slices were increased by ex vivo incubation with CNT. Additionally, intracellular resting Ca2+ level, which is important for gliotransmission, was also increased via TRPV1 on CNT platforms. CONCLUSION: CNT can improve astrocyte function including adhesion, proliferation and gliotransmission by increasing resting Ca2+ level. Therefore, our study suggests that CNT would be utilized as a new therapeutic platform for central nervous system diseases by modulating gliotransmission.

Intratracheal exposure to polyhexamethylene guanidine phosphate disrupts coordinate regulation of FXR-SHP-mediated cholesterol and bile acid homeostasis in mouse liver.

A public health crisis in the form of a significant incidence of fatal pulmonary disease caused by repeated use of humidifier disinfectants containing polyhexamethylene guanidine phosphate (PHMG) recently arose in Korea. Although the mechanisms of pulmonary fibrosis following respiratory exposure to PHMG are well described, distant-organ effect has not been reported. In this study, we investigated whether intratracheal administration of PHMG affects liver pathophysiology and metabolism. Our PHMG mouse model showed a significant decrease in liver cholesterol level. An mRNA-seq analysis of liver samples revealed an alteration in the gene expression associated with cholesterol biosynthesis and metabolism to bile acids. The expression of genes involved in cholesterol synthesis was decreased in a real-time PCR analysis. To our surprise, we found that the coordinate regulation of cholesterol and bile acid homeostasis was completely disrupted. Despite the decreased cholesterol synthesis and low bile acid levels, the farnesoid X receptor/small heterodimer partner pathway, which controls negative feedback of bile acid synthesis, was activated in PHMG mice. As a consequence, gene expression of Cyp7a1 and Cyp7b1, the rate-limiting enzymes of the classical and alternative pathways of bile acid synthesis, was significantly downregulated. Notably, the changes in gene expression were corroborated by the hepatic concentrations of the bile acids. These results suggest that respiratory exposure to PHMG could cause cholestatic liver injury by disrupting the physiological regulation of hepatic cholesterol and bile acid homeostasis.

Amyloid Formation in Nanoliter Droplets.

Processes that monitor the nucleation of amyloids and characterize the formation of amyloid fibrils are vital to medicine and pharmacology. In this study, we observe the nucleation and formation of lysozyme amyloid fibrils using a facile microfluidic system to generate nanoliter droplets that can control the flow rate and movement of monomer-in-oil emulsion droplets in a T-junction microchannel. Using a fluorescence assay, we monitor the nucleation and growth process of amyloids based on the volume of droplets. Using the microfluidic system, we demonstrate that the lag phase, which is vital to amyloid nucleation and growth, is reduced at a lower droplet volume. Furthermore, we report a peculiar phenomenon of high amyloid formation at the edge of a bullet-shaped droplet, which is likely due to the high local monomer concentration. Moreover, we discovered that amyloid fibrils synthesized in the nanoliter droplets are shorter and thicker than fibrils synthesized from a bulk solution via the conventional heating method. Herein, a facile procedure to observe and characterize the nucleation and growth of amyloid fibrils using nanoliter droplets is presented, which is beneficial for investigating new features of amyloid fibril formation as an unconventional synthetic method for amyloid fibrils.

Efficient Channel Feedback Scheme for Multi-User MIMO Hybrid Beamforming Systems.

This paper proposes an efficient channel information feedback scheme to reduce the feedback overhead of multi-user multiple-input multiple-output (MU-MIMO) hybrid beamforming systems. As massive machine type communication (mMTC) was considered in the deployments of 5G, a transmitter of the hybrid beamforming system should communicate with multiple devices at the same time. To communicate with multiple devices in the same time and frequency slot, high-dimensional channel information should be used to control interferences between the receivers. Therefore, the feedback overhead for the channels of the devices is impractically high. To reduce the overhead, this paper uses common sparsity of channel and nonlinear quantization. To find a common sparse part of a wide frequency band, the proposed system uses minimum mean squared error orthogonal matching pursuit (MMSE-OMP). After the search of the common sparse basis, sparse vectors of subcarriers are searched by using the basis. The sparse vectors are quantized by a nonlinear codebook that is generated by conditional random vector quantization (RVQ). For the conditional RVQ, the Linde-Buzo-Gray (LBG) algorithm is used in conditional vector space. Typically, elements of sparse vectors are sorted according to magnitude by the OMP algorithm. The proposed quantization scheme considers the property for the conditional RVQ. For feedback, indices of the common sparse basis and the quantized sparse vectors are delivered and the channel is recovered at a transmitter for precoding of MU-MIMO. The simulation results show that the proposed scheme achieves lower MMSE for the recovered channel than that of the linear quantization scheme. Furthermore, the transmitter can adopt analog and digital precoding matrix freely by the recovered channel and achieve higher sum rate than that of conventional codebook-based MU-MIMO precoding schemes.

Deep Reinforcement Learning for UAV Trajectory Design Considering Mobile Ground Users.

A network composed of unmanned aerial vehicles (UAVs), serving as base stations (UAV-BS network), is emerging as a promising component in next-generation communication systems. In the UAV-BS network, the optimal positioning of a UAV-BS is an essential requirement to establish line-of-sight (LoS) links for ground users. A novel deep Q-network (DQN)-based learning model enabling the optimal deployment of a UAV-BS is proposed. Moreover, without re-learning of the model and the acquisition of the path information of ground users, the proposed model presents the optimal UAV-BS trajectory while ground users move. Specifically, the proposed model optimizes the trajectory of a UAV-BS by maximizing the mean opinion score (MOS) for ground users who move to various paths. Furthermore, the proposed model is highly practical because, instead of the locations of individual mobile users, an average channel power gain is used as an input parameter. The accuracy of the proposed model is validated by comparing the results of the model with those of a mathematical optimization solver.

Determination of pharmaceuticals in solid samples in municipal wastewater treatment plants by online SPE LC-MS/MS using QuEChERS extraction.

In this study, a pretreatment method based on the QuEChERS method has been applied for simultaneously extracting 27 residual pharmaceuticals from wastewater solids. The extracted compounds have been analyzed using online solid-phase extraction (SPE) coupled to liquid chromatography with tandem mass spectrometry (LC-MS/MS). A recovery test was conducted according to the absorbent type, and buffers were added in the sample extraction step. The highest recovery efficiency could be observed when Na2SO4 was used as an absorbent and Na2EDTA was injected during the extraction process; the recovery efficiencies of the proposed method for the target compounds ranged from 61.3 to 137.2%, and the repeatability was 6.8%. These recovery and repeatability data showed that the proposed method could reliably analyze the 27 target residual pharmaceuticals. The concentrations of the target compounds were all below the limits of quantification: 830 ng g-1 for the target compounds in suspended solids, 2353 ng g-1 in activated sludge, and 1929 ng g-1 in waste sludge. The analytical method established in this study can be applied to quantify residual pharmaceuticals in solid samples and to investigate their behaviors in a municipal wastewater treatment plant.

Analysis of incombustibles in the feedstock to incineration facilities in South Korea for optimum sorting and management.

Korea's Ministry of Environment has implemented the Framework Act on Resource Recirculation to activate waste resource recovery. However, industrial waste treatment facilities have some problems related to diversity of waste received for proper management of wastes. Waste incineration facilities are required to receive and process combustible waste and are forbidden to re-consign waste to other waste treatment facilities without any processing. In reality, a large amount of incombustibles is injected into the incinerator because it is impossible to completely separate the incombustible materials. Therefore, it is necessary to develop additional management criteria for optimal operation of the incineration facility. This study was conducted to improve institutional management of incineration facilities in Korea. Through a literature review and statistics study, incombustible waste management trends were investigated. The characteristics of waste entering incineration facilities were surveyed. Physical composition and proximate analysis of incoming waste were conducted, and properties of the incombustibles mixed in feedstocks to waste incineration facilities were examined. As a result of this study, incombustibles mainly consisting of the construction and demolition waste, such as soil, glass, and metals, should be separated from feed sent to incinerators. A mechanical screening technique that sorts particles of 30-40 mm in size can be used to separate the incombustibles. Also, management criteria could be proposed to sort and re-consign the incombustibles.

Analysis of incombustibles in the feedstock to incineration facilities in Republic of Korea for optimum sorting and management.

The Ministry of Environment, Republic of Korea has implemented the "Framework Act on Resource Recirculation" to activate waste resource recovery. However, industrial waste treatment facilities have some problems related to diversity of waste received for proper management of wastes. Waste incineration facilities are required to receive and process combustible waste and are forbidden to re-consign waste to other waste treatment facilities without any processing. In reality, a large quantity of incombustibles is injected into the incinerator because it is impossible to completely separate the incombustible materials. Therefore, it is necessary to develop additional management criteria for optimal operation of the incineration facility. This study was conducted to improve institutional management of incineration facilities in Korea. Through a literature review and statistics study, incombustible waste management trends were investigated. The characteristics of waste entering incineration facilities were surveyed. Physical composition and proximate analysis of incoming waste were conducted, and properties of the incombustibles mixed in feedstock to waste incineration facilities were examined. As a result of this study, incombustibles mainly consisting of the construction and demolition waste, such as soil, glass, and metals should be separated from feed sent to incinerators. A mechanical screening technique that sorts particles of 30-40 mm in size can be used to separate the incombustibles. Also, management criteria could be proposed to sort and re-consign the incombustibles.

National Reconnaissance Survey of Microplastics in Municipal Wastewater Treatment Plants in Korea.

Large quantities of microplastics are thought to be emitted to freshwater environments via wastewater treatment plants (WWTPs). To evaluate the occurrence of microplastics in Korean WWTPs, a nationwide study was conducted for the first time in 50 representative WWTPs with large treatment capacities. Grab sampling and laboratory filtration were used for influents, whereas in situ filtration using a custom-made sampling device was used for effluents. The filtrates were pretreated using wet peroxidation and density separation prior to the identification of microplastics with a dissection microscope and Fourier-transform infrared spectroscopy. Pooled analyses of the microplastics revealed that they were predominantly fragment-shaped, and thermoplastics and synthetic fibers were the dominant microplastic materials in WWTPs. The concentration ranged from 10 to 470 L-1 in influents and 0.004 to 0.51 L-1 in effluents. The removal efficiency of microplastics during wastewater treatment was calculated to be 98.7-99.99% in 31 WWTPs. Additionally, WWTPs using advanced phosphorus removal processes exhibited higher removal efficiency than those not implementing such processes. Power-law distribution was successful in describing microplastic particle sizes down to 100 µm, although it was not applicable for smaller particles. This comprehensive monitoring study provides information on the current level and characteristics of microplastics in WWTPs in Korea.

Distributed Node Scheduling with Adjustable Weight Factor for Ad-hoc Networks.

In this paper, a novel distributed scheduling scheme for an ad-hoc network is proposed. Specifically, the throughput and the delay of packets with different importance are flexibly adjusted by quantifying the importance as weight factors. In this scheme, each node is equipped with two queues, one for packets with high importance and the other for packets with low importance. The proposed scheduling scheme consists of two procedures: intra-node slot reallocation and inter-node reallocation. In the intra-node slot reallocation, self-fairness is adopted as a key metric, which is a composite of the quantified weight factors and traffic loads. This intra-node slot reallocation improves the throughput and the delay performance. Subsequently, through an inter-node reallocation algorithm adopted from LocalVoting (slot exchange among queues having the same importance), the fairness of traffics with the same importance is enhanced. Thorough simulations were conducted under various traffic load and weight factor settings. The simulation results show that the proposed algorithm can adjust packet delivery performance according to a predefined weight factor. Moreover, compared with conventional algorithms, the proposed algorithm achieves better performance in throughput and delay. The low average delay while attaining the high throughput ensures the excellent performance of the proposed algorithm.