Target Site Research Articles

Dose-Dependent Target Engagement of a Clinical iTBS Protocol: An Interleaved TMS-fMRI Study in Healthy Subjects

BackgroundIntermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as a therapeutic intervention in mental health; however, the understanding of its mechanisms is still incomplete. Prior magnetic resonance imaging studies have mainly used offline iTBS or short sequences in concurrent transcranial magnetic stimulation functional magnetic resonance imaging (fMRI). This study investigated a full 600-stimuli iTBS protocol using interleaved transcranial magnetic stimulation fMRI in comparison with 2 control conditions in healthy subjects. MethodsIn a crossover design, 18 participants underwent 3 sessions of interleaved iTBS-fMRI: 1) the left DLPFC at 40% resting motor threshold (rMT) intensity, 2) the left DLPFC at 80% rMT intensity, and 3) the left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood oxygen level–dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS-induced electric field strength at the target sites. ResultsWhole-brain analysis showed increased activation in several regions following iTBS. Specifically, the left DLPFC, as well as the bilateral M1, anterior cingulate cortex, and insula, showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was observed with neither 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and electric field intensities were only correlated for M1 stimulation and not for the DLPFC conditions. ConclusionsThe study showed dosage- and target-specific BOLD activation during interleaved transcranial magnetic stimulation fMRI with 600-stimuli iTBS in healthy individuals. Future studies may use our approach for demonstrating target engagement.

Optimization and Transfollicular Delivery of Finasteride Loaded PLGA Nanoparticles Laden Carbopol Gel for Treatment of Hair Growth Stimulation

Background: One of the frequent side effects of cancer treatment is chemotherapyinduced alopecia (CIA). The psychological discomfort of hair loss may cause patients to stop receiving chemotherapy, lowering the therapy's effectiveness. Finasteride (FNS), a JAK inhibitor, has shown tremendous promise in therapeutic uses for treating baldness. Still, systemic side effects constrained its broad use in alopecia from oral treatment and a low absorption rate at the target site— PLGA-loaded nanoparticles (NPs) for topical delivery of FNS—to overcome these issues. Methods: The nano-precipitation process was used to make FNS-NPs. The independent variables (stabiliser and polymer) were PLGA (X1), P407 (X2), and sonication time (X3). Based on the point prediction method obtainable by the Box Behnken design software, the best FNS-NPs composition was selected. Entrapment efficiency, particle size, zeta potential, and polydispersity index were used to characterize the nanoparticles. Using Carbopol as a polymer, the ideal FNS-NPs composition was further transformed into a gel formulation. The prepared topical gel formulation (FNS-NPs gel) included gel characterization, Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), invitro and in vivo studies. Results: Optimized FNS-NPs (F13) had particle sizes of 175.26±3.85 nm, 0.241±0.11 PDI, 71.04±1.35 % EE, and -33.27±0.39 surface charges. There is no interaction between the drug and the excipients, according to FTIR studies. The FNS were visible in the X-ray diffractogram enclosed in a polymer matrix. The developed FNS-NPs gel formulation shows ideal drug content, viscosity, pH, and spreadability. According to the release and permeation investigation findings, FNS released slowly (68.73±0.94%) but significantly permeated the membrane more than before. In a dose- and time-dependent manner, the produced nanoparticles considerably (p≤0.05) increased FNS delivery compared to the FNS solution. The FNS-NPs gel therapy significantly increases the quantity and size of hair follicles dose-dependently. The effectiveness of the 1% FNSNPs gel and the 2% minoxidil solution were comparable. After 72 hours, the FNS-NPs gel showed no signs of skin irritation. The outcomes, therefore, showed that the trans follicular delivery mechanism of the FNS-NPs gel might stimulate hair growth. Conclusion: These findings imply that the innovative formulation that has been developed has several beneficial properties that make it suitable for FNS dermal delivery in the treatment of alopecia areata

Comprehensive analysis of malabar tamarind fruit rind total extract: HPTLC fingerprinting, in-silico exploration of its metabolites for SARS-cov-2 omicron spike protein, antibacterial and antidiabetic potentials with in vitro evaluation of antidiabetic and antioxidant activities

Malabar tamarind tropical fruit, scientifically known as Garcinia gummi-gutta, is indigenous to Southeast Asia. In this work, the total methanolic extract of the Malabar fruit rind was examined by HPTLC fingerprinting, with quantitative evaluation of the total phenolics and flavonoids. Library of previously reported natural metabolites was utilized to demonstrate their affinity for specific target sites, they were evaluated against Omicron SARS-CoV-2 mainly it's Spike Protein, bacterial tyrosinase, and antidiabetic targets such α-glucosidase, pancreatic lipase and also α-amylase enzymes. The molecular docking revealed that the Guttiferone R possessed the highest binding affinity toward the Omicron Spike Protein with a stable binding mode, −8.67 kcal/mol binding energy and a 1.07 Å RMSD value compared to reference, Azithromycin, which has −8.90 kcal/mol binding affinity and a 1.20 Å RMSD value. On the other hand, the identified polyphenolic compounds; Vitexin, Prunin, Naringin, Hinokiflavone, Kaempherol-3-O-rutinoside, Gallic acid, Naringenin, and Catechin, showed remarkable antidiabetic activity by strong inhibitory activity against α-glucosidase and notable activity against α-amylase compared with acarbose as reference. According to antibacterial activity, the identified compounds showed low affinity with weak activity against screened bacterial strains. In-vitro evaluation of Tamarind antioxidant and antidiabetic potentials, it exhibited a free radical-scavenging potential with 71.75 % retardation and α-glucosidase, α-amylase and pancreatic lipase inhibitor activities with an IC50 of 391.3 ± 26.27, 95.03 ± 0.03 and 0.01043 ± 0.0004 μg/mL, respectively that emphasize the molecular docking study. The findings imply that Malabar tamarind fruit rind possess antioxidant, antidiabetic, antibacterial and antiviral activities.

Three-dimensional culture of human proximal tubular epithelial cells for an in vitro evaluation of drug-induced kidney injury

Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC20) was obtained, and the ratio of EC20 values and clinical maximum concentration (Cmax) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels.

Relevance of distinctions and parallels between the US and EU guidelines for determination of comparative effectiveness and safety of the orally inhaled drug products

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.

Donor DNA Modification with Cas9 Targeting Sites Improves the Efficiency of MTC34 Knock-in into the CXCR4 Locus

Donor DNA Modification with Cas9 Targeting Sites Improves the Efficiency of MTC34 Knock-in into the CXCR4 Locus

Copper(II) and Zinc(II) Complexes with Bacterial Prodigiosin Are Targeting Site III of Bovine Serum Albumin and Acting as DNA Minor Groove Binders.

The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries' approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves.

AB067. New drug development for the use of PARP1-E2F1 transcriptional inhibitors in the treatment of glioblastoma.

Glioblastoma (GBM) is the most malignant brain tumor and ranks among the most lethal of all human cancers, without improvements in survival over the last 30 years. Data obtained in our group suggest that PARP1, a well-known DNA-repairing protein, could also play a key role in the regulation of cell cycle through its interaction with the transcription factor E2F1. Therefore, considering that most oncogenic processes are associated with cell cycle deregulation, we hypothesized that disruption of PARP1-E2F1 interaction would provide a novel therapeutic approach to different types of cancer. The identification of novel compounds disrupting PARP1-E2F1 interaction was carried out by combining in silico and in vitro screening, using a rational drug design. The virtual screen was performed using a molecular library of several million compounds at the selected target site, using AtomNet® (Atomwise, San Francisco, CA, USA), the first deep learning neural network for structure-based drug design and discovery. Since there is no complete structural information of the PARP1-E2F1 protein-protein interaction, a homologous structure of the BRCT domain of BRCA1 complex with the phospho-peptide (PDBID: 1T2V) was used to identify the potential binding interface of BRCT domain of PARP-1 (PDBID: 2COK) and the E2F1 protein. Top scoring compounds were clustered and filtered to obtain a final subset of 83 compounds that were incorporated to our in vitro screening, which included both transcriptional E2F1 activity and survival studies. Complete culture medium supplemented with the compounds selected in the in silico screening (10 μM) were added and incubated for 24 hours. E2F1 activity was observed by measuring luminescence. For the viability assay, the fluorescence reading was performed (excitation 544 nm and emission 590 nm). The in silico and in vitro screening resulted in 12 compounds that inhibited E2F1 transcriptional activity and significantly reduced cell number. The highest inhibition of both E2F1 transcriptional activity and cell growth was observed with compound 3797, which was selected for further studies. Both in silico and in vitro results indicate that inhibition of PARP1-E2F1 transcriptional activity may provide a new rationale for designing novel therapeutic approaches for the treatment of GBM.

Designing a magnetic micro-robot for transporting stiff filamentous microcargo

In recent years, the medical industry has witnessed a growing interest in developing minimally invasive procedures, with magnetic micro-robots emerging as a promising approach. These micro-robots possess the ability to navigate through various media, including viscoelastic and non-Newtonian fluids, enabling targeted drug delivery and medical interventions. Many designs that have been proposed to date employ a contact-based method for transporting a payload. Undesired adhesion between the cargo and the carrier can make release at the target site problematic. The primary objective of our current work is to modify the design of magnetically actuated helical micro-robots to enable transportation of cargo in Newtonian fluids without requiring contact between the robot and the cargo. We conduct a comprehensive study on the shape and geometrical parameters of the helical micro-robot, specifically focusing on its capability to transport passive filaments that are rigid to thermal noise. Based on our analysis, we propose a novel design consisting of three helical sections with alternating handedness, including two pulling and one pushing microhelices. We first focus on naturally straight filaments but also show that the micro-robot can capture filaments with intrinsic curvature and those with a spherical payload attached at one end. Our findings offer valuable insights into the physics of helical micro-robots and their potential for medical procedures and drug delivery. Furthermore, the proposed non-contact method for delivering filamentous cargo could lead to the development of more effective micro-robots for medical applications.

CRISPR-Cas12a bends DNA to destabilize base pairs during target interrogation.

RNA-guided endonucleases are involved in processes ranging from adaptive immunity to site-specific transposition and have revolutionized genome editing. CRISPR-Cas9, -Cas12 and related proteins use guide RNAs to recognize ~20-nucleotide target sites within genomic DNA by mechanisms that are not yet fully understood. We used structural and biochemical methods to assess early steps in DNA recognition by Cas12a protein-guide RNA complexes. We show here that Cas12a initiates DNA target recognition by bending DNA to induce transient nucleotide flipping that exposes nucleobases for DNA-RNA hybridization. Cryo-EM structural analysis of a trapped Cas12a-RNA-DNA surveillance complex and fluorescence-based conformational probing show that Cas12a-induced DNA helix destabilization enables target discovery and engagement. This mechanism of initial DNA interrogation resembles that of CRISPR-Cas9 despite distinct evolutionary origins and different RNA-DNA hybridization directionality of these enzyme families. Our findings support a model in which RNA-mediated DNA engineering begins with local helix distortion by transient CRISPR-Cas protein binding.

Elucidating the Architectural dynamics of MuB filaments in bacteriophage Mu DNA transposition

MuB is a non-specific DNA-binding protein and AAA+ ATPase that significantly influences the DNA transposition process of bacteriophage Mu, especially in target DNA selection for transposition. While studies have established the ATP-dependent formation of MuB filament as pivotal to this process, the high-resolution structure of a full-length MuB protomer and the underlying molecular mechanisms governing its oligomerization remain elusive. Here, we use cryo-EM to obtain a 3.4-Å resolution structure of the ATP(+)-DNA(+)-MuB helical filament, which encapsulates the DNA substrate within its axial channel. The structure categorizes MuB within the initiator clade of the AAA+ protein family and precisely locates the ATP and DNA binding sites. Further investigation into the oligomeric states of MuB show the existence of various forms of the filament. These findings lead to a mechanistic model where MuB forms opposite helical filaments along the DNA, exposing potential target sites on the bare DNA and then recruiting MuA, which stimulates MuB’s ATPase activity and disrupts the previously formed helical structure. When this happens, MuB generates larger ring structures and dissociates from the DNA.

Magnetic Cell Targeting for Cardiovascular Tissue Engineering.

There is a critical need for novel approaches to translate cell therapy and regenerative medicine to clinical practice. Magnetic cell targeting with site specificity has started to open avenues in these fields as a potential therapeutic platform. Magnetic targeting is gaining popularity in the field of biomedicine due to its ability to concentrate and retain at a target site while minimizing deleterious effects at off-target sites. It is regarded as a relatively straightforward and safe approach for a wide range of therapeutic applications. This review discusses the latest advancements and approaches in magnetic cell targeting using endocytosed and surface-bound magnetic nanoparticles as well as invivo tracking using magnetic resonance imaging (MRI). The most common form of magnetic nanoparticles is superparamagnetic iron oxide nanoparticles (SPION). The biodegradable and biocompatible properties of these magnetically responsive particles and capacity for rapid endocytosis into cells make them a breakthrough in targeted therapy. This review further discusses specific applications of magnetic targeting approaches in cardiovascular tissue engineering including myocardial regeneration, therapeutic angiogenesis, and endothelialization of implantable cardiovascular devices.

Kuwanon C Inhibits Tumor Cell Proliferation and Induces Apoptosis by Targeting Mitochondria and Endoplasmic Reticulum.

Kuwanon C is a unique flavonoid found in the mulberry family, characterized by two isopentenyl groups. While previous research has focused on various properties of kuwanon C, such as antioxidant, hypoglycemic, antimicrobial, food preservation, skin whitening, and nematode lifespan extension, little attention has been given to its potential role in oncological diseases. In this study, we investigate the antitumor effect of kuwanon C in cervical cancer cells and elucidate its specific mechanism of action. We assessed the antitumor effects of kuwanon C using various experimental techniques, including cell proliferation assay, wound healing assays, EdU 488 proliferation assay, mitochondrial membrane potential assay, ROS level assay, cell cycle, apoptosis analysis, and studies on kuwanon C target sites and molecular docking. The results revealed that kuwanon C significantly impacted the cell cycle progression of HeLa cells, disrupted their mitochondrial membrane potential, and induced a substantial increase in intracellular ROS levels. Moreover, kuwanon C exhibited notable anti-proliferative and pro-apoptotic effects on HeLa cells, surpassing the performance of commonly used antitumor drugs such as paclitaxel and cisplatin. Notably, kuwanon C demonstrated superior efficacy while also being more easily accessible compared to paclitaxel. Our study demonstrates that kuwanon C exerts potent antitumor effects by its interaction with the mitochondrial and endoplasmic reticulum membranes, induces a significant production of ROS, disrupts their normal structure, inhibits cell cycle progression, and stimulates apoptotic signaling pathways, ultimately resulting in the death of HeLa tumor cells. As an isopentenyl compound derived from Morus alba, kuwanon C holds great promise as a potential candidate for the development of effective antitumor drugs.

Revealing miRNAs patterns by employing matrix representations and energy analysis

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression. Despite their relatively short length (about 21 nucleotides), they can regulate thousands of transcripts within a cell. Due to their low complementarity to targets, studying their activity and binding region preferences (3′UTR, 5′UTR, or CDS) is challenging. In this paper, we analyzed a set of human miRNAs to uncover their general patterns. We began with a sequence logo to verify conservation at specific positions. To discover long-range correlations, we employed chaos game representation (CGR) and genomatrix, methods that enable both graphical and analytical analysis of sequence sets and are well-established in bioinformatics. Our results showed that miRNAs exhibit strongly non-random and characteristic patterns. To incorporate physicochemical properties into the analysis, we applied the electron-ion interaction potential (EIIP) parameter. An important part of our study was to validate the division of miRNAs into two parts—seed and puzzle. The seed region is responsible for target binding, while the puzzle region likely interacts with the RISC complex. We estimated duplex binding energy within the 3′UTR, 5′UTR, and CDS regions using the miRanda tool. Based on the median energy distribution, we divided the miRNAs into two subsets, reflecting different patterns in chaos game representation. Interestingly, one subset displayed significant similarity to conserved and highly confidential miRNAs. Our results confirm the low complementarity of miRNA/mRNA interactions and support the functional division of miRNA structure. Additionally, we present findings related to the localization of transcript target sites, which form the basis for further analyses.

Recent Advances in Marine-Derived Compounds as Potent Antibacterial and Antifungal Agents: A Comprehensive Review.

The increase in antimicrobial resistance (AMR) in microorganisms is a significant global health concern. Various factors contribute to AMR, including alterations in cell membrane permeability, increased efflux pump activity, enzymatic modification or inactivation of antibiotics, target site changes, alternative metabolic pathways, and biofilm formation. Marine environments, with their extensive biodiversity, provide a valuable source of natural products with a wide range of biological activities. Marine-derived antimicrobial compounds show significant potential against drug-resistant bacteria and fungi. This review discusses the current knowledge on marine natural products such as microorganisms, sponges, tunicates and mollusks with antibacterial and antifungal properties effective against drug-resistant microorganisms and their ecological roles. These natural products are classified based on their chemical structures, such as alkaloids, amino acids, peptides, polyketides, naphthoquinones, terpenoids, and polysaccharides. Although still in preclinical studies, these agents demonstrate promising in vivo efficacy, suggesting that marine sources could be pivotal in developing new drugs to combat AMR, thereby fulfilling an essential medical need. This review highlights the ongoing importance of marine biodiversity exploration for discovering potential antimicrobial agents.

Capecitabine-loaded NLC for Breast Cancer Treatment: Preparation, Characterization, and In vitro Evaluation.

Cancer treatment often involves the use of potent antineoplastic drugs like Capecitabine [CAP], which can lead to serious toxicities. There is a need for dosage forms to manage these toxicities that can deliver the medication effectively to the target site while maintaining therapeutic efficacy at lower doses. To achieve the aforesaid objective, NLC containing capecitabine [NANOBIN] was prepared and evaluated. Different formulations of NANOBIN, denoted as CaTS, CaT1S, CaT2S, CaTS1, and CaTS2, were designed and evaluated to improve drug delivery and therapeutic outcomes. The NANOBIN formulations were prepared using the hot homogenization method. The characterization of these formulations was conducted based on various parameters such as particle size, Polydispersity Index [PDI], Zeta Potential [ZP], Transmission Electron Microscopy [TEM] imaging, and Encapsulation Efficiency [EE]. In vitro evaluations included stability testing, release studies to assess drug release kinetics, and a cytotoxicity assay [MTT assay] to evaluate the efficacy of these formulations against human breast cancer cells [MCF-7]. The characterization results revealed that all NANOBIN formulations exhibited particle sizes ranging from 65 to 193 nm, PDI values within the range of 0.26-0.37, ZP values between 46.47 to 61.87 mV [-ve], and high EE percentages ranging from 94.121% to 96.64%. Furthermore, all NANOBIN formulations demonstrated sustained and slow-release profiles of CAP. The MTT assay showed that the NANOBINs exhibited significantly enhanced cytotoxic efficacy, approximately 10 times greater than free CAP when tested on MCF-7 cells. These findings indicate the potential of NANOBINs to deliver CAP effectively to the target site, enabling prolonged drug availability and enhanced therapeutic effects at lower doses. The study demonstrates that NANOBINs can effectively deliver CAP to target sites, prolonging drug exposure and enhancing therapeutic efficacy while reducing the required dose. Further studies are necessary to validate these findings and establish NANOBINs as a preferred treatment option for cancer therapy.

A phased small interfering RNA-derived pathway mediates lead stress tolerance in maize.

Phased small interfering RNAs (phasiRNAs) are a distinct class of endogenous small interfering RNAs, which regulate plant growth, development and environmental stress response. To determine the effect of phasiRNAs on maize (Zea mays L.) tolerance to lead (Pb) stress, the roots of 305 maize lines under Pb treatment were subjected to generation of individual databases of small RNAs. We identified 55 high-confidence phasiRNAs derived from 13 PHAS genes (genes producing phasiRNAs) in this maize panel, of which 41 derived from nine PHAS loci were negatively correlated with Pb content in the roots. The potential targets of the 41 phasiRNAs were enriched in ion transport and import. Only the expression of PHAS_1 (ZmTAS3j, Trans-Acting Short Interference RNA3) was regulated by its cis-expression quantitative trait locus and thus affected the Pb content in the roots. Using the Nicotiana benthamiana (N. benthamiana) transient expression system, 5'-rapid amplification of cDNA ends, and Arabidopsis heterologously expressed, we verified that ZmTAS3j was cleaved by zma-miR390 and thus generated tasiRNA targeting ARF genes (tasiARFs), and that the 5' and 3' zma-miR390 target sites of ZmTAS3j were both necessary for efficient biosynthesis and functional integrity of tasiARFs. We validated the involvement of the zma-miR390-ZmTAS3j-tasiARF-ZmARF3-ZmHMA3 pathway in Pb accumulation in maize seedlings using genetic, molecular, and cytological methods. Moreover, the increased Pb tolerance in ZmTAS3j-overexpressed lines was likely attributed to the zma-miR390-ZmTAS3j-tasiARF-ZmARF3-SAURs pathway, which elevated indole acetic acid levels and thus reactive oxygen species scavenging capacity in maize roots. Our study reveals the importance of the TAS3-derived tasiRNA pathway in plant adaptation to Pb stress.

Cocrystal formulation design of 4-Aminosalicylic acid and isoniazid via spray-drying based on a ternary phase diagram toward simultaneous pulmonary delivery

Cocrystal engineering is a potent strategy for enhancing drug properties, but its application in spray-drying has been limited. Furthermore, concurrently introducing two drugs and realizing simultaneous pharmacological effects at the target site is challenging. This is particularly evident for oral formulations designed for systemic use, but the local administration of drugs at the target site displays the potential to overcome this problem. Herein, we investigated the potential of cocrystallization principles for use in developing dry powder inhaler formulations of anti-tuberculosis drugs. We focused on the formation of cocrystals of 4-aminosalicylic acid (PAS) and isoniazid (INH), which are crucial components of tuberculosis treatment. Via spray-drying, we successfully produced spray-dried particles of PAS-INH that exhibited hydrogen bonding interactions between the molecules. Aerosolization performance evaluation with an Andersen Cascade Impactor (ACI) confirmed the concurrent deposition of both drugs, highlighting the potential of our particle design for use in the co-delivery of PAS-INH. Furthermore, simulated lung dissolution studies using the ACI and Transwell inserts revealed synchronized dissolution patterns, indicating promising prospects for use in effective drug delivery. This innovative approach to tuberculosis therapy has significant implications for improving treatment efficacy and enhancing patient adherence, potentially revolutionizing tuberculosis treatment.

Computational analysis of the divergent neurotranscriptomic signatures of major depression and suicidality

BackgroundSuicide is a leading cause of death globally. Identifying individuals at higher suicidal risk is a key to suicide prevention. Patients with comorbid psychiatric disorders, especially major depressive disorder (MDD), are known to be highly prone to suicidality. However, the behavioural manifestations of MDD and suicidality are distinct, indicating potentially unique molecular underpinnings, of which our current understanding is limited. Delineating the unique and shared molecular etiologies of MDD and suicidality would be imperative to devise effective treatment strategies for suicidal behaviour. To this end, we analysed the existing literature pertaining to transcriptomic alterations in brain samples of individuals who died from MDD or by suicide. Subsequently, biological processes associated with the differentially expressed genes (DEGs) were identified. In addition, we also examined the transcriptional regulators (TRs) potentially driving cortical gene expression changes in MDD and suicidality.ResultsA set of immunological genes was found to be commonly upregulated in MDD but downregulated in suicide. Actin and cytoskeleton organization genes also had a similar trend. In addition, MDD-upregulated and suicide-downregulated genes were found to have overrepresented target sites for 40 TRs associated with epigenetic as well as polymerase-mediated regulation. Any variations in the levels of these TRs could be of behavioural consequence in MDD and suicidality.ConclusionsA clear understanding of the condition-specific neurotranscriptomic differences in MDD and suicidality would be valuable in order to delineate the biological mechanisms underlying these conditions. Importantly, it would provide insights into more effective treatment strategies for suicidality among individuals with or without MDD. However, we have yet to determine the molecular basis of suicidality in the context of MDD and as a standalone mental condition. In this regard, the present findings would be of scientific and clinical relevance and could stimulate further research.

Toward Real-Time Ground-Shaking-Intensity Forecasting Using ETAS and GMM: Insights from the Analysis of the 2022 Taitung Earthquake Sequence

Abstract Earthquake forecasting, combined with precise ground-shaking estimations, plays a pivotal role in safeguarding public safety, fortifying infrastructure, and bolstering the preparedness of emergency services. This study introduces a comprehensive workflow that integrates the epidemic-type aftershock sequence (ETAS) model with a preselected ground-motion model (GMM), facilitating accurate short-term forecasting of ground-shaking intensity (GSI), which is crucial for effective earthquake warning. First, an analysis was conducted on an earthquake catalog spanning from 1994 to 2022 to optimize the ETAS parameters. The dataset used in this analysis allowed for the further calculation of total, background, and clustering seismicity rates, which are crucial for understanding spatiotemporal earthquake occurrence. Subsequently, short-term earthquake activity simulations were performed using these up-to-date seismicity rates to generate synthetic catalogs. The ground-shaking impact on the target sites from each synthetic catalog was assessed by determining the maximum intensity using a selected GMM. This simulation process was repeated to enhance the reliability of the forecasts. Through this process, a probability distribution was created, serving as a robust forecasting for GSI at sites. The performance of the forecasting model was validated through an example of the Taitung earthquake sequence in September 2022, showing its effectiveness in forecasting earthquake activity and site-specific GSI. The proposed forecasting model can quickly deliver short-term seismic hazard curves and warning messages, facilitating timely decision making.