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PubMed2025

Multi-omics Mendelian randomization integrating RNA-seq, eQTL and pQTL data revealed CPXM1 as a potential drug target for osteoporosis.

Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mineral density and increased fracture risk, continues to be a major global health concern. Traditional treatments for osteoporosis have limited efficacy and safety profiles, highlighting the need for novel therapeutic targets. This study integrates multi-omics data, including RNA-seq, expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data, through Mendelian randomization (MR) to identify potential drug targets for osteoporosis. By leveraging bidirectional two-sample MR analysis, we identified CPXM1 (Carboxypeptidase X, M14 family member 1) as a novel gene that is causally linked to osteoporosis risk. Through transcriptomic and proteomic validation, we demonstrate that CPXM1 was upregulated in aged bone tissues and osteoporotic conditions in both human and murine models. Gene set enrichment analysis (GSEA) revealed significant dysregulation of bone homeostasis pathways, including increased extracellular matrix degradation and suppression of osteoblast differentiation in aged mice. Furthermore, phenome-wide association studies (PheWAS) confirmed minimal off-target effects of CPXM1, reinforcing its potential as a therapeutic target. Finally, computational drug repurposing predicted several promising drug candidates, including Doxorubicin, 5-Fluorouracil, and 2-Methylcholine, which may target CPXM1 pathways for osteoporosis treatment. These findings highlight CPXM1 as a potential biomarker and therapeutic target, offering new avenues for osteoporosis therapy.

Osteoporosis↗

PubMed2026

[Research Advances on Mechanisms and Interventions of DNA Methylation-Regulated Aging-Related Imbalance in Bone Metabolism].

Aging can induce age-related bone diseases such as osteoporosis. DNA methylation, a core epigenetic regulatory mechanism, participate in the pathological process of aging-induced bone metabolism imbalance by modulating gene expression at the epigenetic level. Using S-adenosylmethionine as a methyl donor, it exhibits characteristics of hypomethylation in genomic repetitive regions and abnormal methylation in CpG islands of promoters of key bone metabolism genes with advancing age. The "epigenetic clock" constructed based on these features can accurately predict an individual's biological age. In bone metabolism, DNA methylation disrupts the osteoblast-osteoclast balance by targeting key factors. Such abnormalities are driven by aging-related inflammation and oxidative stress, while bone loss feedback exacerbates epigenetic disorders, forming a vicious cycle. Targeted intervention strategies have demonstrated significant potential in addressing bone metabolism-related issues. Low-dose DNA methyltransferase inhibitors can improve bone metabolism; nutrients such as folate and cobalamin maintain methylation homeostasis by optimizing one-carbon metabolism pathways; while CRISPR/dCas technology enables precise regulation in the cellular and animal levels, thereby affecting bone metabolism. However, existing strategies still face challenges such as off-target effects and low delivery efficiency. Future research needs to deepen mechanistic studies, optimize intervention methods, and promote their translation into clinical prevention and treatment of osteoporosis.

DNA Methylation↗

PubMed2004

Inhibition of alpha(1E) Ca(2+) channels by carbonic anhydrase inhibitors.

We examined if a range of carbonic anhydrase inhibitors (CAIs) interacted with the high-voltage activated voltage-sensitive calcium channels (VSCCs) encoded by the human alpha(1E) subunit. Whole-cell recordings were made from HEK293 cells stably expressing human alpha(1E)beta(3)-mediated calcium channels. SNX-482 (an alpha(1E) inhibitor) blocked alpha(1E)-mediated VSCCs with an IC(50) close to 10 nM. The anticonvulsant CAI ethoxyzolamide also inhibited these currents, with an IC(50) close to 1 microM, and produced an accompanying 20-mV hyperpolarizing shift in the steady-state inactivation profile. Other structurally diverse CAIs (e.g., acetazolamide and benzolamide) produced approximately 30 - 40% inhibition of alpha(1E)beta(3)-mediated Ca(2+) currents at 10 microM. Topiramate (10 microM), an anticonvulsant with CAI activity, inhibited these currents by 68 +/- 7%. This off-target activity of CAIs at VSCCs may contribute to some of the effects they produce both in vitro and in vivo.

Calcium Channel Blockers↗

PubMed2024

Diagnosis with Metagenomic Next-Generation Sequencing (mNGS) technology and real-time PCR for SARS-CoV-2 Omicron detection using various nasopharyngeal swabs in SARS-CoV-2 Omicron.

BACKGROUND: The SARS-CoV-2 Omicron variant, with the main subtypes BA.5.2 and BF.7 in China, led to off-target effects on the S and N genes from December 1, 2022, to January 31, 2023. The kits used for studying and developing these agents were not adequately and independently evaluated. It is important to verify the performance of commercial Real-Time quantitative PCR (RT-qPCR) tests. OBJECTIVE: We conducted a clinical evaluation of two Real Time SARS-CoV-2 Omicron assays to verify their performance using various detection reagents and clinical specimens. METHODS: We performed clinical evaluations of two existing Chinese SARS-CoV-2 Omicron RT-qPCR kits 2019-nCoV nucleic acid diagnostic kits (Fosun Biotechnology, National instrument registration 20203400299, Shanghai, China) and COVID-19 nucleic acid detection kits (eDiagnosis Biomedicine, National instrument registration 20203400212, Wuhan, China) and using BSD (Bondson) (Guangzhou Bondson Biotechnology Co. Ltd, batch number 2022101), quality controls provided by the inspection center and a large number of clinically confirmed specimens. RESULTS: The concordance rates for the Fosun and eDiagnosis kits were 95% and 100%, respectively. The detection limit for the Fosun and eDiagnosis kits was verified to be 300 copies/mL and 500 copies/mL. The Fosun assay exhibited the largest coefficient of variation (CV) for ORF1ab and N gene at the detection limit concentration (4.80%, 3.49%), whereas eDiagnosis showed a smaller CV (0.93%, 1.10%). In the reference product from the Hangzhou Clinical Laboratory Center test, it was found that Fosun had the lowest sensitivity of 93.47% and a specificity of 100%, while eDiagnosis exhibited 100% for both sensitivity and specificity. The lowest single target gene detection rate of Fosun reagents was 68.7% for the ORF1ab gene and 87.5% for the N gene, while eDiagnosis detection rate was 100%. Among the clinical group S specimens, the missed detection rate of the Fosun reagent was 10.9%, which was higher than the 3.9% of eDiagnosis. However, there was no significant difference in the clinical diagnostic efficiency of the two reagents. CONCLUSIONS: The ORF1ab and N assays of SARS-CoV-2 Omicron on the eDiagnosis platform yielded higher values compared to those on the Fosun platform. Consequently, the eDiagnosis kit has also been used as standard detection reagents. Considering that the Fosun reagent has a relatively low detection limit and targets three single genes, it is more advantageous as a confirmatory reagent for the new museum.

Humans↗

PubMed2001

92nd Annual Meeting of the American Association for Cancer Research. 24-28 March, 2001, New Orleans, Louisiana, USA.

The 92nd Annual Meeting of the AACR comprised over 5000 abstracts, 12 plenary and award lectures and numerous talks in educational sessions, symposia and mini-symposia. Given the wealth of information presented, we narrowed our coverage to the area of prenyltransferase and protein kinase inhibitors. Many rationally designed drugs are now in clinical trials and exciting results were presented for the Bcr-Abl inhibitor STI-571. The cancer community is beginning to envision new ways to evaluate and administer these well-tolerated drugs which do not fit the traditional anticancer drug profile. There is an emphasis in developing surrogate markers for evaluating the mechanism-based effectiveness as well as identifying off-target toxicities. In addition, there is a large effort in investigating effective drug combinations and the use of these new agents as radiosensitisers. Here we present specific examples of these issues as applied to prenylation and protein kinase inhibitors.

Animals↗

PubMed2004

Expediting target identification and validation through RNAi.

RNA interference (RNAi) is an efficient post-transcriptional gene silencing mechanism that is induced by double-stranded RNA. Applications of RNAi have gained increasing attention since the groundbreaking discovery that small interfering RNA (siRNA) molecules can be used to inhibit gene expression in mammalian cells in a sequence-specific manner. Numerous meetings have recently been held in this field, but the organiser from EF International succeeded in bringing some of the leading academic scientists and company researchers together in London to present and discuss exciting new results. Major topics covered in the meeting included the recent progress in understanding the basic mechanism of RNAi, genome-wide RNAi-based screens for target discovery, and approaches to use RNAi for target validation in cell culture and in animal models. In addition, borders and caveats of the technology, such as off-target effects and a possible induction of the interferon response by siRNA, have been discussed intensively. The use of siRNAs can be regarded as a highly potent strategy to identify and validate new targets for therapeutic interventions against cancer, viral infections, chronic pain and other diseases. Finally, siRNAs themselves hold the promise to become therapeutic agents in the near future.

Animals↗

PubMed2002

Development of the spray drift task force database for aerial applications.

This article is part of a series describing the development of the Spray Drift Task Force (SDTF) database and its application to agricultural chemical exposure risk assessment modeling. The series describes the development of a large generic database (assuming that active ingredient rate is not a factor affecting physical drift) and its use in estimating spray movement immediately following application by aerial methods. The components of the database are described. In agreement with field trials in the open literature, the database shows that the major variables affecting off-target spray deposition are droplet size, spray release position (boom height and length), and wind speed and direction. In addition, secondary parameters that can affect these variables and drift are also discussed.

Aerosols↗

PubMed2004

RNA-based drugs: from RNA interference to short interfering RNAs.

RNA interference consists of a sequence specific post-transcriptional gene silencing phenomenon triggered by a double strand RNA molecule homologous to the silenced gene. The dsRNA is cleaved by DICER enzyme in small dsRNA pieces, named short interfering RNAs (siRNAs). These fragments are thereafter associated to RISC complex where the cleavage of target RNA occurs. The observation that siRNAs can trigger the RNA interference mechanism in mammalian cells represents a fundamental discovery that discloses new horizons in genetic researches in that theoretically each gene can be silenced. The relative simplicity by which active short interfering RNAs can be designed and synthesized explains their widespread use in basic and applied researches, even if appropriate controls that exclude off-target effects are strictly required. The findings that siRNAs are active even when expressed in viral vectors open the possibility that they can be very soon used for gene therapy of several human diseases.

Animals↗

PubMed2004

Chemokine receptor-directed agents as novel anti-HIV-1 therapies.

Historically, therapeutic benefit in the treatment of human immunodeficiency virus infection (HIV-1) infection has been best achieved by targeting viral proteins like HIV protease involved in viral replication rather than host cell proteins, like CD4, which facilitate the process of viral infection. Two discoveries in 1996 presented a novel opportunity to redress this issue: 1) the understanding that heptahelical G-protein coupled chemokine receptors on the surface of T cells and macrophages functioned together with CD4 to mediate viral entry, and 2) the observation that CD4 positive T cells from individuals homozygous for the CCR5 delta 32 null allele were resistant to infection by macrophage-tropic strains of the virus in vitro and in vivo. Since that time, data demonstrating that selective blockade of two chemokine receptors, CCR5 and CXCR4, by small molecule chemokine receptor antagonists or receptor-directed biologics could robustly inhibit the infection of human peripheral blood mononuclear cells (PBMCs) by macrophage-tropic and T-cell line tropic strains respectively in vitro has validated this potential approach to therapy. Early clinical trial data now also confirms that these types of agents will have anti-viral activity in some HIV-1 infected individuals; however to date, dose limiting off-target activities have prohibited a full test of their potential clinical value. It also remains to be seen how these types of agents will fare in synergy with existing HIV-1 targeted antivirals, or those currently in development.

Anti-HIV Agents↗

PubMed1992

Perceptual-motor coordination and style in healthy boys and those with minimal brain dysfunction.

Differences in visual-motor tracking by 8- to 9-yr.-old boys diagnosed with Minimal Brain Dysfunction or healthy have been analyzed. The subject's task was to use two computer keys to control a cursor line within a target which moved horizontally in two directions over the display. Target size and speed were the experimental variables. Off-target incidences and durations were measured and evaluated. The latter were longer and the former were more frequent on small targets for boys with brain dysfunction than for healthy boys. The two measures correlated negatively in most situations. The perceptual-motor style expressed by means of the distribution of coincidences of the two measures being over or under a criterion set equal to the corresponding averages of the healthy boys was different in the two groups. Brain-damaged boys were characterized mostly by the combination of high incidence of low duration misses for small and fast targets and by high incidence of high duration misses for large and slow targets, whereas most healthy boys showed a few misses of low duration for large and slow targets and few misses of high duration for small and fast targets.

Attention↗

PubMed2026

Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.

Inherited genodermatoses are a heterogeneous group of rare monogenic disorders. Among these, epidermolysis bullosa (EB) and ichthyoses represent paradigmatic disorders characterized by severe skin fragility and hyperkeratosis, respectively, and impaired barrier function, often with profound effects on quality of life and systemic health. Current management remains largely palliative, underscoring the urgent need for disease-modifying therapies. Over the past 2 decades, advances in epithelial stem cell biology, vector engineering and genome editing technologies have transformed the therapeutic landscape for genodermatoses. Ex vivo gene therapy has provided the first proof that genetically corrected epidermal stem cells can achieve long-term tissue regeneration in EB skin patients, establishing a new paradigm for regenerative medicine. In parallel, the emergence of programmable genome engineering platforms, including CRISPR/Cas nucleases, base editors and prime editors, have enabled increasingly precise strategies for mutation-specific correction in both recessive and dominant disorders. Furthermore, the development of in vivo topical approaches is expanding the possibility of directly targeting the skin. Despite these advances, substantial translational barriers continue to limit broad clinical implementation. Efficient and durable targeting of epidermal stem cells within a highly regenerative tissue, together with safe delivery across the skin barrier, stringent control of off-target activity, scalable manufacturing and demonstration of long-term safety, remain major challenges for the clinical translation of these approaches. In this Review, we discuss the current state of gene therapy for genodermatoses, highlighting key clinical milestones, emerging genome editing technologies and next-generation delivery systems. We further examine the biological and regulatory challenges that need to be overcome to bridge the gap between experimental innovation and clinically accessible therapies for patients with inherited skin diseases.

epidermolysis bullosa (EB)↗

PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗

PubMed2026

CRISPR-Cas technologies for precision genome editing in plants: advances, applications, and future perspectives.

Developing climate-smart crops with enhanced crop productivity, nutritional quality, resistance to biological and environmental stressors is vital for global food security. While hybrid breeding forms the cornerstone of modern crop improvement, conventional breeding approaches are limited by genetic barriers and prolonged breeding cycles. CRISPR-Cas based genome editing has revolutionized plant biology by allowing precise, efficient, and multiplex genetic modifications. This review provides a comprehensive synthesis of a recent advances in CRISPR-Cas technologies and their strategic applications in crop genetics and hybrid breeding. We summarize major genome-editing strategies, including gene knock-out, base editing (BE), knock-in, gene replacement, epigenome editing, and transcriptional regulation. Furthermore, we contrast stable, transient, and DNA-free delivery systems, highlighting ribonucleoprotein (RNP)-mediated delivery for minimizing off-target effects and avoiding transgene integration. We showcase how these technologies accelerate hybrid breeding by engineering male sterility systems, fixing heterosis, and generating high-throughput mutant libraries for trait discovery. Finally, we synthesize major bottlenecks in tissue culture-independent transformation and delivery systems, while outlining how emerging paradigms like de novo domestication and synthetic biology will shape the future of climate-resilient agriculture.

CRISPR/Cas↗

PubMed2026

Genome Editing in Solanaceae: Harnessing CRISPR-Cas Technology for Precision Crop Improvement.

Malnutrition and climate-induced stress remain major constraints to global food and nutritional security despite the yield gains of the Green Revolution. Solanaceae crops such as tomato, potato, brinjal, and pepper are key sources of vitamins, minerals, and bioactive compounds. Yet, their genetic improvement has been limited by narrow diversity and complex polygenic traits. The advent of CRISPR/Cas-mediated genome editing provides a transformative platform for precision crop improvement by enabling targeted modification of genes controlling stress tolerance, yield, and nutritional quality. In Solanaceae, CRISPR/Cas applications have successfully enhanced resistance against major pathogens (SlMlo1, SlPelo, SlDCL2), improved abiotic stress tolerance through editing of SlMAPK3, SlCBF1, and SlBZR1, and optimized fruit quality traits via modulation of Psy1, CrtR-b2, and fiAD2/3. Emerging innovations, such as base and prime editing, and RNP-mediated transgene-free delivery, are expanding the precision and scope of editing. However, challenges persist, including genotype-dependent transformation, low HDR efficiency, and incomplete understanding of off-target and epigenetic effects. Integrating CRISPR with omics-guided gene discovery, efficient transformation systems, and regulatory harmonization can accelerate the development of nutritionally enriched, stress-resilient, and sustainable Solanaceae varieties. This review synthesizes recent advances, identifies critical limitations, and outlines future opportunities for deploying CRISPR/Cas technology to achieve next-generation breeding and food system resilience.

CRISPR/Cas↗

PubMed2020

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches.

Neurodegenerative diseases (NDDs) are most commonly found in adults and remain essentially incurable. Gene therapy using AAV vectors is a rapidly-growing field of experimental medicine that holds promise for the treatment of NDDs. To date, the delivery of a therapeutic gene into target cells via AAV represents a major obstacle in the field. Ideally, transgenes should be delivered into the target cells specifically and efficiently, while promiscuous or off-target gene delivery should be minimized to avoid toxicity. In the pursuit of an ideal vehicle for NDD gene therapy, a broad variety of vector systems have been explored. Here we specifically outline the advantages of adeno-associated virus (AAV)-based vector systems for NDD therapy application. In contrast to many reviews on NDDs that can be found in the literature, this review is rather focused on AAV vector selection and their preclinical testing in experimental and preclinical NDD models. Preclinical and in vitro data reveal the strong potential of AAV for NDD-related diagnostics and therapeutic strategies.

Animals↗

PubMed2026

CRISPR/Cas9-Mediated Site-Directed Mutagenesis of Genes in Klebsiella pneumoniae.

Constructing target-gene mutants with a common genetic background is crucial for elucidating gene function in antimicrobial resistance (AMR) research. Taking advantage of the single-guide RNA (sgRNA) and protospacer adjacent motif (PAM) sequence (3'-NGG) specificity of the Cas9 protein in the CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system and codon degeneracy, the authors design a repair template that incorporates the desired point mutation while excluding the PAM sequence disrupted by a synonymous substitution, thereby preventing re-cleavage by CRISPR/Cas9. This method employs two available plasmids, pCasKP-apr and pSGKP-spe, offering straightforward operation and high screening specificity. As a result, the approach enables efficient generation of genetically defined mutant strains of Klebsiella pneumoniae (K. pneumoniae) and is readily adaptable to routine laboratory settings. Furthermore, the protocol minimizes off-target editing, shortens experimental timelines, reduces screening workload, and provides a reliable platform for investigating resistance mechanisms, validating candidate genes, and supporting functional genomics studies in clinically relevant bacterial pathogens.

Klebsiella pneumoniae↗

PubMed1999

Contrast enhancement in microplanar beam radiography.

In x-ray radiography, the target produces a useful shadow from absorption of the primary beam, while the scattered radiation into the off-target region decreases the contrast of the target image. A bundle of closely spaced microplanar beams can reduce the scattered radiation and give superior image contrast compared with a single macrobeam of the same dimensions. To further reduce the scattered radiation and increase the image contrast, we place an air gap between the tissue phantom and the detector. The primary and scattered photon flux of a single microplanar beam is measured as a function of thickness inside the phantom and in the air gap. Results show that a bundle of closely spaced, microplanar beams increase the image contrast by 22% and a 2 cm air gap decreases the scattered photon flux by about half, improving the contrast by an additional 16%. Thus an overall improvement of 41% in contrast can be achieved with microplanar beam radiography.

Cadmium Radioisotopes↗

PubMed2000

Monte Carlo calculation for microplanar beam radiography.

In radiography the scattered radiation from the off-target region decreases the contrast of the target image. We propose that a bundle of collimated, closely spaced, microplanar beams can reduce the scattered radiation and eliminate the effect of secondary electron dose, thus increasing the image dose contrast in the detector. The lateral and depth dose distributions of 20-200 keV microplanar beams are investigated using the EGS4 Monte Carlo code to calculate the depth doses and dose profiles in a 6 cm x 6 cm x 6 cm tissue phantom. The maximum dose on the primary beam axis (peak) and the minimum inter-beam scattered dose (valley) are compared at different photon energies and the optimum energy range for microbeam radiography is found. Results show that a bundle of closely spaced microplanar beams can give superior contrast imaging to a single macrobeam of the same overall area.

Humans↗