FEBS Open Bio. 2025 Jan 15. doi: 10.1002/2211-5463.13939. Online ahead of print.

ABSTRACT

Malaria, a life-threatening disease caused by Plasmodium parasites, continues to pose a significant global health threat, with nearly 250 million infections and over 600 000 deaths reported annually by the WHO. Fighting malaria is particularly challenging partly due to the complex life cycle of the parasite. However, technological breakthroughs such as the development of the nucleoside-modified mRNA lipid nanoparticle (mRNA-LNP) vaccine platform, along with the discovery of novel conserved Plasmodium antigens such as the E140 protein, present new opportunities in malaria prevention. Importantly, production of recombinant proteins for malaria vaccine evaluation by serological assays often represents an additional hurdle because many Plasmodium proteins are complex and often contain transmembrane domains that make production and purification particularly difficult. This research protocol provides a step-by-step guide for the production and purification of P. berghei and P. vivax E140 protein fragments that can be used to test humoral immune responses against this novel malaria vaccine target. We demonstrate that the purified proteins can be successfully used in enzyme-linked immunosorbent assay (ELISA) to evaluate antigen-specific binding antibody responses in sera obtained from E140 mRNA-LNP-vaccinated mice. Therefore, these proteins can contribute to the development and evaluation of E140-based malaria vaccines.

PMID:39815669 | DOI:10.1002/2211-5463.13939

Funding Opportunity RFA-HL-26-011 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to renew the MACS/WIHS Combined Cohort Study of HIV in United States Adults (MWCCS) for a 6-year project period (2026-2032). Continuation of this epidemiological cohort study of middle-aged and older people living with HIV (PLWH), along with comparable individuals living without HIV (PLWOH) will enable the continued follow-up of a deeply phenotyped cohort of approximately 5,600 participants from across the United States. This initiative will utilize a populomics approach, i.e., examination of health determinants across multiple scales of influence (e.g. molecular, cellular, physiological, lifestyle/behavioral, household, neighborhood, environmental, cultural, and sociopolitical) using multi-disciplinary methods to investigate the web of influences impacting the health, quality of life, and survival of adults living with HIV. This NOFO seeks applications to fund a single Leadership and Coordination Center (LACC) for the MWCCS. This NOFO runs in parallel with two companion U01 NOFOs: RFA-HL-26-009 (Limited Competition: Clinical Research Sites (CRS) for the MACS/WIHS Combined Cohort Study (MWCCS) (U01 Clinical Trials Not Allowed)) and RFA-HL-26-010 (Limited Competition: Data Analysis and Sharing Center (DASC) for the MACS/WIHS Combined Cohort Study (MWCCS) (U01 Clinical Trials Not Allowed))

Funding Opportunity RFA-HL-26-010 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to renew the MACS/WIHS Combined Cohort Study of HIV in United States Adults (MWCCS) for a 7-year project period (2026-2033). Continuation of this epidemiological cohort study of middle-aged and older people living with HIV (PLWH), along with comparable individuals living without HIV (PLWOH) will enable the continued follow-up of a deeply phenotyped cohort of approximately 5,500 participants from across the United States. This initiative will utilize a populomics approach, i.e., examination of health determinants across multiple scales of influence (e.g. molecular, cellular, physiological, lifestyle/behavioral, household, neighborhood, environmental, cultural, and sociopolitical) using multi-disciplinary methods to investigate the web of influences impacting the health, quality of life, and survival of adults living with HIV. This NOFO seeks applications to fund a single Data Analysis and Sharing Center (DASC) for the MWCCS, with competition limited to institutions who were funded under RFA-HL-19-007.

Funding Opportunity RFA-HL-26-009 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to renew the MACS/WIHS Combined Cohort Study of HIV in United States Adults (MWCCS) for a 6-year project period (2026-2032). Continuation of this epidemiological cohort study of middle-aged and older people living with HIV (PLWH), along with comparable people living without HIV (PLWOH) will enable the continued follow-up of a deeply phenotyped cohort of more than 5,600 participants from across the United States. This initiative will utilize a populomics approach, i.e., examination of health determinants across multiple scales of influence (e.g. molecular, cellular, physiological, lifestyle/behavioral, household, neighborhood, environmental, cultural, and sociopolitical) using multi-disciplinary methods to investigate the web of influences impacting the health, quality of life, and survival of adults living with HIV. This NOFO is limited to institutions who were funded under RFA-HL-19-008 and will fund up to 13 Clinical Research Sites (CRS) for the MWCCS. This NOFO runs in parallel with two companion U01 NOFOs: RFA-HL-26-010 (Limited Competition: Data Analysis and Sharing Center (DASC) for the MACS/WIHS Combined Cohort Study (MWCCS) (U01 Clinical Trials Not Allowed)) and RFA-HL-26-011 (Leadership and Coordination Center (LACC) for the MACS/WIHS Combined Cohort Study (MWCCS) (U01 Clinical Trials Not Allowed)).

Funding Opportunity RFA-AI-24-079 from the NIH Guide for Grants and Contracts. The purpose of this notice of funding opportunity (NOFO) is to invite applications from single institutions or consortia of institutions to participate in the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) program. The program will support centers that integrate clinical and translational research to conduct studies on the mechanisms underlying the onset and progression of diseases of interest, including asthma, rhinitis (allergic and non-allergic), chronic rhinosinusitis, atopic dermatitis, food allergy, and drug allergy. The overarching goal of the program is to improve the understanding of the pathogenesis of these conditions and to provide a rational foundation for new, effective treatments and prevention strategies.

Notice NOT-AG-24-098 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-25-356 from the NIH Guide for Grants and Contracts. The purpose of this notice of funding opportunity (NOFO) is to enhance the participation of individuals from nationally underrepresented backgrounds to enhance the participation of individuals from nationally underrepresented backgrounds in cardiovascular, pulmonary, hematologic and sleep disorders research across the career development continuum by providing support to institutions that promote diversity. The NHLBI's T32 Training Program for Institutions That Promote Diversity is a Ruth L. Kirschstein National Research Service Award Program intended to support training of predoctoral and health professional students and individuals in postdoctoral training institutions with an institutional mission focused on serving health disparity populations not well represented in scientific research, or institutions that have been identified by federal legislation as having an institutional mission focused on these populations, with the potential to develop meritorious training programs in cardiovascular, pulmonary, and hematologic diseases, and sleep disorders. These institutions are uniquely positioned to engage minority and other health disparity populations in research, translation, and implementation of research advances that impact health outcomes, as well as provide health care for these populations. This NOFO does not allow appointed trainees to lead an independent clinical trial but does allow them to obtain research experience in a clinical trial led by a mentor or co-mentor.

NIH (including help desks) will be closed on Monday, February 17, 2025 for the federal holiday (Washington’s Birthday). If a grant application due date falls on a federal holiday, the application deadline is automatically extended to the next business day.

We invite you to join us for two webinars that spotlight our NIH Research Enhancement Award (R15) and Fellowship programs.

NIH Research Enhancement Award (R15): What You Need to Know and Recent Changes
January 30, 2025, 2:30-4:00 PM ET
Register now!

In this virtual event, you will learn about the two NIH R15 programs:

• Academic Research Enhancement Award for Undergraduate-Focused Institutions (AREA)
• Research Enhancement Award Program for Health Professional and Graduate Schools (REAP).

R15 research project grants are designed to provide support for meritorious research at institutions that have not been major recipients of NIH support, to strengthen the research environment at these institutions, and to give students an opportunity to gain significant biomedical research experience.

An Introduction to the NIH Fellowship Program for Prospective Candidates

February 11, 2025, 10:00 – 11:30 AM ET

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You may already know that there’s a lot that goes into an NIH fellowship application, and you may be wondering where to start. At this live, virtual event NIH experts will:

• Discuss NIH’s fellowship programs
• Break down the fellowship application and peer review process
• Share Practical tips for preparing a competitive application
• Answer your questions at live Q&A sessions

The NIH fellowship program provides individual training opportunities to support fellows at various career stages, including at graduate, and postdoctoral levels. This webinar is valuable for fellowship candidates, sponsors, and research program administrators new to the NIH and the fellowship application process.

Don’t miss out on the opportunities to explore these exciting programs.

Funding Opportunity PAR-25-353 from the NIH Guide for Grants and Contracts. Reissue of PAR-20-119. This FOA encourages applications to advance the discovery, preclinical development, and proof of concept (PoC) testing of new, rationally based candidate agents and neurostimulation approaches to treat mental disorders, substance use disorders (SUDs) or alcohol use disorder (AUD), and to develop novel ligands and circuit-engagement devices as tools to further characterize existing or to validate new drug/device targets. Partnerships between academia and industry are strongly encouraged. This FOA supports a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. Projects seeking support for a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies should consider the companion U01 FOA.

The Personal Profile module in eRA Commons is where you — as a principal investigator, award recipient, trainee, reviewer or other Commons user — tell NIH and other awarding agencies about yourself. Awarding agencies need to know about you to grant awards, process those awards and more. Here are a few reasons that it is extremely important to keep your Personal Profile updated.

• All communications between awarding agencies and you are sent to contact methods that you enter into your Personal Profile.
• Reports, such as the Research Performance Progress Report (RPPR), cannot be submitted if award recipients have incomplete Personal Profiles.
• Trainees cannot be appointed without complete Personal Profiles.
• Early Stage Investigator (ESI) status is calculated from Personal Profile data entered by principal investigators in the Education section.
• Personal Profile data is used to help agency review staff identify reviewers’ conflict of interest with applications they are reviewing; and is the place reviewers enter information to get their review meeting honorariums.

Personal Profile is the central repository of information about all Commons registered users. It lets you own and maintain the accuracy for your own personal information. This profile information is integrated throughout eRA systems. It is used to determine reviewer conflicts, link publications, populate application data, track trainee effort, and to ensure that Early Stage Investigator status is accurately calculated. In addition, you have the option to provide demographic information to help NIH better understand its research workforce. Read more about how to manage your Personal Profile.

Linking your ORCID iD (Open Researcher and Contributor ID) to your eRA Commons account enables automatic importation of publications into biosketches, reducing burden and saving you time. You can use Personal Profile to connect your eRA Commons account to your ORCID iD (Open Researcher and Contributor ID), which is a unique 16-digit identifier that enables connections between researchers and their research and scholarship. A linked ORCID iD is required for all senior/ key personnel listed on  an application for a  due date on or after May 25, 2025. See the video titled Link Your ORCID iD to Your eRA Commons Account.

So, if you have not recently updated your Personal Profile, please do so soon. It will benefit both the awarding agency and you.

Also see:

• Manage Personal Profile webpage
• Personal Profile Module online help
• Update on Linking ORCID To Implement Persistent Identifier Requirements While Reducing Burden and Improving Transparency blog post
• NIH All About Grants Podcast: Growing ORCIDs podcast episode

Funding Opportunity PAR-25-352 from the NIH Guide for Grants and Contracts. Reissue of PAR-20-118. This Notice of Funding Opportunity (NOFO) encourages applications to advance the discovery, preclinical development, and proof of concept (PoC) testing of new, rationally based candidate agents and neurostimulation approaches to treat mental disorders, substance use disorders (SUDs) or alcohol use disorder (AUD), and to develop novel ligands and circuit-engagement devices as tools to further characterize existing or to validate new drug/device targets. Partnerships between academia and industry are strongly encouraged. This NOFO using the U01 mechanism supports a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies Projects seeking support for a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach should consider the companion U19 FOA.

Notice NOT-RM-25-001 from the NIH Guide for Grants and Contracts

Notice NOT-AG-24-031 from the NIH Guide for Grants and Contracts

Notice NOT-CA-25-021 from the NIH Guide for Grants and Contracts

Drug Metab Rev. 2025 Jan 20:1-24. doi: 10.1080/03602532.2025.2453521. Online ahead of print.

ABSTRACT

Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and more frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as HLA-B*57:01, HLA-B*15:02, and HLA-B*58:01, are known risk factors for adverse reactions induced by multiple drugs. However, the structural basis underlying most HLA-associated adverse events remains poorly understood. This review summarizes the application of molecular docking to reveal the mechanisms of IDR-related HLA associations, covering studies using this technique to examine drug-HLA binding pockets and identify key binding residues. We provide a comprehensive overview of risk HLA alleles associated with IDRs, followed by a discussion of the utility and limitations of commonly used molecular docking tools in simulating complex molecular interactions within the HLA binding pocket. Through examples, including the binding of abacavir and flucloxacillin to HLA-B*57:01, carbamazepine to HLA-B*15:02, and allopurinol to HLA-B*58:01, we demonstrate how docking analyses can provide insights into the drug and HLA allele-specificity of adverse events. Furthermore, the use of molecular docking to screen drugs with unknown IDR liability is examined, targeting either multiple HLA variants or a single specific variant. Despite multiple challenges, molecular docking presents a promising toolkit for investigating drug-HLA interactions and understanding IDR mechanisms, with significant implications for preemptive HLA typing and safer drug development.

PMID:39811883 | DOI:10.1080/03602532.2025.2453521

BMC Bioinformatics. 2025 Jan 15;26(1):16. doi: 10.1186/s12859-024-06028-6.

ABSTRACT

In recent years, combined drug screening has played a very important role in modern drug discovery. Generally, synergistic drug combinations are crucial in treatment for many diseases. However, the toxic side effects of drug combinations are probably increased with the increase of drugs numbers, so the accurate prediction of toxic side effects of drug combinations is equally important. In this paper, we built a Metapath-based Aggregated Embedding Model on Single Drug-Side Effect Heterogeneous Information Network (MAEM-SSHIN), which extracts feature from a heterogeneous information network of single drug side effects, and a Graph Convolutional Network on Combinatorial drugs and Side effect Heterogeneous Information Network (GCN-CSHIN), which transforms the complex task of predicting multiple side effects between drug pairs into the more manageable prediction of relationships between combinatorial drugs and individual side effects. MAEM-SSHIN and GCN-CSHIN provided a united novel framework for predicting potential side effects in combinatorial drug therapies. This integration enhances prediction accuracy, efficiency, and scalability. Our experimental results demonstrate that this combined framework outperforms existing methodologies in predicting side effects, and marks a significant advancement in pharmaceutical research.

PMID:39815175 | DOI:10.1186/s12859-024-06028-6

Discov Oncol. 2025 Jan 16;16(1):53. doi: 10.1007/s12672-025-01763-5.

ABSTRACT

OBJECTIVES: Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC).

METHODS: To evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice.

RESULTS: LEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization.

CONCLUSION: LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.

PMID:39815040 | DOI:10.1007/s12672-025-01763-5

Sci Rep. 2025 Jan 15;15(1):2093. doi: 10.1038/s41598-025-85947-7.

ABSTRACT

Alzheimer's Disease (AD) significantly aggravates human dignity and quality of life. While newly approved amyloid immunotherapy has been reported, effective AD drugs remain to be identified. Here, we propose a novel AI-driven drug-repurposing method, DeepDrug, to identify a lead combination of approved drugs to treat AD patients. DeepDrug advances drug-repurposing methodology in four aspects. Firstly, it incorporates expert knowledge to extend candidate targets to include long genes, immunological and aging pathways, and somatic mutation markers that are associated with AD. Secondly, it incorporates a signed directed heterogeneous biomedical graph encompassing a rich set of nodes and edges, and node/edge weighting to capture crucial pathways associated with AD. Thirdly, it encodes the weighted biomedical graph through a Graph Neural Network into a new embedding space to capture the granular relationships across different nodes. Fourthly, it systematically selects the high-order drug combinations via diminishing return-based thresholds. A five-drug lead combination, consisting of Tofacitinib, Niraparib, Baricitinib, Empagliflozin, and Doxercalciferol, has been selected from the top drug candidates based on DeepDrug scores to achieve the maximum synergistic effect. These five drugs target neuroinflammation, mitochondrial dysfunction, and glucose metabolism, which are all related to AD pathology. DeepDrug offers a novel AI-and-big-data, expert-guided mechanism for new drug combination discovery and drug-repurposing across AD and other neuro-degenerative diseases, with immediate clinical applications.

PMID:39814937 | DOI:10.1038/s41598-025-85947-7

Drug Metab Pers Ther. 2025 Jan 2;39(4):163-165. doi: 10.1515/dmpt-2024-0091. eCollection 2024 Dec 1.

NO ABSTRACT

PMID:39814711 | DOI:10.1515/dmpt-2024-0091