Nucleic Acids Res. 2025 Jan 11;53(2):gkae1312. doi: 10.1093/nar/gkae1312.

ABSTRACT

The expansion of single-cell analytical techniques has empowered the exploration of diverse biological questions at the individual cells. Droplet-based single-cell RNA sequencing (scRNA-seq) methods have been particularly widely used due to their high-throughput capabilities and small reaction volumes. While commercial systems have contributed to the widespread adoption of droplet-based scRNA-seq, their relatively high cost limits the ability to profile large numbers of cells and samples. Moreover, as the scale of single-cell sequencing continues to expand, accommodating diverse workflows and cost-effective multi-biospecimen profiling becomes more critical. Herein, we present inDrops-2, an open-source scRNA-seq technology designed to profile live or preserved cells with a sensitivity matching that of state-of-the-art commercial systems but at a 6-fold lower cost. We demonstrate the flexibility of inDrops-2, by implementing two prominent scRNA-seq protocols, based on exponential and linear amplification of barcoded-complementary DNA, and provide useful insights into the advantages and disadvantages inherent to each approach. We applied inDrops-2 to simultaneously profile multiple human lung carcinoma samples that had been subjected to cell preservation, long-term storage and multiplexing to obtain a multiregional cellular profile of the tumor microenvironment. The scalability, sensitivity and cost efficiency make inDrops-2 stand out among other droplet-based scRNA-seq methods, ideal for large-scale studies on rare cell molecular signatures.

PMID:39797728 | DOI:10.1093/nar/gkae1312

J Fish Biol. 2025 Jan 11. doi: 10.1111/jfb.16056. Online ahead of print.

ABSTRACT

Animal growth is a fundamental component of population dynamics, which is closely tied to mortality, fecundity, and maturation. As a result, estimating growth often serves as the basis of population assessments. In fish, analysing growth typically involves fitting a growth model to age-at-length data derived from counting growth rings in calcified structures. Additionally, fish growth can be estimated using length-frequency data or data on changes in length derived from mark-recapture events. In our study of the European grayling (Thymallus thymallus L.) in the alpine region of Germany, we utilized all three types of datasets to develop the initial growth model. For the age-at-length data from scales, we applied the traditional von Bertalanffy growth function using both a Bayesian and a frequentist approach. Furthermore, we adopted the mark-recapture data along with the Fabens model for reparametrizing the von Bertalanffy growth model. The electronic length-frequency analysis (ELEFAN) was employed to examine the length-frequency data of the grayling, encompassing multiple sampling events from 2013 to 2022. Our findings indicated that the mark-recapture data, in conjunction with the Fabens model, yielded the most plausible values for both statistical approaches. When the von Bertalanffy growth function was used, the frequentist approach generated unreasonably high values, whereas the Bayesian version produced meaningful results when appropriate priors were applied, suggesting potential issues with the age-at-length data related to ageing. The ELEFAN approach produced the smallest yet reasonable growth parameters, contradicting other studies on the European grayling. The lower values may be attributed to the lack of larger fish in most of the sampling events, resulting in a relatively low asymptotic length and slow growth rate. As demonstrated in this case study on grayling from the River Inn, the use of growth characteristics may be a currently underestimated yet very useful indicator of target species assessment that can nicely complement other population health indicators.

PMID:39797550 | DOI:10.1111/jfb.16056

J Clin Med. 2025 Jan 6;14(1):288. doi: 10.3390/jcm14010288.

ABSTRACT

Objective: The clinical trial Effect of Modulated Auditory Stimulation on Interaural Auditory Perception (NCT0544189) aimed to determine whether an auditory intervention (AI)-"Bérard in 10"-can enhance the effect of standard therapies for people with anxiety and/or depression. Methods: Design: unblinded, randomized, controlled clinical trial.

LOCATION: Mejorada del Campo Health Centre, Madrid (Primary Care).

PARTICIPANTS: A total of 233 patients selected by systematic sampling and meeting the following selection criteria: age of majority, absence of severe acute pathology or chronic decompensated pathology. They were evaluated with the Goldberg and Hamilton tests and classified into the Emotional Well-Being group (EWB, n = 86) or the Anxiety and/or Depression group (AD, n = 147). Just half of each group received an AI.

INTERVENTION: Listening to classical music processed through a frequency modulator (Earducator) to attenuate abnormal frequencies, 30 min per session, two sessions a day for 5 days.

MAIN MEASUREMENTS: Hamilton Tests for Anxiety and Hamilton Test for Depression, at 3 and 6 months. Results: In the analysis by protocol, EWB with AI (n = 14) obtained lower scores in anxiety and depression at 3 and 6 months than EWB without AI (n = 36) (p < 0.05), the effects being large and moderate, respectively; AD with AI (n = 31) had lower scores on anxiety and depression at 3 months and anxiety at 6 months than AD without AI (n = 52) (p < 0.05), the effect being small. No damage reported. Conclusions: The AI "Bérard in 10" significantly prevents the onset of anxiety and depression and somewhat improves the effect of standard treatments in primary care.

PMID:39797370 | DOI:10.3390/jcm14010288

Cancers (Basel). 2024 Dec 25;17(1):19. doi: 10.3390/cancers17010019.

ABSTRACT

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.

PMID:39796650 | DOI:10.3390/cancers17010019

Int J Mol Sci. 2024 Dec 31;26(1):275. doi: 10.3390/ijms26010275.

ABSTRACT

Cancer occurrence rates exhibit diverse age-related patterns, and understanding them may shed new and important light on the drivers of cancer evolution. This study systematically analyzes the age-dependent occurrence rates of 23 carcinoma types, focusing on their age-dependent distribution patterns, the determinants of peak occurrence ages, and the significant difference between the two genders. According to the SEER reports, these cancer types have two types of age-dependent occurrence rate (ADOR) distributions, with most having a unimodal distribution and a few having a bimodal distribution. Our modeling analyses have revealed that (1) the first type can be naturally and simply explained using two age-dependent parameters: the total number of stem cell divisions in an organ from birth to the current age and the availability levels of bloodborne growth factors specifically needed by the cancer (sub)type, and (2) for the second type, the first peak is due to viral infection, while the second peak can be explained as in (1) for each cancer type. Further analyses indicate that (i) the iron level in an organ makes the difference between the male and female cancer occurrence rates, and (ii) the levels of sex hormones are the key determinants in the onset age of multiple cancer types. This analysis deepens our understanding of the dynamics of cancer evolution shared by diverse cancer types and provides new insights that are useful for cancer prevention and therapeutic strategies, thereby addressing critical gaps in the current paradigm of oncological research.

PMID:39796131 | DOI:10.3390/ijms26010275

Int J Mol Sci. 2024 Dec 30;26(1):248. doi: 10.3390/ijms26010248.

ABSTRACT

Sharka disease, caused by the plum pox virus (PPV), negatively impacts stone fruit production, resulting in economic losses. It has been demonstrated that grafting the almond (Prunus dulcis (Miller) D.A. Webb) variety 'Garrigues' into susceptible peach (Prunus persica (L.) Batsch) rootstocks can result in PPV resistance. The molecular circuits related to grafting in Prunus species, however, have not been fully investigated. In this study, susceptible peach rootstocks 'GF305' were either heterografted with 'Garrigues' almond or homografted with the same cultivar. Peach samples were collected at two stages of scion development, with ungrafted plants utilized as controls. Profiles of transcripts, small RNAs (sRNAs), and DNA methylation were obtained and analyzed on a genome-wide scale. Homografting and heterografting significantly altered the transcriptome and methylome of peach rootstocks, with these modifications being more pronounced during the early stages of scion development. The profiles of sRNAs were significantly more impacted when almonds were used as a scion as opposed to peaches, likely due to the transmission of PPV-unrelated viral sequences. Gene expression differences resulting from DNA methylation alterations are more thoroughly documented at the promoter sequences of genes than within their bodies. This study suggests that the 'Garrigues' almond variety triggers a complex defense response in the peach rootstock, potentially involving the interplay of epigenetic modifications and small RNA-mediated priming of antiviral defenses, which ultimately may contribute to PPV resistance.

PMID:39796109 | DOI:10.3390/ijms26010248

Int J Mol Sci. 2024 Dec 28;26(1):183. doi: 10.3390/ijms26010183.

ABSTRACT

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context. It reveals their multifaceted impact on hallmark cancer processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, resisting cell death, inducing angiogenesis, and enabling replicative immortality. SIRT1, for example, fosters chemoresistance and castration-resistant prostate cancer through metabolic reprogramming, immune modulation, androgen receptor signaling, and enhanced DNA repair. SIRT3 and SIRT4 suppress oncogenic pathways by regulating cancer metabolism, while SIRT2 and SIRT6 influence tumor aggressiveness and androgen receptor sensitivity, with SIRT6 promoting metastatic potential. Notably, SIRT5 oscillates between oncogenic and tumor-suppressive roles by regulating key metabolic enzymes; whereas, SIRT7 drives PCa proliferation and metabolic stress adaptation through its chromatin and nucleolar regulatory functions. Furthermore, we provide a comprehensive summary of the roles of individual sirtuins, highlighting their potential as biomarkers in PCa and exploring their therapeutic implications. By examining each of these specific mechanisms through which sirtuins impact PCa, this review underscores the potential of sirtuin modulation to address gaps in managing advanced PCa. Understanding sirtuins' regulatory effects could redefine therapeutic approaches, promoting precision strategies that enhance treatment efficacy and improve outcomes for patients with aggressive disease.

PMID:39796040 | DOI:10.3390/ijms26010183

Int J Mol Sci. 2024 Dec 28;26(1):172. doi: 10.3390/ijms26010172.

ABSTRACT

Heat stress transcription factors (HSFs) play a critical role in orchestrating cellular responses to elevated temperatures and various stress conditions. While extensively studied in model plants, the HSF gene family in Betula platyphylla remains unexplored, despite the availability of its sequenced genome. In this study, we employed bioinformatics approaches to identify 21 BpHSF genes within the Betula platyphylla genome, revealing their uneven distribution across chromosomes. These genes were categorized into three subfamilies: A, B, and C. Each was characterized by conserved protein motifs and gene structures, with notable divergence observed between subfamilies. Collinearity analysis suggested that segmental duplication events have driven the evolutionary expansion of the BpHSF gene family. Promoter region analysis identified an array of cis-acting elements linked to growth, development, hormonal regulation, and stress responses. Subcellular localization experiments confirmed the nuclear localization of BpHSFA2a, BpHSFB1a, and BpHSFC1a, consistent with in silico predictions. RNA-seq and RT-qPCR analyses revealed tissue-specific expression patterns of BpHSF genes and their dynamic responses to heat stress, with qPCR validation highlighting a significant upregulation of BpHSFA2a under high-temperature conditions. In summary, this study provided a comprehensive characterization of the HSF gene family in Betula platyphylla, laying a solid foundation for future functional studies. Particularly, BpHSFA2a emerges as a promising candidate gene for enhancing heat tolerance in Betula platyphylla, warranting further detailed investigation.

PMID:39796031 | DOI:10.3390/ijms26010172

Int J Mol Sci. 2024 Dec 28;26(1):163. doi: 10.3390/ijms26010163.

ABSTRACT

Over the last three decades, adult neurogenesis in mammals has been a central focus of neurobiological research, providing insights into brain plasticity and function. However, interest in this field has recently waned due to challenges in translating findings into regenerative applications and the ongoing debate about the persistence of this phenomenon in the adult human brain. Despite these hurdles, significant progress has been made in understanding how adult neurogenesis plays a critical role in the adaptation of brain circuits to environmental stimuli regulating key brain functions. This review focuses on the role of olfactory neurogenesis in the brain's response to social reproductive cues in rodents, highlighting its influence on animal behaviors critical for survival. We also address open questions and propose future directions to advance our understanding of the relationship between adult neurogenesis and reproductive function regulation.

PMID:39796023 | DOI:10.3390/ijms26010163

Int J Mol Sci. 2024 Dec 24;26(1):33. doi: 10.3390/ijms26010033.

ABSTRACT

DNA gyrase is a bacterial type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology and an archetypical target of antibiotics. The widely used quinolone class of drugs use a water-metal ion bridge in interacting with the GyrA subunit of DNA gyrase. Zoliflodacin sits in the same pocket as quinolones but interacts with the GyrB subunit and also stabilizes lethal double-stranded DNA breaks. Gepotidacin has been observed to sit on the twofold axis of the complex, midway between the two four-base-pair separated DNA-cleavage sites and has been observed to stabilize singe-stranded DNA breaks. Here, we use information from three crystal structures of complexes of Staphlococcus aureus DNA gyrase (one with a precursor of gepotidacin and one with the progenitor of zoliflodacin) to propose a simple single moving metal-ion-catalyzed DNA-cleavage mechanism. Our model explains why the catalytic tyrosine is in the tyrosinate (negatively charged) form for DNA cleavage. Movement of a single catalytic metal-ion (Mg2+ or Mn2+) guides water-mediated protonation and cleavage of the scissile phosphate, which is then accepted by the catalytic tyrosinate. Type IIA topoisomerases need to be able to rapidly cut the DNA when it becomes positively supercoiled (in front of replication forks and transcription bubbles) and we propose that the original purpose of the small Greek Key domain, common to all type IIA topoisomerases, was to allow access of the catalytic metal to the DNA-cleavage site. Although the proposed mechanism is consistent with published data, it is not proven and other mechanisms have been proposed. Finally, how such mechanisms can be experimentally distinguished is considered.

PMID:39795899 | DOI:10.3390/ijms26010033

Molecules. 2024 Dec 26;30(1):43. doi: 10.3390/molecules30010043.

ABSTRACT

Curcumin is among the most well-studied natural substances, known for its biological actions within the central nervous system, its antioxidant and anti-inflammatory properties, and human health benefits. However, challenges persist in effectively utilising curcumin, addressing its metabolism and passage through the blood-brain barrier (BBB) in therapies targeting cerebrovascular diseases. Current challenges in curcumin's applications revolve around its effects within neoplastic tissues alongside the development of intelligent formulations to enhance its bioavailability. Formulations have been discovered including curcumin's complexes with brain-derived phospholipids and proteins, or its liposomal encapsulation. These novel strategies aim to improve curcumin's bioavailability and stability, and its capability to cross the BBB, thereby potentially enhancing its efficacy in treating cerebrovascular diseases. In summary, this review provides a comprehensive overview of molecular pathways involved in interactions of curcumin and its metabolites, and brain vascular homeostasis. This review explores cellular and molecular current aspects, of curcumin-based effects with an emphasis on curcumin's metabolism and its impact on pathological conditions, such as neurodegenerative diseases, schizophrenia, and cerebral angiopathy. It also highlights the limitations posed by curcumin's poor bioavailability and discusses ongoing efforts to surpass these impediments to harness the full therapeutic potential of curcumin in neurological disorders.

PMID:39795101 | DOI:10.3390/molecules30010043

Eur J Hosp Pharm. 2024 Dec 16:ejhpharm-2024-004429. doi: 10.1136/ejhpharm-2024-004429. Online ahead of print.

NO ABSTRACT

PMID:39797685 | DOI:10.1136/ejhpharm-2024-004429

Drug Ther Bull. 2024 Dec 22:dtb-2024-000070. doi: 10.1136/dtb.2024.000070. Online ahead of print.

NO ABSTRACT

PMID:39797682 | DOI:10.1136/dtb.2024.000070

Drug Ther Bull. 2024 Dec 22:dtb-2024-000069. doi: 10.1136/dtb.2024.000069. Online ahead of print.

NO ABSTRACT

PMID:39797681 | DOI:10.1136/dtb.2024.000069

Drug Ther Bull. 2024 Dec 22:dtb-2024-000068. doi: 10.1136/dtb.2024.000068. Online ahead of print.

NO ABSTRACT

PMID:39797680 | DOI:10.1136/dtb.2024.000068

Cancers (Basel). 2024 Dec 29;17(1):76. doi: 10.3390/cancers17010076.

ABSTRACT

Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis. Several risk factors, such as pre-existing autoimmune and liver diseases, the type of immunotherapy, and combination regimens, play a role in immune-related hepatotoxicity (irH), although reliable predictive markers or models are still lacking. The severity of irH ranges from mild to severe cases, up to, in rare instances, acute liver failure. Management strategies require regular monitoring for early diagnosis and interventions, encompassing strict monitoring for mild cases to the permanent suspension of immunotherapy for severe forms. Corticosteroids are the backbone of treatment in moderate and high-grade damage, alone or in combination with additional immunosuppressive drugs for resistant or refractory cases. Given the relatively low number of events and the lack of dedicated prospective studies, much uncertainty remains about the optimal management of irH, especially in the most severe cases. This review presents the main features of irH, focusing on injury patterns and mechanisms, and provides an overview of the management landscape, from standard care to the latest evidence.

PMID:39796705 | DOI:10.3390/cancers17010076

Funding Opportunity RFA-HL-26-007 from the NIH Guide for Grants and Contracts. The B2B Pediatric Cardiac Genomics Consortium (PCGC) (http://www.benchtobassinet.com/) will evolve to the B2B CHANGE Cohort (Congenital Heart disease Advancing New understanding in GEnomics). The B2B CHANGE Cohorts mission will be to conduct long-term clinical follow up on participants from the original PCGC Cohort, to perform deeper cohort phenotyping and to support investigators in applying for funding to conduct multi-center, collaborative ancillary studies to further understand how genetic variants relate to clinical outcomes. The Administrative Coordinating Center (ACC) will serve to lead and advance data and resource management and sharing, and coordinate critical data collection and participant outreach efforts at the clinical research sites. The ACC will work in a collaborative fashion with site PIs, as well as the broader congenital heart disease (CHD) research community.

Funding Opportunity RFA-MH-26-105 from the NIH Guide for Grants and Contracts. This initiative will leverage cutting edge generative AI technology to augment existing narrow AI/ML approaches used in clinical care that will expand our capacity to address the dynamic, complex, and evolving HIV epidemic.

Funding Opportunity PAR-25-358 from the NIH Guide for Grants and Contracts. The NEI supports large-scale clinical vision research projects, including randomized clinical trials and epidemiologic studies on eye/vision conditions. At the time of submission, applications requesting support for these activities are expected to provide detailed information regarding the study rationale, design, analytic methods, protocols and procedures, facilities and environment, organizational structure, and collaborative arrangements. This information is best conveyed in a study protocol and Manual of Procedures (MOP), the development of which represents a costly and time-consuming activity. This clinical research planning grant funding opportunity supports applicants in their planning efforts to conduct collaborative clinical research. The grant may be used to support the development of a study protocol and MOP, as well as to conduct preliminary studies to refine study procedures or document recruitment potential. The grant must not be used to generate data on the effects of a proposed intervention. This NEI NOFO is applicable to both epidemiologic and clinical trial research studies.

Notice NOT-CA-25-032 from the NIH Guide for Grants and Contracts