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Abstract Using the Mediterranean coral Balanophyllia europaea naturally growing along a pH gradient close to Panarea island (Italy) as a model, we explored the role of host-associated microbiomes in coral acclimatization to ocean acidification (OA). Coral samples were collected at three sites along the gradient, mimicking seawater conditions projected for 2100 under different IPCC (The Intergovernmental Panel on Climate Change) scenarios, and mucus, soft tissue and skeleton associated microbiomes were characterized by shotgun metagenomics. According to our findings, OA induced functional changes in the microbiomes genetic potential that could mitigate the sub-optimal environmental conditions at three levels: i. selection of bacteria genetically equipped with functions related to stress resistance; ii. shifts in microbial carbohydrate metabolism from energy production to maintenance of cell membranes and walls integrity; iii. gain of functions able to respond to variations in nitrogen needs at the holobiont level, such as genes devoted to organic nitrogen mobilization. We hence provided hypotheses about the functional role of the coral associated microbiome in favoring host acclimatation to OA, remarking on the importance of considering the crosstalk among all the components of the holobiont to unveil how and to what extent corals will maintain their functionality under forthcoming ocean conditions.

Ex vivo activation is a prerequisite to reaching adequate levels of gene editing by homology-directed repair (HDR) for hematopoietic stem and progenitor cell (HSPC)-based clinical applications. Here, we show that shortening culture time mitigates the p53-mediated DNA damage response to CRISPR-Cas9-induced DNA double-strand breaks, enhancing the reconstitution capacity of edited HSPCs. However, this results in lower HDR efficiency, rendering ex vivo culture necessary yet detrimental. Mechanistically, ex vivo activation triggers a multi-step process initiated by p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression and subsequent proliferation-induced DNA damage. Thus, p38 inhibition before gene editing delays G1/S transition and expands transcriptionally defined HSCs, ultimately endowing edited cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, and better-preserved genome integrity. Our data identify proliferative stress as a driver of HSPC dysfunction with fundamental implications for designing more effective and safer gene correction strategies for clinical applications., Competing Interests: Declaration of interests R.D.M., L.d.V., F.M., A.C., L.N., and S.F. are inventors of patents on applications of gene editing in HSPCs owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation. L.N. is a founder and quota holder of GeneSpire., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the minimal clinically important difference (MCID) and the patient acceptable symptom state (PASS) threshold for the visual analog scale (VAS), Constant, Single Assessment Numeric Evaluation (SANE), and American Shoulder and Elbow Surgeons (ASES) scores following arthroscopic capsular release for the treatment of idiopathic shoulder adhesive capsulitis., Methods: A retrospective review of prospective collected data was performed in patients undergoing arthroscopic capsular release for the treatment of idiopathic adhesive capsulitis at a single institution from January 2018 through January 2019. Patient-reported outcome measures were collected preoperatively and 6 months' postoperatively. Delta was defined as the change between preoperative and 6 months' postoperative scores. Distribution-based and anchored-based (response to a satisfaction question at 1 year) approaches were used to estimate MCIDs and PASS, respectively. The optimal cut-off point where sensitivity and specificity were maximized (Youden index) and the percentage of patients achieving those thresholds were also calculated., Results: Overall, a total of 100 patients without diabetes who underwent arthroscopic capsular release and completed baseline and 6-month patient-reported outcome measures were included. The distribution-based MCID for VAS, Constant, SANE, and ASES were calculated to be 1.1, 10.1, 9.3, and 8.2, respectively. The rate of patients who achieved MCID thresholds was 98% for VAS, 96% for Constant, 98% for SANE, and 99% for ASES. The PASS threshold values for VAS, Constant, and ASES were ≤2, ≥70, ≥80, and ≥80, respectively. The rate of patients who achieved PASS thresholds was 84% for VAS, 84% for Constant, 89% for SANE, and 78% for ASES., Conclusions: In patients without diabetes and idiopathic adhesive capsulitis, high rates of MCID and PASS thresholds can be achieved with arthroscopic anteroinferior capsular release LEVEL OF EVIDENCE: Level IV, retrospective cohort study., (Copyright © 2023 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

There is a growing interest in the named "acidic sterolbiome" and in the genetic potential of the gut microbiome (GM) to modify bile acid (BA) structure. Indeed, the qualitative composition of BAs in feces correlates with the bowel microorganisms and their collective genetic material. GM is responsible for the production of BA metabolites, such as secondary and oxo-BAs. The specific BA profiles, as microbiome-host co-metabolic products, could be useful to investigate the GM-host interaction in animals under physiological conditions, as well as in specific diseases. In this context, we developed and validated an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method for the simultaneous analysis of up to 21 oxo-BAs and their 9 metabolic precursors. Chromatographic separation was achieved in 7 min with adequate analytical performance in terms of selectivity, sensitivity (LOQ from 0.05 to 0.1 µg/mL), accuracy (bias% < 5%), precision (CV% < 5%) and matrix effect (ME% < 10%). A fast solvent extraction protocol has been fine-tuned, achieving recoveries > 90%. In parallel, the gut microbiota assessment in farming animals was evaluated by 16S rRNA next-generation sequencing, and the correlation with the BA composition was performed by multivariate analysis, allowing to reconstruct species-specific associations between the BA profile and specific GM components., (© 2022. The Author(s).)

The human gut microbiome has received a crescendo of attention in recent years due to the countless influences on human pathophysiology, including cancer. Research on cancer and anticancer therapy is constantly looking for new hints to improve the response to therapy while reducing the risk of relapse. In this scenario, the gut microbiome and the plethora of microbial-derived metabolites are considered a new opening in the development of innovative anticancer treatments for a better prognosis. This narrative review summarizes the current knowledge on the role of the gut microbiome in the onset and progression of cancer, as well as in response to chemo-immunotherapy. Recent findings regarding the tumor microbiome and its implications for clinical practice are also commented on. Current microbiome-based intervention strategies (i.e., prebiotics, probiotics, live biotherapeutics and fecal microbiota transplantation) are then discussed, along with key shortcomings, including a lack of long-term safety information in patients who are already severely compromised by standard treatments. The implementation of bioinformatic tools applied to microbiomics and other omics data, such as machine learning, has an enormous potential to push research in the field, enabling the prediction of health risk and therapeutic outcomes, for a truly personalized precision medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antibiotic resistance (AR) is indisputably a major health threat which has drawn much attention in recent years. In particular, the gut microbiome has been shown to act as a pool of AR genes, potentially available to be transferred to opportunistic pathogens. Herein, we investigated for the first time changes in the human gut resistome during aging, up to extreme longevity, by analyzing shotgun metagenomics data of fecal samples from a geographically defined cohort of 62 urban individuals, stratified into four age groups: young adults, elderly, centenarians, and semisupercentenarians, i.e., individuals aged up to 109 years. According to our findings, some AR genes are similarly represented in all subjects regardless of age, potentially forming part of the core resistome. Interestingly, aging was found to be associated with a higher burden of some AR genes, including especially proteobacterial genes encoding multidrug efflux pumps. Our results warn of possible health implications and pave the way for further investigations aimed at containing AR accumulation, with the ultimate goal of promoting healthy aging. IMPORTANCE Antibiotic resistance is widespread among different ecosystems, and in humans it plays a key role in shaping the composition of the gut microbiota, enhancing the ecological fitness of certain bacterial populations when exposed to antibiotics. A considerable component of the definition of healthy aging and longevity is associated with the structure of the gut microbiota, and, in this regard, the presence of antibiotic-resistant bacteria is critical to many pathologies that come about with aging. However, the structure of the resistome has not yet been sufficiently elucidated. Here, we show distinct antibiotic resistance assets and specific microbial consortia characterizing the human gut resistome through aging.

Malaria is one of the most impacting public health problems in tropical and subtropical areas of the globe, with approximately 200 million cases worldwide annually. In the absence of an effective vaccine, rapid treatment is vital for effective malaria control. However, parasite resistance to currently available drugs underscores the urgent need for identifying new antimalarial therapies with new mechanisms of action. Among potential drug targets for developing new antimalarial candidates, protein kinases are attractive. These enzymes catalyze the phosphorylation of several proteins, thereby regulating a variety of cellular processes and playing crucial roles in the development of all stages of the malaria parasite life cycle. Moreover, the large phylogenetic distance between Plasmodium species and its human host is reflected in marked differences in structure and function of malaria protein kinases between the homologs of both species, indicating that selectivity can be attained. In this review, we describe the functions of the different types of Plasmodium kinases and highlight the main recent advances in the discovery of kinase inhibitors as potential new antimalarial drug candidates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aging is accompanied by physiological changes affecting body composition and functionality, including accumulation of fat mass at the expense of muscle mass, with effects upon morbidity and quality of life. The gut microbiome has recently emerged as a key environmental modifier of human health that can modulate healthy aging and possibly longevity. However, its associations with adiposity in old age are still poorly understood. Here we profiled the gut microbiota in a well-characterized cohort of 201 Italian elderly subjects from the NU-AGE study, by 16S rRNA amplicon sequencing. We then tested for association with body composition from dual-energy X-ray absorptiometry (DXA), with a focus on visceral and subcutaneous adipose tissue. Dietary patterns, serum metabolome and other health-related parameters were also assessed. This study identified distinct compositional structures of the elderly gut microbiota associated with DXA parameters, diet, metabolic profiles and cardio-metabolic risk factors.

The discovery and development of a new drug is a complex, time consuming and costly process that typically takes over 10 years and costs around 1 billion dollars from bench to market. This scenario makes the discovery of novel drugs targeting neglected tropical diseases (NTDs), which afflict in particular people in low-income countries, prohibitive. Despite the intensive use of High-Throughput Screening (HTS) in the past decades, the speed with which new drugs come to the market has remained constant, generating doubts about the efficacy of this approach. Here we review a few of the yeast-based high-throughput approaches that can work synergistically with parasite-based, in vitro, or in silico methods to identify and optimize novel antiparasitic compounds. These yeast-based methods range from HTP screens to identify novel hits against promising parasite kinase targets to the identification of potential antiparasitic kinase inhibitors extracted from databases of yeast chemical genetic screens., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, we characterize the structural variation of the microbiota of Mytilus galloprovincialis at the tissue scale, also exploring the connection with the microbial ecosystem of the surrounding water. Mussels were sampled within a farm located in the North-Western Adriatic Sea and microbiota composition was analyzed in gills, hemolymph, digestive glands, stomach and foot by Next Generation Sequencing marker gene approach. Mussels showed a distinctive microbiota structure, with specific declinations at the tissue level. Indeed, each tissue is characterized by a distinct pattern of dominant families, reflecting a peculiar adaptation to the respective tissue niche. For instance, the microbiota of the digestive gland is characterized by Ruminococcaceae and Lachnospiraceae, being shaped to ferment complex polysaccharides of dietary origin into short-chain fatty acids, well matching the general asset of the animal gut microbiota. Conversely, the gill and hemolymph ecosystems are dominated by marine microorganisms with aerobic oxidative metabolism, consistent with the role played by these tissues as an interface with the external environment. Our findings highlight the putative importance of mussel microbiota for different aspects of host physiology, with ultimate repercussions on mussel health and productivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The gut microbiome of long-lived people display an increasing abundance of subdominant species, as well as a rearrangement in health-associated bacteria, but less is known about microbiome functions. In order to disentangle the contribution of the gut microbiome to the complex trait of human longevity, we here describe the metagenomic change of the human gut microbiome along with aging in subjects with up to extreme longevity, including centenarians (aged 99 to 104 years) and semisupercentenarians (aged 105 to 109 years), i.e., demographically very uncommon subjects who reach the extreme limit of the human life span. According to our findings, the gut microbiome of centenarians and semisupercentenarians is more suited for xenobiotic degradation and shows a rearrangement in metabolic pathways related to carbohydrate, amino acid, and lipid metabolism. Collectively, our data go beyond the relationship between intestinal bacteria and physiological changes that occur with aging by detailing the shifts in the potential metagenomic functions of the gut microbiome of centenarians and semisupercentenarians as a response to progressive dietary and lifestyle modifications. IMPORTANCE The study of longevity may help us understand how human beings can delay or survive the most frequent age-related diseases and morbidities. In this scenario, the gut microbiome has been proposed as one of the variables to monitor and possibly support healthy aging. Indeed, the disruption of host-gut microbiome homeostasis has been associated with inflammation and intestinal permeability as well as a general decline in bone and cognitive health. Here, we performed a metagenomic assessment of fecal samples from semisupercentenarians, i.e., 105 to 109 years old, in comparison to young adults, the elderly, and centenarians, shedding light on the longest compositional and functional trajectory of the human gut microbiome with aging. In addition to providing a fine taxonomic resolution down to the species level, our study emphasizes the progressive age-related increase in degradation pathways of pervasive xenobiotics in Western societies, possibly as a result of a supportive process within the molecular continuum characterizing aging., (Copyright © 2020 Rampelli et al.)

Cells responds to diverse stimuli by changing the levels of specific effector proteins. These changes are usually examined using high throughput RNA sequencing data (RNA-Seq); transcriptional regulation is generally assumed to directly influence protein abundances. However, the correlation between RNA-Seq and proteomics data is in general quite limited owing to differences in protein stability and translational regulation. Here we perform RNA-Seq, ribosome profiling and proteomics analyses in baker's yeast cells grown in rich media and oxidative stress conditions to examine gene expression regulation at various levels. With the exception of a small set of genes involved in the maintenance of the redox state, which are regulated at the transcriptional level, modulation of protein expression is largely driven by changes in the relative ribosome density across conditions. The majority of shifts in mRNA abundance are compensated by changes in the opposite direction in the number of translating ribosomes and are predicted to result in no net change at the protein level. We also identify a subset of mRNAs which is likely to undergo specific translational repression during stress and which includes cell cycle control genes. The study suggests that post-transcriptional buffering of gene expression may be more common than previously anticipated.