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OBJECTIVE: Kidney failure increases in-hospital mortality (IHM); however, comorbidity is crucial for predicting mortality in dialysis patients. Our aim was to evaluate the impact of comorbidity, assessed by modified Elixhauser index (mEI), Charlson Comorbidity Index (CCI), and age-adjusted CCI, on IHM in a cohort of peritoneal dialysis patients admitted to hospitals of the Emilia Romagna region (ERR) of Italy. PATIENTS AND METHODS: All hospital admissions of peritoneal dialysis patients recorded between 2007 and 2021 in the ERR database were analyzed. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9- CM) was used for detecting diagnoses and procedures, and the inclusion criterion was code 5498. Comorbidity burden was evaluated by three different scores, and hemodialysis (HD) treatment need was considered. IHM was our outcome. RESULTS: During the 15 years of the study, 3,242 hospitalized peritoneal dialysis patients (62.7% males) were evaluated. Mean age was 62.8±20.6 years, 9.6% underwent HD, and IHM was 5.9% (n=192). IHM mortality was stable throughout the study period. Deceased subjects were older, were hospitalized longer, had a higher comorbidity burden, and had a higher percentage of HD treatment needs than survivors. Age, male sex, comorbidity burden, and HD treatment were predictors of IHM. Receiver operating characteristics (ROC) analysis confirmed the impact of comorbidity burden on IHM, especially when age was considered. CONCLUSIONS: We conclude that in male, elderly hospitalized peritoneal dialysis patients with failing dialysis technique, comorbidity burden should be considered being a predictor of IHM. [ABSTRACT FROM AUTHOR]

Abstract: Migrants have accounted for more than 40% of new HIV diagnoses in Europe in 2022. Among the population of asylum seekers currently present in the Trento Province, screening for HIV infection is poorly carried out for various reasons. Here we report our experience about screening for HIV infection in asylum seekers present in that area using rapid self HIV-testing.

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

Background: Telemedicine has been widely used to deliver healthcare to outpatients during the COVID-19 pandemic. The effectiveness of this modality is unclear in patients with a pre-dialysis stage of chronic kidney disease (CKD). This study aims to describe the clinical characteristics and management of CKD patients receiving telemedicine care during the COVID-19 pandemic., Materials and Methods: A retrospective single-center cohort study enrolled outpatients with pre-dialytic stage of CKD from March 9 to June 21, 2020. Telemedicine was proposed for all patients with a stable CKD to reduce the risk of in-hospital transmission whereas in-person visit was performed for patients requiring urgent evaluation., Results: In a 15-week period, 97 patients received 116 nephrological visits. According to the modality of healthcare delivery, the patients were subdivided into telemedicine (66%) and in-person visit (34%) groups. Mean age of all CKD patients was 72.8 ± 12.5 years and males were 50.5% of the population. The average estimated glomerular filtration rate (eGFR) was 14.6 ± 6 mL/min. Patients evaluated by telemedicine had better kidney function (GFR, 16.2 ± 6.4 vs. 13.6 ± 5.9 mL/min/1.73m 2 ; p = 0.037), a lower body mass index (BMI) (24.1 ± 1.7 vs. 30.6 ± 5.7; p = 0.019), and a lower risk of CKD progression (51.1 vs. 25.4%, p = 0.017) than patients requiring in-person visit. Telemedicine-visit patients experienced a significantly lower number of pharmacological changes than patients managed in the ambulatory setting. Telemedicine was also used to conduct 20% of educational meetings on the choice of dialysis modality and 18.9% of pre-eligibility visits for kidney transplantation., Conclusion: Telemedicine made it possible to provide care to and maintain close monitoring of 2/3 of patients with pre-dialytic stage of CKD during the COVID-19 pandemic.

Objective: Exosomes are extracellular vesicles found in saliva and other body fluids. These vesicles range in size from 30 to 150 nm and play a crucial role in intercellular communication, transporting different biomolecules, actively targeting cells. These vesicles regulate both physiological and pathological processes within recipient cells. MicroRNAs (miRs) are transported within exosomes and are delivered to target cells where they influence signaling pathways, taking on a crucial regulatory role in oncogenesis; for example, they are implicated in progression and infiltration of various cancers, such as head and neck squamous cell carcinoma (HNSCC)., Material and Methods: A systematic literature search based on specific keywords, according to the PRISMA guidelines, was carried out on PubMed, Web of Science, Scopus, and Google Scholar. Only original articles were selected during this review. The risk of bias was assessed by QUADAS-2., Results: At the end of the selection process 9 articles were included. In these studies, 41 miRs showed differential expression between healthy subjects and patient with HNSCC. The techniques varied among studies for the extraction and analysis of exosomal miRs. We presented also salivary exosomal miRs pathways, to give insights about pathogenetic mechanisms., Conclusions: Exosomal microRNA are promising biomarkers for HNSCC detection. MiR-10b-5p, miR-486-5p, miR-24-3p, miR-412-3p, and miR-512-3p are the most promising markers applicable to diagnostics, while miR-1307-5p and miR-519c-3p resulted overexpressed and correlated to worse survival outcomes., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Herein, we investigated the toxicity and membrane-permeabilizing capabilities of Lpt and Lpt-like peptides, belonging to type I toxin-antitoxin systems carried by plasmid DNA of Lacticaseibacillus strains. These 29 amino acid peptides are predicted to form α-helical structures with a conserved central hydrophobic sequence and differently charged hydrophilic termini. Like Lpt, the expression of Lpt-like in E. coli induced growth arrest, nucleoid condensation, and cell membrane damage, suggesting membrane interaction as the mode of action. The membrane permeabilization activity of both peptides was evaluated by using liposome leakage assays, dynamic light scattering, and CD spectroscopy. Lpt and Lpt-like showed liposome leakage activity, which did not lead to liposome disruption but depended on peptide concentration. Lpt was generally more effective than Lpt-like, probably due to different physical chemical properties. Leakage was significantly reduced in larger liposomes and increased with negatively charged PCPS liposomes, indicating that electrostatic interactions and membrane curvature influence peptide activity. Contrary to most membrane-active peptides, Lpt an Lpt-like progressively lost their α-helical structure upon interaction with liposomes. Our data are inconsistent with the formation of membrane-spanning peptide pores but support a mechanism relying on the transient failure of the membrane permeability barrier possibly through the formation of "lipid pores".

Background: Disseminated non-tuberculous mycobacteria (dNTM) infections are mostly reported among individuals with an underlying congenital or acquired immunodeficiency or receiving immunosuppressive treatment, but are rarely documented in otherwise healthy subjects., Case Presentation: We describe a case of recurrent disseminated mycobacterial infection in an apparently immunocompetent Chinese woman. Mycobacterium szulgai and Mycobacterium avium-complex were identified in distinct episodes. Long-term antimycobacterial therapy was administered given the occurrence of recurrent events when off-treatment. Successful management over more than 10 years and immunologic data are reported., Conclusions: This case-report highlights that dNTM should be suspected also among apparently immunocompetent hosts and that thorough assessment of underling immune-impairments is helpful to define patients' management. Long-term antimycobacterial therapy and close monitoring is required to grant successful outcomes in case of recurrent dNTM infections., (© 2024. The Author(s).)

Identifying biological factors which contribute to the clinical progression of heterogeneous motor and non-motor phenotypes in Parkinson's disease may help to better understand the disease process. Several lipid-related genetic risk factors for Parkinson's disease have been identified, and the serum lipid signature of Parkinson's disease patients is significantly distinguishable from controls. However, the extent to which lipid profiles are associated with clinical outcomes remains unclear. Untargeted high-performance liquid chromatography-tandem mass spectrometry identified >900 serum lipids in Parkinson's disease subjects at baseline (n = 122), and the potential for machine learning models using these lipids to predict motor and non-motor clinical scores after 2 years (n = 67) was assessed. Machine learning models performed best when baseline serum lipids were used to predict the 2-year future Unified Parkinson's disease rating scale part three (UPDRS III) and Geriatric Depression Scale scores (both normalised root mean square error = 0.7). Feature analysis of machine learning models indicated that species of lysophosphatidylethanolamine, phosphatidylcholine, platelet-activating factor, sphingomyelin, diacylglycerol and triacylglycerol were top predictors of both motor and non-motor scores. Serum lipids were overall more important predictors of clinical outcomes than subject sex, age and mutation status of the Parkinson's disease risk gene LRRK2. Furthermore, lipids were found to better predict clinical scales than a panel of 27 serum cytokines previously measured in this cohort (The Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium). These results suggest that lipid changes may be associated with clinical phenotypes in Parkinson's disease., (© 2024. The Author(s).)

A novel approach using diffusive gradients in thin films (DGT) with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) for two-dimensional mapping of elemental solute release at sub-picogram levels during aqueous corrosion of Al alloys is presented. Evaluation of different DGT gels with mixed micro-sized binding phases (polyacrylamide-Chelex-Metsorb, polyurethane (PU)-Chelex-Metsorb, PU-Chelex-Zr(OH) 4 ) demonstrated the superior performance of PU gels due to their tear-proof handling, low shrinkage, and compliance with green chemistry. DGT devices containing PU-Chelex-Zr(OH) 4 gels, which have not been characterized for Al sampling before, showed quantitative uptake of Al, Zn, and Cu solutes over time (t = 4-48 h) with higher Al capacity (Γ DGT  = 6.25 µg cm -2 ) than different gels. Application of PU-Chelex-Zr(OH) 4 gels on a high-strength Al-Cu alloy (Al2219) exposed to NaCl (w = 1.5%, pH = 4.5, T = 21 °C) for 15 min in a novel piston-type configuration revealed reproducible patterns of Al and Zn co-solubilization with a spatial expansion ranging between 50 and 1000 µm. This observation, together with complementary solid-state data from secondary electron microscopy with energy-dispersive X-ray spectroscopy, showed the presence of localized pitting corrosion at the material surface. Detection limits for total solute masses of Al, Zn, and Cu were ≤0.72 pg, ≤8.38 pg, and ≤0.12 pg, respectively, for an area of 0.01 mm 2 , demonstrating the method's unique capability to localize and quantify corrosion processes at ultra-trace levels and high resolution. Our study advances the assessment of Al alloy degradation in aqueous environments, supporting the design of corrosion-resistant materials for fostering technological safety and sustainability., (© 2024. The Author(s).)

Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 μg/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume ( P  = .0028), Trabecular Number ( P  = .0076), Trabecular Fractal Dimension ( P  = .0044), and increasing Trabecular Separation ( P  = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot., Competing Interests: All the authors declare that there is no conflict of interest regarding the publication of this work. All authors read and approved the final version of the submitted manuscript and consent to be responsible for all aspects of the research. They ensure that all questions related to the integrity or accuracy of the research are properly explored and solved., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Nontuberculous mycobacteria are a rare but still emerging cause of difficult-to-treat prosthetic joint infection. To our knowledge only 17 cases of M. abscessus complex prosthetic joint infection are reported in literature, of which only 1 is by M. abscessus subps. abscessus . No guidelines are available for this clinical scenario. We describe a 68-years-old female patient with an early-onset M. abscessus subsp. abscessus prosthetic joint infection, successfully treated with a tailored medical-surgical strategy, and present an overview of cases currently available in the literature to assist physicians in the management of these uncommon infections., Competing Interests: 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., (© 2024 The Authors.)

Menthyl ester of valine (MV) has been developed as a plant defense potentiator to induce pest resistance in crops. In this study, we attempted to establish MV hydrochloride (MV-HCl) in lettuce and tomato crops. When MV-HCl solutions were used to treat soil or leaves of potted tomato and lettuce plants, 1 µM MV-HCl solution applied to potted plant soil was most effective in increasing the transcript level of defense genes such as pathogenesis-related 1 ( PR1 ). As a result, leaf damage caused by Spodoptera litura and oviposition by Tetranychus urticae were significantly reduced. In addition, MV-HCl-treated plants showed an increased ability to attract Phytoseiulus persimilis , a predatory mite of T. urticae , when they were attacked by T. urticae . Overall, our findings showed that MV-HCl is likely to be effective in promoting not only direct defense by activating defense genes, but also indirect defense mediated by herbivore-induced plant volatiles. Moreover, based on the results of the sustainability of PR1 expression in tomato plants treated with MV-HCl every 3 days, field trials were conducted and showed a 70% reduction in natural leaf damage. Our results suggest a practical approach to promoting organic tomato and lettuce production using this new plant defense potentiator.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non- Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole ( n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction ( n = 2), 3.25 (0.0013, 12.76) in consolidation ( n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy ( n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim).

Calcium signaling is critical for successful fertilization. In spermatozoa, calcium influx into the sperm flagella mediated by the sperm-specific CatSper calcium channel is necessary for hyperactivated motility and male fertility. CatSper is a macromolecular complex and is repeatedly arranged in zigzag rows within four linear nanodomains along the sperm flagella. Here, we report that the Tmem249 -encoded transmembrane (TM) domain-containing protein, CATSPERθ is essential for the CatSper channel assembly during sperm tail formation. CATSPERθ facilitates the channel assembly by serving as a scaffold for a pore-forming subunit CATSPER4. CATSPERθ is specifically localized at the interface of a CatSper dimer and can self-interact, suggesting its potential role in CatSper dimer formation. Male mice lacking CATSPERθ are infertile because the sperm lack the entire CatSper channel from sperm flagella, rendering sperm unable to hyperactivate, regardless of their normal expression in the testis. In contrast, genetic abrogation of any of the other CatSper TM subunits results in loss of CATSPERθ protein in the spermatid cells during spermatogenesis. CATSPERθ might act as a checkpoint for the properly assembled CatSper channel complex to traffic to sperm flagella. This study provides insights into the CatSper channel assembly and elucidates the physiological role of CATSPERθ in sperm motility and male fertility.

Uric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that the Gallus gallus gene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property that we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with the transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with β-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

To avoid hydrogen flaking in rail production, it is of crucial importance to understand the differences in hydrogen diffusion and trapping between different production steps. Therefore, as-cast unfinished material was compared with two finished rails, hot-rolled and head-hardened, using electron backscattered diffraction (EBSD), electrochemical permeation, and thermal desorption spectroscopy (TDS). A significant increase in dislocation density was in the head-hardened rail compared with the other material states. This leads to an effective hydrogen diffusion coefficient of 5.8 × 10 -7 cm 2 /s which is lower by a factor of four than the diffusion coefficients examined in the other states. Thermal desorption spectroscopy analyses show a clear difference between unfinished and finished rail materials. While a peak in activation energy between 32 and 38 kJ/mol is present at all states, only as-cast unfinished material shows a second peak with an activation energy of 47 kJ/mol, which is related to microvoids. The results show that in the investigated material, the effect of increasing dislocation density has a stronger influence on the effective diffusion coefficient than the presence of a second active trapping site.

Background: Redox signaling and energy metabolism are known to be involved in controlling the balance between self-renewal and proliferation/differentiation of stem cells. In this study we investigated metabolic and redox changes occurring during in vitro human dental pulp stem cells (hDPSCs) osteoblastic (OB) differentiation and tested on them the impact of the reactive oxygen species (ROS) signaling., Methods: hDPSCs were isolated from dental pulp and subjected to alkaline phosphatase and alizarin red staining, q-RT-PCR, and western blotting analysis of differentiation markers to assess achievement of osteogenic/odontogenic differentiation. Moreover, a combination of metabolic flux analysis and confocal cyto-imaging was used to profile the metabolic phenotype and to evaluate the redox tone of hDPSCs., Results: In differentiating hDPSCs we observed the down-regulation of the mitochondrial respiratory chain complexes expression since the early phase of the process, confirmed by metabolic flux analysis, and a reduction of the basal intracellular peroxide level in its later phase. In addition, dampened glycolysis was observed, thereby indicating a lower energy-generating phenotype in differentiating hDPSCs. Treatment with the ROS scavenger Trolox, applied in the early-middle phases of the process, markedly delayed OB differentiation of hDPSCs assessed as ALP activity, Runx2 expression, mineralization capacity, expression of stemness and osteoblast marker genes (Nanog, Lin28, Dspp, Ocn) and activation of ERK1/2. In addition, the antioxidant partly prevented the inhibitory effect on cell metabolism observed following osteogenic induction., Conclusions: Altogether these results provided evidence that redox signaling, likely mediated by peroxide species, influenced the stepwise osteogenic expansion/differentiation of hDPSCs and contributed to shape its accompanying metabolic phenotype changes thus improving their efficiency in bone regeneration and repair., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Shorter and more effective treatment regimens as well as new drugs are urgent priorities for reducing the immense global burden of tuberculosis (TB). As treatment of TB currently requires multiple antibiotics with diverse mechanisms of action, any new drug lead requires assessment of potential interactions with existing TB antibiotics. We previously described the discovery of wollamides, a new class of Streptomyces -derived cyclic hexapeptides with antimycobacterial activity. To further assess the value of the wollamide pharmacophore as an antimycobacterial lead, we determined wollamide interactions with first- and second-line TB antibiotics by determining fractional inhibitory combination index and zero interaction potency scores. In vitro two-way and multiway interaction analyses revealed that wollamide B1 synergizes with ethambutol, pretomanid, delamanid, and para-aminosalicylic acid in inhibiting the replication and promoting the killing of phylogenetically diverse clinical and reference strains of the Mycobacterium tuberculosis complex (MTBC). Wollamide B1 antimycobacterial activity was not compromised in multi- and extensively drug-resistant MTBC strains. Moreover, growth-inhibitory antimycobacterial activity of the combination of bedaquiline/pretomanid/linezolid was further enhanced by wollamide B1, and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination. Collectively, these findings add new dimensions to the desirable characteristics of the wollamide pharmacophore as an antimycobacterial lead compound. IMPORTANCE Tuberculosis (TB) is an infectious disease that affects millions of people globally, with 1.6 million deaths annually. TB treatment requires combinations of multiple different antibiotics for many months, and toxic side effects can occur. Therefore, shorter, safer, more effective TB therapies are required, and these should ideally also be effective against drug-resistant strains of the bacteria that cause TB. This study shows that wollamide B1, a chemically optimized member of a new class of antibacterial compounds, inhibits the growth of drug-sensitive as well as multidrug-resistant Mycobacterium tuberculosis isolated from TB patients. In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics, including complex drug combinations that are currently used for TB treatment. These new insights expand the catalogue of the desirable characteristics of wollamide B1 as an antimycobacterial lead compound that might inspire the development of improved TB treatments., Competing Interests: The authors declare no conflict of interest.

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration.

Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4 , one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation.

Statement of Problem: The buccal bone in an edentulous maxilla loses thickness over time because of physiological changes. However, the dimensional changes of the buccal bone in an edentulous maxilla with an implant-supported fixed dental prosthesis are unknown., Purpose: The purpose of this retrospective clinical study was to evaluate cone beam computed tomography (CBCT) images of the dimensional changes of the buccal bone in edentulous maxillae with complete arch telescopic-retained implant-supported fixed dental prostheses (CTI-FDPs) after 6 years by using a professional retrieval system., Material and Methods: This study included 17 participants with edentulous maxillae who had been provided with CTI-FDP with 121 taper joint implants. A three-dimensional radiographic analysis by using CBCT was performed at implant insertion (0 years) and after 6 years. Vertical and horizontal bone measurement values were evaluated. During horizontal bone thickness measurement, 4 different levels, 0, 2, 4, and 6 mm apical to the implant shoulder, were evaluated as bone value (BV) 0mm , BV 2mm , BV 4mm , and BV 6mm , respectively. The BVs were compared with the Wilcoxon signed-rank test and Kruskal-Wallis test (α=.05). In addition, the Spearman rank correlation coefficient was used to identify 0yBV factors that influence the 6yBVs. A nonlinear regression analysis was used to clarify the slopes of 0yBVs and 6yBV 0mm ., Results: Significant decreases in vertical and horizontal BVs were found between 0 years and 6 years (P<.05). However, no significant difference was observed in bone loss at 6 years at any of the vertical and horizontal measurement points (P≥.05). When 0yBVs related to 6yBV 0mm were analyzed, 0yBV 0mm and 0yBV 2mm showed strong correlations with 6yBV 0mm (|r|≥.7). In the regression analysis, a 0yBV 0mm of 0.58 mm and 0yBV 2mm of 0.78 mm could be critical factors associated with a 6yBV 0mm of 0 mm. A 6yBV 0mm of 0yBV 0mm more than 0.58 mm was significantly higher than a 6yBV 0mm of 0yBV 0mm less than 0.58 mm (P<.001). Moreover, a 6yBV 0mm of 0yBV 2mm more than 0.78 mm was significantly higher than a 6yBV 0mm of 0yBV 2mm less than 0.78 mm (P<.001)., Conclusions: The buccal bone in an edentulous maxilla with fixed implant-supported prostheses lost significant vertical and horizontal bone thicknesses after 6 years. At implant insertion, both a 0.58-mm buccal bone on the platform and a 0.78-mm buccal bone at 2 mm apical to the implant shoulder are necessary for longer term maintenance of bone on the platform of implants specifically supporting CTI-FDPs., (Copyright © 2021 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

As a result of physical exercise, muscle releases multiple exerkines, such as "irisin", which is thought to induce pro-cognitive and antidepressant effects. We recently demonstrated in young healthy mice the mitigation of depressive behaviors induced by consecutive 5 day irisin administration. To understand which molecular mechanisms might be involved in such effect, we here studied, in a group of mice previously submitted to a behavioral test of depression, the gene expression of neurotrophins and cytokines in the hippocampus and prefrontal cortex (PFC), two brain areas frequently investigated in the depression pathogenesis. We found significantly increased mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 2 (FGF-2) in the hippocampus and brain-derived growth factor (BDNF) in the PFC. We did not detect a difference in the mRNA levels of interleukin 6 (IL-6) and IL-1β in both brain regions. Except for BDNF in the PFC, two-way ANOVA analysis did not reveal sex differences in the expression of the tested genes. Overall, our data evidenced a site-specific cerebral modulation of neurotrophins induced by irisin treatment in the hippocampus and the PFC, contributing to the search for new antidepressant treatments targeted at single depressive events with short-term protocols.

Breeding fruit species is time-consuming and expensive. With few exceptions, trees are likely the worst species to work with in terms of genetics and breeding. Most are characterized by large trees, long juvenile periods, and intensive agricultural practice, and environmental variability plays an important role in the heritability evaluations of every single important trait. Although vegetative propagation allows for the production of a significant number of clonal replicates for the evaluation of environmental effects and genotype × environment interactions, the spaces required for plant cultivation and the intensity of work necessary for phenotypic surveys slow down the work of researchers. Fruit breeders are very often interested in fruit traits: size, weight, sugar and acid content, ripening time, fruit storability, and post-harvest practices, among other traits relevant to each individual species. The translation of trait loci and whole-genome sequences into diagnostic genetic markers that are effective and affordable for use by breeders, who must choose genetically superior parents and subsequently choose genetically superior individuals among their progeny, is one of the most difficult tasks still facing tree fruit geneticists. The availability of updated sequencing techniques and powerful software tools offered the opportunity to mine tens of fruit genomes to find out sequence variants potentially useful as molecular markers. This review is devoted to analysing what has been the role of molecular markers in assisting breeders in selection processes, with an emphasis on the fruit traits of the most important fruit crops for which examples of trustworthy molecular markers have been developed, such as the MDo.chr9.4 marker for red skin colour in apples, the CCD4 -based marker CPRFC1, and LG3&#95;13.146 marker for flesh colour in peaches, papayas, and cherries, respectively.

Limnospira fusiformis (also known as Spirulina) is a cyanobacterium that is widely cultivated due to its economic importance. It has specific pigments such as phycocyanin that allow it to grow at different light wavelengths compared to other cultivated algae. Our study investigated the effect of yellow (590 nm) and blue (460 nm) light fields on various biochemical features, including the pigment concentration, protein content, dry weight, and cell ultrastructure of L. fusiformis . Our findings revealed that biomass growth was faster in yellow light compared to blue light, with a higher relative amount of proteins even after one day of exposure. However, after eight days, the relative protein content in yellow versus blue light was not statistically different. Furthermore, in yellow light, we observed a decrease in chlorophyll a , an increase in cyanophycin granules, and an increase in the amount of dilated thylakoids. On the other hand, in blue light, there was an increase in phycocyanin after one day, along with an increase in electron-dense bodies, which are attributable to carboxysomes. However, after eight days, the differences in pigment content compared to the control were not statistically significant. Our study showed that using specific wavelengths during the harvesting phase of spirulina growth can enhance phycocyanin content with blue light (after one day) and biomass, growth rates, and protein content with yellow light after six days. This highlights the biotechnological potential of this approach.

Granulomas are key histopathological features of Mycobacterium tuberculosis (Mtb) infection, with complex roles in pathogen control and dissemination. Thus, understanding drivers and regulators of granuloma formation is important for improving tuberculosis diagnosis, treatment, and prevention. Yet, molecular mechanisms underpinning granuloma formation and dynamics remain poorly understood. Here we used low-dose Mtb infection of C57BL/6 mice, which elicits structured lung granulomas composed of central macrophage clusters encased by a lymphocyte mantle, alongside the disorganized lymphocyte and macrophage clusters commonly observed in Mtb-infected mice. Using gene-deficient mice, we observed that Toll-like receptor (TLR) 2 and the TLR-related Radioprotective 105 kDa protein (RP105) contributed to the extent and spatial positioning of pathology in infected lung tissues, consistent with functional cooperation between TLR2 and RP105 in the innate immune recognition of Mtb. In mice infected with the highly virulent Mtb clinical isolate HN878, TLR2, but not RP105, positively regulated the extent of central macrophage regions within structured granulomas. Moreover, RP105, but not TLR2, promoted the formation of structured lung granulomas, suggesting that the functions of RP105 as an innate immune sensor for Mtb reach beyond its roles as TLR2 co-receptor. TLR2 and RP105 contributions to lung pathology are governed by Mtb biology, as neither receptor affected the frequency or architecture of structured granulomas in mice infected with the reference strain Mtb H37Rv. Thus, by revealing distinctive as well as cooperative functions of TLR2 and RP105 in lung pathology, our data identify TLRs as molecular determinants of TB granuloma formation and architecture, and expand understanding of how interactions between innate immune receptors and Mtb shape TB disease manifestation., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)

Coevolution at the gene level, as reflected by correlated events of gene loss or gain, can be revealed by phylogenetic profile analysis. The optimal method and metric for comparing phylogenetic profiles, especially in eukaryotic genomes, are not yet established. Here, we describe a procedure suitable for large-scale analysis, which can reveal coevolution based on the assessment of the statistical significance of correlated presence/absence transitions between gene pairs. This metric can identify coevolution in profiles with low overall similarities and is not affected by similarities lacking coevolutionary information. We applied the procedure to a large collection of 60,912 orthologous gene groups (orthogroups) in 1,264 eukaryotic genomes extracted from OrthoDB. We found significant cotransition scores for 7,825 orthogroups associated in 2,401 coevolving modules linking known and unknown genes in protein complexes and biological pathways. To demonstrate the ability of the method to predict hidden gene associations, we validated through experiments the involvement of vertebrate malate synthase-like genes in the conversion of ( S )-ureidoglycolate into glyoxylate and urea, the last step of purine catabolism. This identification explains the presence of glyoxylate cycle genes in metazoa and suggests an anaplerotic role of purine degradation in early eukaryotes.

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders.

Background: Although discontinuation of antiplatelet agents at least 5 days before kidney biopsy is commonly recommended, the evidence behind this practice is of low level. Indeed, few non-randomized studies previously showed an equivalent risk of bleeding in patients receiving aspirin therapy., Methods: We conducted a single center retrospective study comparing the risk of complications after percutaneous native kidney biopsy in patients who received low-dose aspirin (ASA) within 5 days from biopsy and those who did not. The main outcome was the difference in the incidence of major complications (red blood cell transfusion, need for selective arterial embolization, surgery, nephrectomy). Secondary outcomes included difference in minor complications, comparison between patients who received ASA within 48 h or within 3-5 days, identification of independent factors predictive of major complications., Results: We analyzed data on 750 patients, of whom 94 received ASA within 5 days from biopsy. There were no significant differences in the proportion of major complications in patients receiving or not receiving ASA (2.59% and 3.19%, respectively, percentage point difference 1%, 95% CI - 3 to 4%, p = 0.74). Groups were also comparable for minor complications; among patients receiving ASA, there were no differences in major bleeding between those who received ASA within 48 h or 3-5 days from biopsy. Significant baseline predictors of major bleeding in our cohort were platelet count lower than 120*10 3 /microliter, higher diastolic blood pressure and higher blood urea., Conclusions: Treatment with low-dose ASA within 5 days from kidney biopsy did not increase the risk of complications after the procedure., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Irisin is a recently discovered cytokine, better known as an exercise-induced myokine, produced primarily in skeletal muscle tissue as a response to exercise. Although the skeleton was initially identified as the main target of Irisin, its action is also proving effective in many other tissues. Physical activity determines a series of beneficial effects on health, including the possibility of counteracting the damage that is caused by arthritis to the cartilage of people suffering from osteoarthritis. Nevertheless, up to now, the studies that have taken into consideration the possible involvement of Irisin on the well-being of cartilage tissue are particularly limited. In this study, we postulated that the protective effect of physical activity on cartilage tissue may depend on the paracrine action of Irisin secreted during exercise; therefore, we analyzed the effects of Irisin, in vitro, on chondrogenic differentiation. To achieve this goal, three-dimensional cultures of commercially available human articular chondrocytes (HACs) were treated with the molecule under study. Our results revealed new crosstalk mechanisms between muscle and cartilage tissue. Furthermore, the confirmation of Irisin ability to induce chondrogenic differentiation could favor the development of exercise-mimetic drugs, with application relevance for patients who cannot perform physical activity.