UMG1/CD3ε-bispecific T-cell engager redirects T-cell cytotoxicity against diffuse large B-cell lymphoma.

UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non-haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%-24% of diffuse large B-cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow-infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε-bispecific T-cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε-BTCE is a promising therapeutic for DLBCLs.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Prognostic Value of APACHE IV Score in Patients Bridged to Heart Transplantation on ECMO.

BACKGROUND: Methods for risk stratification of candidates for heart transplantation (HTx) supported by extracorporeal membrane oxygenation (ECMO) are limited. We evaluated the reliability of the APACHE IV score to identify the risk of mortality in this patient subset in a multicenter study. METHODS: Between January 2010 and December 2022, 167 consecutive ECMO patients were bridged to HTx; they were divided into two groups, according to a cutoff value of APACHE IV score, obtained by receiver operating characteristic curve analysis for 90-day mortality. Kaplan-Meier survival curves were plotted, and compared through the log-Rank test. Cox regression model was used to estimate which factors were associated with survival. RESULTS: The 90-day mortality prediction of the APACHE IV score showed an area under the curve of 0.87 (95% CI: 0.80-0.94), with a cutoff value of 49 (specificity 91.7%-sensibility 69.6%). 125 patients (74.8%) showed an APACHE IV score value < 49 (Group A), and 42 (25.2%) ≥ 49 (Group B). 90-day mortality was 11.2% in Group A and 76.2% in Group B (p < 0.01). Survival at 1 and 5 years was 85.5%, 77% versus 23.4%, 23.4% (p < 0.01) in Groups A and B. Mortality correlated at univariable analysis with recipient age, body mass index, mechanical ventilation, APACHE IV score, and platelets number. At multivariable analysis only APACHE IV score (HR: 1.07 [1.05-1.09, 95% CI]) independently affected survival. CONCLUSIONS: The APACHE IV score represents a powerful predictor of survival in patients bridged to HTx on ECMO support, and could guide candidacy of patients on ECMO.

Influence of mobility on the long-term risk of tooth extraction/loss in periodontitis patients. A systematic review and meta-analysis.

The aim of this systematic review (SR) was to assess whether tooth mobility (TM) increases the risk of tooth extraction/loss. The protocol was registered in PROSPERO database (CRD42023485425). The focused PECO questions were as follows: (1) "In patients with periodontitis, undergoing periodontal treatment, are teeth affected by mobility at higher risk of being extracted/lost compared to non-mobile teeth, with a minimum follow-up of 10 years?" and (2) "In these patients, does varying degrees of tooth mobility increase the risk of tooth extraction/loss, with a minimum follow-up of 10 years?". Results were reported according to PRISMA statement. Electronic and manual searches were conducted to identify longitudinal studies. The different assessments of tooth mobility were pooled into three groups: TM0: Undetectable tooth mobility, TM1: Horizontal/Mesio-distal mobility ≤1 mm, TM2: Horizontal/Mesio-distal mobility >1 mm or vertical tooth mobility. Tooth loss was the primary outcome. Various meta-analyses were conducted, including subgroup analyses considering different follow-up lengths and the timing of TM assessment, along with sensitivity analyses. A trial sequential analysis was also performed. Eleven studies were included (1883 patients). The mean follow-up range was 10-25 years. The weighted total of included teeth, based on the sample size, was 18 918, with a total of 1604 (8.47%) extracted/lost teeth. The overall rate of tooth extraction/loss increased with increasing mobility: TM0 was associated with a 5.85% rate (866/14822), TM1 with the 11.8% (384/3255), TM2 with the 40.3% (339/841). Mobile teeth (TM1/TM2) were at an increased risk for tooth extraction/loss, compared to TM0 (HR: 2.85; [95% CI 1.88-4.32]; p < .00001). TM1 had a higher risk than TM0 (HR: 1.96; [95% CI 1.09-3.53]; p < .00001). TM2 had a higher risk than TM1 (HR: 2.85; [95% CI 2.19-3.70]; p < .00001) and TM0 (HR: 7.12; [95% CI 3.27-15.51]; p < .00001). The results of the tests for subgroup differences were not significant. Sensitivity meta-analyses yielded consistent results with other meta-analyses. Within the limits of the quality of the studies included in the meta-analyses, mobile teeth were at higher risk of being extracted/lost in the long-term and higher degrees of TM significantly influenced clinicians' decision to extract a tooth. However, most teeth can be retained in the long-term and thus TM should not be considered a reason for extraction or a risk factor for tooth loss, regardless of the degree of TM.

Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers.

The gut epithelium serves to maximize the surface for nutrient and fluid uptake, but at the same time must provide a tight barrier to pathogens and remove damaged intestinal epithelial cells (IECs) without jeopardizing barrier integrity. How the epithelium coordinates these tasks remains a question of significant interest. We used imaging and an optical flow analysis pipeline to study the dynamicity of untransformed murine and human intestinal epithelia, cultured atop flexible hydrogel supports. Infection with the pathogen Salmonella Typhimurium (STm) within minutes elicited focal contractions with inward movements of up to ∼1,000 IECs. Genetics approaches and chimeric epithelial monolayers revealed contractions to be triggered by the NAIP/NLRC4 inflammasome, which sensed type-III secretion system and flagellar ligands upon bacterial invasion, converting the local tissue into a contraction epicenter. Execution of the response required swift sublytic Gasdermin D pore formation, ion fluxes, and the propagation of a myosin contraction pulse across the tissue. Importantly, focal contractions preceded, and could be uncoupled from, the death and expulsion of infected IECs. In both two-dimensional monolayers and three-dimensional enteroids, multiple infection-elicited contractions coalesced to produce shrinkage of the epithelium as a whole. Monolayers deficient for Caspase-1(-11) or Gasdermin D failed to elicit focal contractions but were still capable of infected IEC death and expulsion. Strikingly, these monolayers lost their integrity to a markedly higher extent than wild-type counterparts. We propose that prompt NAIP/NLRC4/Caspase-1/Gasdermin D/myosin-dependent contractions allow the epithelium to densify its cell packing in infected regions, thereby preventing tissue disintegration due to the subsequent IEC death and expulsion process.

Contaminants from dredged sediments alter the transcriptome of Manila clam and induce shifts in microbiota composition.

BACKGROUND: The reuse of dredged sediments in ports and lagoons is a big issue as it should not affect the quality and the equilibrium of ecosystems. In the lagoon of Venice, sediment management is of crucial importance as sediments are often utilized to built-up structures necessary to limit erosion. However, the impact of sediment reuse on organisms inhabiting this delicate area is poorly known. The Manila clam is a filter-feeding species of high economic and ecological value for the Venice lagoon experiencing a drastic decline in the last decades. In order to define the molecular mechanisms behind sediment toxicity, we exposed clams to sediments sampled from different sites within one of the Venice lagoon navigable canals close to the industrial area. Moreover, we investigated the impacts of dredged sediments on clam's microbial communities. RESULTS: Concentrations of the trace elements and organic chemicals showed increasing concentrations from the city of Venice to sites close to the industrial area of Porto Marghera, where PCDD/Fs and PCBs concentrations were up to 120 times higher than the southern lagoon. While bioaccumulation of organic contaminants of industrial origin reflected sediments' chemical concentrations, metal bioaccumulation was not consistent with metal concentrations measured in sediments probably due to the activation of ABC transporters. At the transcriptional level, we found a persistent activation of the mTORC1 signalling pathway, which is central in the coordination of cellular responses to chemical stress. Microbiota characterization showed the over-representation of potential opportunistic pathogens following exposure to the most contaminated sediments, leading to host immune response activation. Despite the limited acquisition of new microbial species from sediments, the latter play an important role in shaping Manila clam microbial communities. CONCLUSIONS: Sediment management in the Venice lagoon will increase in the next years to maintain and create new canals as well as to allow the operation of the new mobile gates at the three Venice lagoon inlets. Our data reveal important transcriptional and microbial changes of Manila clams after exposure to sediments, therefore reuse of dredged sediments represents a potential risk for the conservation of this species and possibly for other organisms inhabiting the Venice lagoon.

Emotions and Narrative Reappraisal Strategies of Users of Breast Cancer Screening: Reconstructing the Past, Passing Through the Present, and Predicting Emotions.

Emotional forecasting, meaning how a person anticipates feeling as a consequence of their choices, drives healthcare decision-making. Research, however, suggests that people often do not fully anticipate or otherwise grasp the future emotional impacts of their decisions. Emotional reappraisal strategies, such as putting emotions into words and sharing emotions with others, may mitigate potential undesirable effects of emotions on decision-making. The use of such strategies is important for consequential decisions, such as obtaining timely mammography screening for breast cancer, whereby earlier diagnosis may impact the success of treatment. In this study, we explored the use of emotional reappraisal strategies for decision-making regarding breast cancer screening attendance among women aged 50-69 years. Data were collected through semi-structured interviews following mammography with a reflexive thematic methodological approach employed for analysis. Results shed light on how participants' emotional response narratives were reconstructed before the mammography, felt during the mammography, and forecasted while awaiting the results. Future research should consider how individuals experience and manage their emotions as they access breast screening services.

Extracellular vesicle features are associated with COVID-19 severity.

COVID-19 is heterogeneous; therefore, it is crucial to identify early biomarkers for adverse outcomes. Extracellular vesicles (EV) are involved in the pathophysiology of COVID-19 and have both negative and positive effects. The objective of this study was to identify the potential role of EV in the prognostic stratification of COVID-19 patients. A total of 146 patients with severe or critical COVID-19 were enrolled. Demographic and comorbidity characteristics were collected, together with routine haematology, blood chemistry and lymphocyte subpopulation data. Flow cytometric characterization of the dimensional and antigenic properties of COVID-19 patients' plasma EVs was conducted. Elastic net logistic regression with cross-validation was employed to identify the best model for classifying critically ill patients. Features of smaller EVs (i.e. the fraction of EVs smaller than 200 nm expressing either cluster of differentiation [CD] 31, CD 140b or CD 42b), albuminemia and the percentage of monocytes expressing human leukocyte antigen DR (HLA-DR) were associated with a better outcome. Conversely, the proportion of larger EVs expressing N-cadherin, CD 34, CD 56, CD31 or CD 45, interleukin 6, red cell width distribution (RDW), N-terminal pro-brain natriuretic peptide (NT-proBNP), age, procalcitonin, Charlson Comorbidity Index and pro-adrenomedullin were associated with disease severity. Therefore, the simultaneous assessment of EV dimensions and their antigenic properties complements laboratory workup and helps in patient stratification.

A motile doublet form of Salmonella Typhimurium diversifies target search behavior at the epithelial surface.

The behaviors of infectious bacteria are commonly studied in bulk. This is effective to define the general properties of a given isolate, but insufficient to resolve subpopulations and unique single-microbe behaviors within the bacterial pool. We here employ microscopy to study single-bacterium characteristics among Salmonella enterica serovar Typhimurium (S.Tm), as they prepare for and launch invasion of epithelial host cells. We find that during the bacterial growth cycle, S.Tm populations switch gradually from fast planktonic growth to a host cell-invasive phenotype, characterized by flagellar motility and expression of the Type-three-secretion-system-1. The indistinct nature of this shift leads to the establishment of a transient subpopulation of S.Tm "doublets"-waist-bearing bacteria anticipating cell division-which simultaneously express host cell invasion machinery. In epithelial cell culture infections, these S.Tm doublets outperform their "singlet" brethren and represent a hyperinvasive subpopulation. Atop both glass and enteroid-derived monolayers, doublets swim along markedly straighter trajectories than singlets, thereby diversifying search patterns and improving the surface exploration capacity of the total bacterial population. The straighter swimming, combined with an enhanced cell-adhesion propensity, suffices to account for the hyperinvasive doublet phenotype. This work highlights bacterial cell length heterogeneity as a key determinant of target search patterns atop epithelia.

A Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) for ovarian cancer.

BACKGROUND: Pronectins™ are a new class of fibronectin-3-domain 14th-derived (14Fn3) antibody mimics that can be engineered as bispecific T cell engager (BTCE) to redirect immune effector cells against cancer. We describe here the in vitro and in vivo activity of a Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) against Epithelial Ovarian Cancer (EOC). METHODS: pAXLxCD3ε T-cell mediated cytotoxicity was evaluated by flow cytometry and bioluminescence. pAXLxCD3ε mediated T-cell infiltration, activation and proliferation were assessed by immunofluorescence microscopy and by flow cytometry. Activity of pAXLxCD3ε was also investigated in combination with poly-ADP ribose polymerase inhibitors (PARPi). In vivo antitumor activity of pAXLxCD3ε was evaluated in immunocompromised (NSG) mice bearing intraperitoneal or subcutaneous EOC xenografts and immunologically reconstituted with human peripheral blood mononuclear cells (PBMC). RESULTS: pAXLxCD3ε induced dose-dependent cytotoxicity by activation of T lymphocytes against EOC cells, regardless of their histologic origin. The addition of PARPi to cell cultures enhanced pAXLxCD3ε cytotoxicity. Importantly, in vivo, pAXLxCD3ε was highly effective against EOC xenografts in two different NSG mouse models, by inhibiting the growth of tumor cells in ascites and subcutaneous xenografts. This effect translated into a significantly prolonged survival of treated animals. CONCLUSION: pAXLxCD3ε is an active therapeutics against EOC cells providing a rational for its development as a novel agent in this still incurable disease. The preclinical validation of a first-in-class agent opens the way to the development of a new 14Fn3-based scaffold platform for the generation of innovative immune therapeutics against cancer.

Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia.

Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

Anal incontinence following obstetric anal sphincter injury: Is there a difference between subtypes? A systematic review.

AIMS: Obstetric anal sphincter injury (OASI) is associated with long-term anal incontinence (AI). We aimed to address the following questions: (a) are women with major OASI (grade 3c and 4) at higher risk of developing AI when compared to women with minor OASI (grade 3a and 3b)? (b) is a fourth-degree tear more likely to cause AI over a third-degree tear? METHODS: A systematic literature search from inception until September 2022. We considered prospective and retrospective cohort studies, cross-sectional and case-control studies without language restrictions. The quality was assessed by the Newcastle-Ottawa Scale and the Joanna Briggs Institute critical appraisal checklist. Risk ratios (RRs) were calculated to measure the effect of different grades of OASI. RESULTS: Out of 22 studies, 8 were prospective cohort, 8 were retrospective cohort, and 6 were cross-sectional studies. Length of follow-up ranged from 1 month to 23 years, with the majority of the reports (n = 16) analysing data within 12-months postpartum. Third-degree tears evaluated were 6454 versus 764 fourth-degree tears. The risk of bias was low in 3, medium in 14 and high in 5 studies, respectively. Prospective studies showed that major tears are associated with a twofold risk of AI for major tears versus minor tears, while retrospective studies consistently showed a risk of fecal incontinence (FI) which was two- to fourfold higher. Prospective studies showed a trend toward worsening AI symptoms for fourth-degree tears, but this failed to reach statistical significance. Cross-sectional studies with long-term (≥5 years) follow-up showed that women with fourth-degree tear were more likely to develop AI, with an RR ranging from 1.4 to 2.2. Out of 3, 2 retrospective studies showed similar findings, but the follow-up was significantly shorter (≤1 year). Contrasting results were noted for FI rates, as only 5 out of 10 studies supported an association between fourth-degree tear and FI. CONCLUSIONS: Most studies investigate bowel symptoms within few months from delivery. Data heterogeneity hindered a meaningful synthesis. Prospective cohort studies with adequate power and long-term follow-up should be performed to evaluate the risk of AI for each OASI subtype.

Stem Cells mobilization and collection in allogeneic related and unrelated donors: a single center experience with focus on plerixafor.

INTRODUCTION: Poor CD34 + cells mobilization in allogeneic donors could affect transplant outcome. In a subgroup of patient mobilization with granulocyte colony-stimulating factor (G-CSF) alone is unsatisfactory, and Plerixafor could be used to enhance CD34 + cells release from bone marrow niche. MATERIALS AND METHODS: We conducted a retrospective single-center, cohort study on healthy allogeneic donors both related and unrelated, treated by Udine Transfusion Center over the last 10 years (2012-2022). In the 195 allogeneic donors treated we analyzed age, sex, body weight, BMI, comorbidities, G-CSF dosage and even baseline white blood cell count as possible predictor of insufficient CD34 + cells mobilization on day 5. In the subgroup of related donors we evaluated even baseline CD34 + cells (measured before mobilization start). Processed donor blood volume, collection efficiency and apheresis product were examined. Additionally a comparative analysis was conducted between G-CSF alone treated donors and poor mobilizing ones, in which Plerixafor was administered at a dose of 0.24 mg/kg as a pre-emptive or rescue agent. RESULTS: In 9 donors, due to poor mobilization (defined as CD34 + < 20/µL or estimated yield < 1 ×106 kg/recipient body weight), the use of plerixafor was necessary. PLX at a dose of 0.24 mg/kg was administered 5 h before collection, inducing an average increase of 5.1 (1.7-12.6) in CD34 + circulating cells. In this subgroup of patients, BMI and weight were significantly lower (p = 0.03). Interestingly, baseline CD34 + cells (measured before the onset of mobilization) also seems to predict poor mobilization (p = 0.003). In donors additionally treated with Plerixafor compared to those who received G-CSF alone, collection efficiency was higher (p = 0.02) and CD34 + cells collected were comparable (p = 0.2). Side effects related to the administration of plerixafor, if they occurred, were well tolerated. CONCLUSIONS: Plerixafor is a safe and effective drug in the rescue and prevention of poor mobilization. New prospective studies on allogeneic donors should be performed to increase the treatable population to avoid inadequate collection and mobilization. New laboratory predictors such as baseline CD34 + cells should be investigated in larger cohorts and then used as early screening.

The impact of COVID-19 on Italian dentists: A cross-sectional survey on 2443 participants.

OBJECTIVE: To evaluate the impact of COVID-19 pandemic among a sample of Italian dentists in terms of infection, strategies for infection control, organization of the dental clinic, attitude, and behavior. MATERIAL AND METHODS: This was a cross-sectional survey. The sample consisted of 8000 Italian dentists selected among 63,375 using a computerized random sampling method. An electronic informed consent had to be signed. The questionnaire categories were on demographic, infection risk management, organization, and dentists' attitude and behavior. Geographic macro-areas were used for subgroup analysis. RESULTS: Among 8000 invited dentists, 2443 agreed to participate to the survey (30.6%). Mean age was 51.2 years, women were 34.5%. A total of 6.1% self-reported COVID-19 experience and higher rate of infection was reported in north Italy compared to the south (p < 0.05). FFP2/FFP3 respirators (97.1%) and visors (97.4%) were used by almost all dentists. While, natural ventilation and mouthwashes were the most frequent approaches used to reduce the infection risk. Most of the dentists reported positive attitude, nevertheless 83.6% felt an increased responsibility. CONCLUSION: The self-reported COVID-19 prevalence was 6.1% with some differences among geographic areas. COVID 19 had a deep impact on preventive strategies, dental office organization, and behavior within this sample.

Lessons learnt while designing and conducting a longitudinal study from the first Italian COVID-19 pandemic wave up to 3 years.

BACKGROUND: Several scientific contributions have summarized the "lessons learnt" during the coronavirus disease 2019 (COVID-19) pandemic, but only a few authors have discussed what we have learnt on how to design and conduct research during a pandemic. The main intent of this study was to summarize the lessons learnt by an Italian multidisciplinary research group that developed and conducted a longitudinal study on COVID-19 patients infected during the first wave in March 2020 and followed-up for 3 years. METHODS: A qualitative research approach embedded into the primary CORonavirus MOnitoRing study (CORMOR) study was developed, according to the the consolidated criteria for reporting qualitative research. Multiple data collection strategies were performed: each member was invited to report the main lessons learnt according to his/her perspective and experience from the study design throughout its conduction. The narratives collected were summarized and discussed in face-to-face rounds. The narratives were then thematically analysed according to their main topic in a list that was resent to all members to check the content and their organization. The list of the final "lessons learnt" has been agreed by all members, as described in a detailed fashion. RESULTS: Several lessons were learnt while designing and conducting a longitudinal study during the COVID-19 pandemic and summarised into ten main themes: some are methodological, while others concern how to conduct research in pandemics/epidemics/infectious disease emergencies. CONCLUSIONS: The multidisciplinary approach, which also included patients' perspective, helped us to protect the consistency and quality of the research provided in pandemic times. The lesson learnt suggest that our research approach may benefit from changes in education, clinical practice and policies.

Gut microbe Lactiplantibacillus plantarum undergoes different evolutionary trajectories between insects and mammals.

BACKGROUND: Animals form complex symbiotic associations with their gut microbes, whose evolution is determined by an intricate network of host and environmental factors. In many insects, such as Drosophila melanogaster, the microbiome is flexible, environmentally determined, and less diverse than in mammals. In contrast, mammals maintain complex multispecies consortia that are able to colonize and persist in the gastrointestinal tract. Understanding the evolutionary and ecological dynamics of gut microbes in different hosts is challenging. This requires disentangling the ecological factors of selection, determining the timescales over which evolution occurs, and elucidating the architecture of such evolutionary patterns. RESULTS: We employ experimental evolution to track the pace of the evolution of a common gut commensal, Lactiplantibacillus plantarum, within invertebrate (Drosophila melanogaster) and vertebrate (Mus musculus) hosts and their respective diets. We show that in Drosophila, the nutritional environment dictates microbial evolution, while the host benefits L. plantarum growth only over short ecological timescales. By contrast, in a mammalian animal model, L. plantarum evolution results to be divergent between the host intestine and its diet, both phenotypically (i.e., host-evolved populations show higher adaptation to the host intestinal environment) and genomically. Here, both the emergence of hypermutators and the high persistence of mutated genes within the host's environment strongly differed from the low variation observed in the host's nutritional environment alone. CONCLUSIONS: Our results demonstrate that L. plantarum evolution diverges between insects and mammals. While the symbiosis between Drosophila and L. plantarum is mainly determined by the host diet, in mammals, the host and its intrinsic factors play a critical role in selection and influence both the phenotypic and genomic evolution of its gut microbes, as well as the outcome of their symbiosis.

Hit identification of novel small molecules interfering with MALAT1 triplex by a structure-based virtual screening.

Nowadays, RNA is an attractive target for the design of new small molecules with different pharmacological activities. Among several RNA molecules, long noncoding RNAs (lncRNAs) are extensively reported to be involved in cancer pathogenesis. In particular, the overexpression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in the development of multiple myeloma (MM). Starting from the crystallographic structure of the triple-helical stability element at the 3'-end of MALAT1, we performed a structure-based virtual screening of a large commercial database, previously filtered according to the drug-like properties. After a thermodynamic analysis, we selected five compounds for the in vitro assays. Compound M5, characterized by a diazaindene scaffold, emerged as the most promising molecule enabling the destabilization of the MALAT1 triplex structure and antiproliferative activity on in vitro models of MM. M5 is proposed as a lead compound to be further optimized for improving its affinity toward MALAT1.

An Uncharacterised lncRNA Coded by the ASAP1 Locus Is Downregulated in Serum of Type 2 Diabetes Mellitus Patients.

Diabetes mellitus (DM) is a complex and multifactorial disease characterised by high blood glucose. Type 2 Diabetes (T2D), the most frequent clinical condition accounting for about 90% of all DM cases worldwide, is a chronic disease with slow development usually affecting middle-aged or elderly individuals. T2D represents a significant problem of public health today because its incidence is constantly growing among both children and adults. It is also estimated that underdiagnosis prevalence would strongly further increase the real incidence of the disease, with about half of T2D patients being undiagnosed. Therefore, it is important to increase diagnosis accuracy. The current interest in RNA molecules (both protein- and non-protein-coding) as potential biomarkers for diagnosis, prognosis, and treatment lies in the ease and low cost of isolation and quantification with basic molecular biology techniques. In the present study, we analysed the transcriptome in serum samples collected from T2D patients and unaffected individuals to identify potential RNA-based biomarkers. Microarray-based profiling and subsequent validation using Real-Time PCR identified an uncharacterised long non-coding RNA (lncRNA) transcribed from the ASAP1 locus as a potential diagnostic biomarker. ROC curve analysis showed that a molecular signature including the lncRNA and the clinicopathological parameters of T2D patients as well as unaffected individuals showed a better diagnostic performance compared with the glycated haemoglobin test (HbA1c). This result suggests that the application of this biomarker in clinical practice would help to improve the diagnosis, and therefore the clinical management, of T2D patients. The proposed biomarker would be useful in the context of predictive, preventive, and personalised medicine (3PM/PPPM).

Evaluation of Kinesio Taping for Edema, Ecchymosis, and Pain After Liposuction: A Prospective Pilot Study.

BACKGROUND: Liposuction is a safe, simple, and effective method of body contouring. Pain, ecchymosis, and edema are often local complications at the removal site, especially in the first weeks after surgery. Several studies have shown that kinesiology (kinesio) taping improves blood and lymphatic flow, removing congestions of lymphatic fluid and alleviating hemorrhage. However, there are limited data on the effect of kinesio taping in mitigating local complications at fat grafting donor sites. OBJECTIVES: The aim of this pilot study was to evaluate the impact of kinesio taping in reducing postoperative edema, pain, and ecchymosis in the liposuction area. METHODS: Over a period of 18 months (January 2021-June 2022), 52 patients underwent liposuction of both flanks with subsequent breast fat grafting. Immediately after the surgery, kinesio taping was used on the right abdomen flank in all patients. Degree of edema as well as ecchymosis and pain were quantified at 7, 14, and 21 days after surgery. RESULTS: There were statistically significant differences in the taping area for ecchymosis at 7 days after surgery, edema at 14 and 21 days after surgery, and in pain, rated on a visual analog scale, at 7, 14 and 21 days after surgery. CONCLUSIONS: Kinesio taping, as used in this study, is beneficial in the reduction of edema and pain and the resolution of ecchymosis after liposuction.

Twin-Engine Janus Supramolecular Nanomotors with Counterbalanced Motion.

Supramolecular nanomotors were created with two types of propelling forces that were able to counterbalance each other. The particles were based on bowl-shaped polymer vesicles, or stomatocytes, assembled from the amphiphilic block copolymer poly(ethylene glycol)-block-polystyrene. The first method of propulsion was installed by loading the nanocavity of the stomatocytes with the enzyme catalase, which enabled the decomposition of hydrogen peroxide into water and oxygen, leading to a chemically induced motion. The second method of propulsion was attained by applying a hemispherical gold coating on the stomatocytes, on the opposite side of the opening, making the particles susceptible to near-infrared laser light. By exposing these Janus-type twin engine nanomotors to both hydrogen peroxide (H2O2) and near-infrared light, two competing driving forces were synchronously generated, resulting in a counterbalanced, "seesaw effect" motion. By precisely manipulating the incident laser power and concentration of H2O2, the supramolecular nanomotors could be halted in a standby mode. Furthermore, the fact that these Janus stomatocytes were equipped with opposing motile forces also provided a proof of the direction of motion of the enzyme-activated stomatocytes. Finally, the modulation of the "seesaw effect", by tuning the net outcome of the two coexisting driving forces, was used to attain switchable control of the motile behavior of the twin-engine nanomotors. Supramolecular nanomotors that can be steered by two orthogonal propulsion mechanisms hold considerable potential for being used in complex tasks, including active transportation and environmental remediation.