Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

5-Bromo-2'-deoxyuridine labeling:historical perspectives,factors infiuencing the detection,toxicity,and its implications in the neurogenesis

The halopyrimidine 5-bromo-2′-deoxyuridine(BrdU)is an exogenous marker of DNA synthesis.Since the introduction of monoclonal antibodies against BrdU,an increasing number of methodologies have been used for the immunodetection of this synthesized bromine-tagged base analogue into replicating DNA.BrdU labeling is widely used for identifying neuron precursors and following their fate during the embryonic,perinatal,and adult neurogenesis in a variety of vertebrate species including birds,reptiles,and mammals.Due to BrdU toxicity,its incorporation into replicating DNA presents adverse consequences on the generation,survival,and settled patterns of cells.This may lead to false results and misinterpretation in the identification of proliferative neuroblasts.In this review,I will indicate the detrimental effects of this nucleoside during the development of the central nervous system,as well as the reliability of BrdU labeling to detect proliferating neuroblasts.Moreover,it will show factors influencing BrdU immunodetection and the contribution of this nucleoside to the study of prenatal,perinatal,and adult neurogenesis.Human adult neurogenesis will also be discussed.It is my hope that this review serves as a reference for those researchers who focused on detecting cells that are in the synthetic phase of the cell cycle.

Pelvic fractures in blunt trauma patients:A comparative study

BACKGROUND Pelvic fractures(PF)with concomitant injuries are on the rise due to an increase of high-energy trauma.Increase of the elderly population with age related comorbidities further complicates the management.Abdominal organ injuries are kindred with PF due to the proximity to pelvic bones.Presence of contrast blush(CB)on computed tomography in patients with PF is considered a sign of active bleeding,however,its clinical significance and association with outcomes is debatable.AIM To analyze polytrauma patients with PF with a focus on the geriatric population,co-injuries and the value of contrast blush.METHODS This retrospective cohort study included 558 patients with PF admitted to level 1 trauma center(01/2017-01/2023).Analyzed variables included:Age,sex,mechanism of injury(MOI),injury severity score(ISS),Glasgow coma scale(GCS),abbreviated injury scale(AIS),co-injuries,transfusion requirements,pelvic angiography,embolization,laparotomy,orthopedic pelvic surgery,intensive care unit and hospital lengths of stay,discharge disposition and mortality.The study compared geriatric and non-geriatric patients,patients with and without CB and abdominal co-injuries.Propensity score matching was implemented in comparison groups.RESULTS PF comprised 4%of all trauma admissions.89 patients had CB.286(52%)patients had concomitant injuries including 93(17%)patients with abdominal co-injuries.Geriatric patients compared to non-geriatric had more falls as MOI,lower ISS and AIS pelvis,higher GCS,less abdominal co-injuries,similar CB and angio-embolization rates,less orthopedic pelvic surgeries,shorter lengths of stay and higher mortality.After propensity matching,orthopedic pelvic surgery rates remained lower(8%vs 19%,P<0.001),hospital length of stay shorter,and mortality higher(13%vs 4%,P<0.001)in geriatric patients.Out of 89 patients with CB,45(51%)were embolized.After propensity matching,patients with CB compared to without CB had more pelvic angiography(71%vs 12%,P<0.001),higher embolization rates(64%vs 22%,P=0.02)and comparable mortality.CONCLUSION Half of the patients with PF had concomitant co-injuries,including abdominal co-injuries in 17%.Similarly injured geriatric patients had higher mortality.Half of the patients with CB required an embolization.

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats withα-synucleinopathy

Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As Nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection.This study found that rNurr1-V5 expression but not that of the green fluorescent protein(the negative control)reducedβ-sitosterolβ-D-glucoside-induced neuropathology.Accordingly,a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum.In addition,tyrosine hydroxylase-positive cells displayed less senescence markerβ-galactosidase and more neuron-cytoskeleton markerβIII-tubulin and brain-derived neurotrophic factor.A significant decrease in activated microglia(positive to ionized calcium-binding adaptor molecule 1)and neurotoxic astrocytes(positive to glial fibrillary acidic protein and complement component 3)and increased neurotrophic astrocytes(positive to glial fibrillary acidic protein and S100 calcium-binding protein A10)also occurred in the substantia nigra.These effects followed the bilateral reduction inα-synuclein aggregates in the nigrostriatal system,improving sensorimotor behavior.Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration(senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells),neuroinflammation(activated microglia,neurotoxic astrocytes),α-synuclein aggregation,and sensorimotor deficits.Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect,supporting its potential clinical use in the treatment of Parkinson’s disease.

Patellar reconstruction in primary total knee arthroplasty using bone chips from routine cuts:A case report and review of literature

BACKGROUND Total patellectomy is currently reserved for exceptional cases,such as recalcitrant patellofemoral instability and comminuted fractures,due to its demonstrated negative impact on knee biomechanics.Therefore,managing patellectomy is crucial to mitigate its inherent deleterious effects.Various techniques have been described,including autologous or allogeneic bone grafts for reconstruction and soft tissue realignment to enhance the extensor mechanism.CASE SUMMARY A 73-year-old male underwent a patellectomy due to a comminuted fracture,subsequently developing osteoarthritis and experiencing a decline in functional status.Concurrent with total knee replacement,we conducted a patellar reconstruction,incorporating routine bone cuts and utilizing bone chips to fashion a new patella.This intervention resulted in the restoration of full extension and improvement of knee function.CONCLUSION Patellar reconstruction demonstrates benefits on knee mechanics and stabilization,contributing to enhanced outcomes and satisfaction following knee replacement.We present an affordable technique for managing patellectomized patients undergoing total knee replacement.

Competitive effect, but not competitive response, varies along a climatic gradient depending on tree species identity

Background: Understanding the role of species identity in interactions among individuals is crucial for assessing the productivity and stability of mixed forests over time. However, there is limited knowledge concerning the variation in competitive effect and response of different species along climatic gradients. In this study, we investigated the importance of climate, tree size, and competition on the growth of three tree species: spruce(Picea abies), fir(Abies alba), and beech(Fagus sylvatica), and examined their competitive response and effect along a climatic gradient.Methods: We selected 39 plots distributed across the European mountains with records of the position and growth of 5,759 individuals. For each target species, models relating tree growth to tree size, climate and competition were proposed. Competition was modelled using a neighbourhood competition index that considered the effects of inter-and intraspecific competition on target trees. Competitive responses and effects were related to climate.Likelihood methods and information theory were used to select the best model.Results: Our findings revealed that competition had a greater impact on target species growth than tree size or climate. Climate did influence the competitive effects of neighbouring species, but it did not affect the target species? response to competition. The strength of competitive effects varied along the gradient, contingent on the identity of the interacting species. When the target species exhibited an intermediate competitive effect relative to neighbouring species, both higher inter-than intraspecific competitive effects and competition reduction occurred along the gradient. Notably, species competitive effects were most pronounced when the target species' growth was at its peak and weakest when growing conditions were far from their maximum.Conclusions: Climate modulates the effects of competition from neighbouring trees on the target tree and not the susceptibility of the target tree to competition. The modelling approach should be useful in future research to expand our knowledge of how competition modulates forest communities across environmental gradients.

Knowledge, attitudes, and practices regarding Covid-19 and their relationship with Covid-19 booster vaccination status among women with infertility

Objective:To elucidate the relationship among knowledge,attitudes,and practices regarding Covid-19 and their relationship with booster vaccination status among women with infertility.Methods:This questionnaire-based cross-sectional study was performed online and offline among women with infertility who visited an infertility clinic in Jakarta,Indonesia.We assessed the patient’s knowledge,attitudes,and practices regarding Covid-19 and their relationship with booster vaccination status and sociodemographic profile.Results:A total of 178 subjects participated in this study,and most participants(92.6%)had received booster Covid-19 vaccines.From the questionnaire,74.2%had good knowledge,and 99.4%had good attitudes regarding Covid-19;however,only 57.9%of patients had good practices.A weak positive correlation existed between knowledge and attitudes(r=0.11,P=0.13)and a moderate negative correlation between attitudes and practices(r=-0.44,P=0.56).Participants’knowledge about vaccines and infertility was correlated with booster vaccination status(P=0.04).Academic background(P=0.01)and attitudes(P=0.01)were also correlated with booster vaccination status.The significant determinants of hesitance of receiving Covid-19 booster vaccines were high school education or below(OR=0.08,95%CI 0.02-0.36)and poor practices(OR=0.21,95%CI 0.05-0.95).Conclusions:The majority of the participants had received the Covid-19 booster vaccine and had good knowledge and attitudes but poor practices regarding Covid-19.Most participants had poor knowledge about the relationship between infertility and the Covid-19 vaccine.The general population should be more informed and reminded about practices to prevent Covid-19 and the relationship between vaccination and fertility to increase the number of people who receive Covid-19 booster vaccines.

Confirmation of a Sub-Saturn-size Transiting Exoplanet Orbiting a G Dwarf:TOI-1194 b and a Very Low Mass Companion Star: TOI-1251 B from TESS

We report the confirmation of a sub-Saturn-size exoplanet,TOI-1194 b,with a mass of about 0.456+0.055-0.051M_(J),and a very low mass companion star with a mass of about 96.5±1.5 MJ,TOI-1251 B.Exoplanet candidates provided by the Transiting Exoplanet Survey Satellite(TESS)are suitable for further follow-up observations by ground-based telescopes with small and medium apertures.The analysis is performed based on data from several telescopes worldwide,including telescopes in the Sino-German multiband photometric campaign,which aimed at confirming TESS Objects of Interest(TOIs)using ground-based small-aperture and medium-aperture telescopes,especially for long-period targets.TOI-1194 b is confirmed based on the consistent periodic transit depths from the multiband photometric data.We measure an orbital period of 2.310644±0.000001 days,the radius is 0.767+0.045-0.041RJ and the amplitude of the RV curve is 69.4_(-7.3)^(+7.9)m s^(-1).TOI-1251 B is confirmed based on the multiband photometric and high-resolution spectroscopic data,whose orbital period is 5.963054+0.000002-0.000001days,radius is 0.947+0.035-0.033 R_(J) and amplitude of the RV curve is 9849_(-40)^(+42)ms^(-1).

Major liver resections,perioperative issues and posthepatectomy liver failure:A comprehensive update for the anesthesiologist

Significant advances in surgical techniques and relevant medium-and long-term outcomes over the past two decades have led to a substantial expansion in the indications for major liver resections.To support these outstanding results and to reduce perioperative complications,anesthesiologists must address and master key perioperative issues(preoperative assessment,proactive intraoperative anesthesia strategies,and implementation of the Enhanced Recovery After Surgery approach).Intensive care unit monitoring immediately following liver surgery remains a subject of active and often unresolved debate.Among postoperative complications,posthepatectomy liver failure(PHLF)occurs in different grades of severity(A-C)and frequency(9%-30%),and it is the main cause of 90-d postoperative mortality.PHLF,recently redefined with pragmatic clinical criteria and perioperative scores,can be predicted,prevented,or anticipated.This review highlights:(1)The systemic consequences of surgical manipulations anesthesiologistsmust respond to or prevent,to positively impact PHLF(a proactive approach);and(2)the maximal intensivetreatment of PHLF,including artificial options,mainly based,so far,on Acute Liver Failure treatment(s),to buytime waiting for the recovery of the native liver or,when appropriate and in very selected cases,toward livertransplant.Such a clinical context requires a strong commitment to surgeons,anesthesiologists,and intensivists towork together,for a fruitful collaboration in a mandatory clinical continuum.

Use of priming strategies to advance the clinical application of mesenchymal stromal/stem cell-based therapy

Mesenchymal stromal/stem cells(MSCs)have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential.MSCs play a pivotal role in maintaining tissue homeostasis and possess diverse functions in tissue repair and recovery in various organs.These cells are charac-terized by easy accessibility,few ethical concerns,and adaptability to in vitro cultures,making them a valuable resource for cell therapy in several clinical conditions.Over the years,it has been shown that the true therapeutic power of MSCs lies not in cell engraftment and replacement but in their ability to produce critical paracrine factors,including cytokines,growth factors,and exosomes(EXOs),which modulate the tissue microenvironment and facilitate repair and regeneration processes.Consequently,MSC-derived products,such as condi-tioned media and EXOs,are now being extensively evaluated for their potential medical applications,offering advantages over the long-term use of whole MSCs.However,the efficacy of MSC-based treatments varies in clinical trials due to both intrinsic differences resulting from the choice of diverse cell sources and non-standardized production methods.To address these concerns and to enhance MSC therapeutic potential,researchers have explored many priming strategies,including exposure to inflammatory molecules,hypoxic conditions,and three-dimensional culture techniques.These approaches have optimized MSC secretion of functional factors,empowering them with enhanced immunomodulatory,angiogenic,and regenerative properties tailored to specific medical conditions.In fact,various priming strategies show promise in the treatment of numerous diseases,from immune-related disorders to acute injuries and cancer.Currently,in order to exploit the full therapeutic potential of MSC therapy,the most important challenge is to optimize the modulation of MSCs to obtain adapted cell therapy for specific clinical disorders.In other words,to unlock the complete potential of MSCs in regenerative medicine,it is crucial to identify the most suitable tissue source and develop in vitro manipulation protocols specific to the type of disease being treated.

Epidemiology,therapy and outcome of hepatocellular carcinoma between 2010 and 2019 in Piedmont,Italy

BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and the second leading cause of cancer deaths worldwide.It is often diagnosed at an advanced stage and therefore its prognosis remains poor with a low 5-year survival rate.HCC patients have increasingly complex and constantly changing characteristics,thus up-to-date and comprehensive data are fundamental.AIM To analyze the epidemiology and main clinical characteristics of HCC patients in a referral center hospital in the northwest of Italy between 2010 and 2019.METHODS In this retrospective study,we analyzed the clinical data of all consecutive patients with a new diagnosis of HCC recorded at"Santa Croce e Carle"Hospital in Cuneo(Italy)between 1 January 2010 and 31 December 2019.To highlight possible changes in HCC patterns over the 10-year period,we split the population into two 5-year groups,according to the diagnosis period(2010-2014 and 2015-2019).RESULTS Of the 328 HCC patients who were included(M/F 255/73;mean age 68.9±11.3 years),154 in the first period,and 174 in the second.Hepatitis C virus infection was the most common HCC risk factor(41%,135 patients).The alcoholic etiology rate was 18%,the hepatitis B virus infection etiology was 5%,and the non-viral/non-alcoholic etiology rate was 22%.The Child-Pugh score distribution of the patients was:class A 75%,class B 21%and class C 4%.The average Mayo end-stage liver disease score was 10.6±3.7.A total of 55 patients(17%)were affected by portal vein thrombosis and 158(48%)by portal hypertension.The average nodule size of the HCC was 4.6±3.1 cm.A total of 204 patients(63%)had more than one nodule<3,and 92%(305 patients)had a non-metastatic stage of the disease.The Barcelona Clinic Liver Cancer(BCLC)staging distribution of all patients was:4%very early,32%early,23%intermediate,34%advanced,and 7%terminal.Average survival rate was 1.6±0.3 years.Only 20%of the patients underwent treatment.Age,presence of ascites,BCLC stage and therapy were predictors of a better prognosis(P<0.01).A comparison of the two 5-year groups revealed a statistically significant difference only in global etiology(P<0.05)and alpha-fetoprotein(AFP)levels(P<0.01).CONCLUSION In this study analyzing patients with a new diagnosis of HCC between 2010-2019,hepatitis C virus infection was the most common etiology.Most patients presented with an advanced stage disease and a poor prognosis.When comparing the two 5-year groups,we observed a statistically significant difference only in global etiology(P<0.05)and AFP levels(P<0.01).

Deterministic and probabilistic analysis of great-depth braced excavations:A 32 m excavation case study in Paris

The Fort d’Issy-Vanves-Clamart(FIVC)braced excavation in France is analyzed to provide insights into the geotechnical serviceability assessment of excavations at great depth within deterministic and probabilistic frameworks.The FIVC excavation is excavated at 32 m below the ground surface in Parisian sedimentary basin and a plane-strain finite element analysis is implemented to examine the wall deflections and ground surface settlements.A stochastic finite element method based on the polynomial chaos Kriging metamodel(MSFEM)is then proposed for the probabilistic analyses.Comparisons with field measurements and former studies are carried out.Several academic cases are then conducted to investigate the great-depth excavation stability regarding the maximum horizontal wall deflection and maximum ground surface settlement.The results indicate that the proposed MSFEM is effective for probabilistic analyses and can provide useful insights for the excavation design and construction.A sensitivity analysis for seven considered random parameters is then implemented.The soil friction angle at the excavation bottom layer is the most significant one for design.The soil-wall interaction effects on the excavation stability are also given.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection:A systematic review

BACKGROUND Hepatitis C virus(HCV)is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality.Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma(HCC)in people with cirrhosis.Of the 6 HCV genotypes(G1-G6),genotype-3 accounts for 17.9%of infections.HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis.AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings.Consequently,we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023.METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations.We searched Web of Science,Medline,EMBASE,and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings,1946-2023.RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates.Three thousand eight hundred and eighty-four records were screened with 3514 excluded.Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis.Of the seven studies,three studies were retrospective case-control trials,two retrospective cohort studies,one a prospective cohort study and one a cross-sectional study design.All were based in hospital settings with four in Pakistan,two in South Korea and one in the United States.The total number of participants were 9621 of which 167 developed HCC(1.7%).All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age(five-studies),with two studies each showing male sex,high alpha feto-protein,directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC.CONCLUSION Although,studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease,HCC,and liver-related death,there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3.Only cirrhosis and age have demonstrated an association;however,the number of studies is very small,and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

challenges of advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an aggressive malignancy,resulting as the third cause of death by cancer each year. The management of patients with HCC is complex,as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging,clinical and biochemical parameters is routinely performed,a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice,several phase Ⅲ clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Locoregional therapies have also been tested as first line treatment,but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally,robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials.

Genomic signatures of selection,local adaptation and production type characterisation of East Adriatic sheep breeds

Background The importance of sheep breeding in the Mediterranean part of the eastern Adriatic has a long tradition since its arrival during the Neolithic migrations.Sheep production system is extensive and generally carried out in traditional systems without intensive systematic breeding programmes for high uniform trait production(carcass,wool and milk yield).Therefore,eight indigenous Croatian sheep breeds from eastern Adriatic treated here as metapopulation(EAS),are generally considered as multipurpose breeds(milk,meat and wool),not specialised for a particular type of production,but known for their robustness and resistance to certain environmental conditions.Our objective was to identify genomic regions and genes that exhibit patterns of positive selection signatures,decipher their biological and productive functionality,and provide a"genomic"characterization of EAS adaptation and determine its production type.Results We identified positive selection signatures in EAS using several methods based on reduced local variation,linkage disequilibrium and site frequency spectrum(eROHi,iHS,nSL and CLR).Our analyses identified numerous genomic regions and genes(e.g.,desmosomal cadherin and desmoglein gene families)associated with environmental adaptation and economically important traits.Most candidate genes were related to meat/production and health/immune response traits,while some of the candidate genes discovered were important for domestication and evolutionary processes(e.g.,HOXa gene family and FSIP2).These results were also confirmed by GO and QTL enrichment analysis.Conclusions Our results contribute to a better understanding of the unique adaptive genetic architecture of EAS and define its productive type,ultimately providing a new opportunity for future breeding programmes.At the same time,the numerous genes identified will improve our understanding of ruminant(sheep)robustness and resistance in the harsh and specific Mediterranean environment.

Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Stabilisation of estuarine sediments with an alkali-activated cement for deep soil mixing applications

In this work,an alternative alkali-activated cement(AAC)made of ladle slag precursor mixed with sodium hydroxide and sodium silicate has been developed to enhance the bearing capacity of estuarine soils in coastal conditions via deep soil mixing(DSM).The AAC was optimized to use a low reactivity precursor(ladle slag)and to deal with a contaminated high-water content natural sediment cured under water.The material performance was analysed by comparison to a mixture made with Portland cement and cured in the same conditions.Flexural and unconfined compressive strength tests as well as seismic waves measurements after 3-,7-,14-and 28-d curing were performed to obtain a relationship between elastic stiffness and strength with curing time for both mixtures.Remarkably,the AAC mix demonstrated superior strength results,exhibiting almost double flexural and compressive strengths after 28 d compared to the Portland cement mix.The AAC mix also showed a higher rate of stiffness increase than the Portland cement mix,which has a higher initial stiffness at young ages but lower stiffness evolution.Leachate analysis confirmed that the proposed AAC could effectively immobilise any contaminants from soil or precursors.The effect of curing under stress was analysed in triaxial compression tests and found to be insignificant,indicating that laboratory data obtained without stress curing can represent the material's behaviour in a DSM column,which will cure under the weight of the column.

Historical biogeography and evolutionary diversification of Lilium(Liliaceae): New insights from plastome phylogenomics

Here, we infer the historical biogeography and evolutionary diversification of the genus Lilium. For this purpose, we used the complete plastomes of 64 currently accepted species in the genus Lilium(14plastomes were newly sequenced) to recover the phylogenetic backbone of the genus and a timecalibrated phylogenetic framework to estimate biogeographical history scenarios and evolutionary diversification rates of Lilium. Our results suggest that ancient climatic changes and geological tectonic activities jointly shaped the distribution range and drove evolutionary radiation of Lilium, including the Middle Miocene Climate Optimum(MMCO), the late Miocene global cooling, as well as the successive uplift of the Qinghai-Tibet Plateau(QTP) and the strengthening of the monsoon climate in East Asia during the late Miocene and the Pliocene. This case study suggests that the unique geological and climatic events in the Neogene of East Asia, in particular the uplift of QTP and the enhancement of monsoonal climate, may have played an essential role in formation of uneven distribution of plant diversity in the Northern Hemisphere.

Updates on management of gliomas in the molecular age

Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.