Highly conserved bifidobacteria in the human gut: Bifidobacterium longum subsp. longum as a potential modulator of elderly innate immunity.

Aging is a physiological and immunological process involving the deterioration of human health, characterised by the progressive alteration of organs and their functions. The speed and extent of such decline are dependent on lifestyle, environment, and genetic factors. Moreover, with advancing age, humans become progressively more fragile and prone to acute and chronic diseases. Although the intestinal microbiota is predisposed to perturbations that accompany aging and frailty, it is generally accepted that the gut microbiota engages in multiple interactions that affect host health throughout the host life span. In the current study, an exhaustive in silico investigation of gut-associated bifidobacteria in healthy individuals from birth to old age revealed that Bifidobacterium longum subsp. longum is the most prevalent member, especially during infancy and in centenarians. Moreover, B. longum subsp. longum genome reconstruction and strain tracing among human gut microbiomes allowed the identification of prototypes of this taxon in the human gut microbiota of healthy elderly individuals. Such analyses guided culturomics attempts to isolate B. longum subsp. longum strains that matched the genomic content of B. longum subsp. longum prototypes from healthy elderly individuals. The molecular effects of selected B. longum subsp. longum strains on the human host were further investigated using in vitro microbe-host interactions, revealing differences in the host immune system transcriptome, with a reduction in gene expression of inflammation-related cytokines. These intriguing findings support the potential anti-aging effects of elderly associated prototypes of B. longum subsp. longum.

Pesticide-induced alterations in zebrafish (Danio rerio) behavior, histology, DNA damage and mRNA expression: An integrated approach.

To assess the impact of glyphosate and 2,4-D herbicides, as well as the insecticide imidacloprid, both individually and in combination, the gills of adult zebrafish were used due to their intimate interaction with chemicals diluted in water. Bioassays were performed exposing the animals to the different pesticides and their mixture for 96 h. The behavior of the fish was analyzed, a histological examination of the gills was carried out, and the genotoxic effects were also analyzed by means of the comet assay (CA) and the change in the expression profiles of genes involved in the pathways of the oxidative stress and cellular apoptosis. The length traveled and the average speed of the control fish, compared to those exposed to the pesticides and mainly those exposed to the mixture, were significantly greater. All the groups exposed individually exhibited a decrease in thigmotaxis time, indicating a reduction in the behavior of protecting themselves from predators. Histological analysis revealed significant differences in the structures of the gill tissues. The quantification of the histological lesions showed mild lesions in the fish exposed to imidacloprid, moderate to severe lesions for glyphosate, and severe lesions in the case of 2,4-D and the mixture of pesticides. The CA revealed the sensitivity of gill cells to DNA damage following exposure to glyphosate, 2,4-D, imidacloprid and the mixture. Finally, both genes involved in the oxidative stress pathway and those related to the cell apoptosis pathway were overexpressed, while the ogg1 gene, involved in DNA repair, was downregulated.

DNA damage, alterations in the expression of antioxidant enzyme genes and in the histoarchitecture of gill cells of zebrafish exposed to 17-α-ethinylestradiol.

Endocrine disruptors, such as estrogen, are chemical substances with the potential to alter the hormonal balance of organisms. Their origin can be natural or artificial, and they can act at very low doses. The estrogen 17α-ethinylestradiol (EE2) is used worldwide as an oral contraceptive and is a potential contaminant in aquatic ecosystems. It is well documented that these environmental pollutants can act directly or indirectly on the reproductive system, impairing development and fertility. However, little is known about the alteration of the cell oxidative status induced by EE2. The main objective of this study was to evaluate the effect on the gill cells of adult zebrafish exposed in vivo to EE2, analyzing cell histology, DNA damage and the expression levels of genes encoding the main enzymes involved in oxidative stress pathways. The histological study showed that EE2 produces moderate to high damage to the gill tissue, an increase in gill cell DNA damage and the mRNA levels of the genes corresponding to the manganese superoxide dismutase (Mn-sod) and catalase (cat) after exposure to 5 ng/L EE2. The results indicate that EE2 causes tissue alterations, DNA damage and oxidative stress. EE2 produced important alterations in the gills, a fundamental organ for the survival of fish. There is a clear need for further research on the ecological consequences of EDCs on non-target organisms.

Medical and Personal Characteristics Can Predict the Risk of Lung Metastasis.

AIMS: Understanding the correlations between underlying medical and personal characteristics of a patient with cancer and the risk of lung metastasis may improve clinical management and outcomes. We used machine learning methodologies to predict the risk of lung metastasis using readily available predictors. MATERIALS AND METHODS: We retrospectively analysed a cohort of 11 164 oncological patients, with clinical records gathered between 2000 and 2020. The input data consisted of 94 parameters, including age, body mass index (BMI), sex, social history, 81 primary cancer types, underlying lung disease and diabetes mellitus. The strongest underlying predictors were discovered with the analysis of the highest performing method among four distinct machine learning methods. RESULTS: Lung metastasis was present in 958 of 11 164 oncological patients. The median age and BMI of the study population were 63 (±19) and 25.12 (±5.66), respectively. The random forest method had the most robust performance among the machine learning methods. Feature importance analysis revealed high BMI as the strongest predictor. Advanced age, smoking, male gender, alcohol dependence, chronic obstructive pulmonary disease and diabetes were also strongly associated with lung metastasis. Among primary cancers, melanoma and renal cancer had the strongest correlation. CONCLUSIONS: Using a machine learning-based approach, we revealed new correlations between personal and medical characteristics of patients with cancer and lung metastasis. This study highlights the previously unknown impact of predictors such as obesity, advanced age and underlying lung disease on the occurrence of lung metastasis. This prediction model can assist physicians with preventive risk factor control and treatment strategies.

Diffusion of precision livestock farming technologies in dairy cattle farms.

The rising global demand for animal products and the growing public concerns about the environment and animal welfare require dairy farms to improve their efficiency and apply more sustainable farming systems. Precision Livestock Farming (PLF) could represent a valuable support in addressing these challenges. In recent years, dairy farms have been modernising and introducing new sensors and automatic systems for managing the herd. However, the diffusion of new technologies in Italian dairy farms is still limited and farmers are reluctant to invest in precision systems. The aim of the study was to investigate the presence of PLF tools in Italian dairy farms, the motivations, benefits and limits of technological investments from the farmers' point of view and the factors affecting the diffusion of technology. From November 2020 to June 2021, an online questionnaire was distributed and 52 responses were obtained. About 79% of the farms were located in Lombardy. The more represented milking system was the conventional milking parlour (73%), followed by automatic milking (19%). The average age of respondents was quite low: 35% of them was less than 40 years old and more than 50% was between 40 and 60. Statistical analyses were performed to evaluate the effects of different factors on the presence of technology at farm. The age of the farmer, the milk production level and the presence of an automatic milking system influenced the technological level of the farm. Precision systems that provide information on animal activity for the management of reproduction and on milk yield and flow are the most popular and are considered among the most useful. Management of reproduction and milk production are the areas where farmers appear to show interest for future investments as well. Younger farmers appear to have implemented more PLF systems than older ones, and they show a propensity to invest in latest generation precision tools. Farmers seem to have a growing interest in PLF, but some limits have been identified: the investment costs, followed by the lack of time to check information from sensor systems and the difficulty in data interpretation. As PLF technologies can play an important role in the development of sustainable, animal-friendly and efficient livestock production, further improvements and efforts are necessary to increase the propensity to PLF of dairy farmers. Results can be useful in the Italian context but also in other countries where dairy farming is rapidly intensifying but PLF is encountering resistance.

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Circulating levels of PIN1 and glucose metabolism in young people with obesity.

PURPOSE: Impaired activity of the peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) isomerase might contribute to link disturbed glucose metabolism and risk of glucose related neurotoxicity, neurodegeneration and cognitive decline. The isomerase modulates also pathways of peripheral insulin sensitivity and secretion. We aimed at investigating the levels of circulating PIN1 in adolescents with obesity and any association with their glucose metabolism. METHODS: We enrolled 145 adolescents (age 12-17.8 years); 67 lean controls (46.2%) and 78 (53.8%) with overweight or obesity (males n = 62, 46%). We estimated glucose and insulin in fasting condition and after a standard oral glucose tolerance test; fasting serum levels of PIN1, amyloid ß-protein 42 (Aß42), presenilin 1 (PSEN1), glucagon-like peptide 1 (GLP1) and Non Esterified Fatty Acids (NEFA). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), the ß cell function (HOMA-ß) and the Adipo-IR. RESULTS: There was no difference in PIN1 serum levels between normal weight individuals and patients with obesity. However, there was an inverse correlation between serum fasting PIN1 and glucose (r - 0.183 and p = 0.027). We confirmed levels of Aß42 and PSEN1 were higher in teens with obesity than in lean controls and their correlation with the body mass index (Aß42: r = 0.302, p = 0.0001, PSEN1 r = 0.231, p = 0.005) and the HOMA-IR (Aß42: r = 0.219, p = 0.009, r = 0.170, p < 0.042). CONCLUSIONS: There was no significant rise of circulating PIN1 levels in young individuals with obesity. Increased levels reported in the literature in adult patients are likely to occur late in the natural history of the disease with the onset of an overt impairment of glucose homeostasis.

SARS-CoV-2 mRNA vaccine BNT162b2 triggers a consistent cross-variant humoral and cellular response.

As the SARS-CoV-2 pandemic continues to rage worldwide, the emergence of numerous variants of concern (VOC) represents a challenge for the vaccinal protective efficacy and the reliability of commercially available high-throughput immunoassays. Our study demonstrates the administration of two doses of the BNT162b2 vaccine that elicited a robust SARS-CoV-2-specific immune response which was assessed up to 3 months after full vaccination in a cohort of 37 health care workers (HCWs). SARS-CoV-2-specific antibody response, evaluated by four commercially available chemiluminescence immunoassays (CLIA), was qualitatively consistent with the results provided by the gold-standard in vitro neutralization assay (NTA). However, we could not observe a correlation between the quantity of the antibody detected by CLIA assays and their neutralizing activity tested by NTA. Almost all subjects developed a SARS-CoV-2-specific T-cell response. Moreover, vaccinated HCWs developed a similar protective neutralizing antibodies response against the EU (B.1), Alpha (B.1.1.7), Gamma (P.1), and Eta (B.1.525) SARS-CoV-2 variants, while Beta (B.1.351) and Delta (B.1.617.2) strains displayed a consistent partial immune evasion. These results underline the importance of a solid vaccine-elicited immune response and a robust antibody titre. We believe that these relevant results should be taken into consideration in the definition of future vaccinal strategies.

Paracetamol (acetaminophen) rescues cognitive decline, neuroinflammation and cytoskeletal alterations in a model of post-operative cognitive decline (POCD) in middle-aged rats.

Post-operative cognitive dysfunction (POCD) is a debilitating clinical phenomenon in elderly patients. Management of pain in elderly is complicated because analgesic opiates elicit major side effects. In contrast, paracetamol (acetaminophen) has shown analgesic efficacy, no impact on cognition, and its side effects are well tolerated. We investigated the efficacy of paracetamol, compared to the opioid analgesic buprenorphine, in a model of POCD by investigating cognitive decline, allodynia, peripheral and hippocampal cytokines levels, and hippocampal microtubule dynamics as a key modulator of synaptic plasticity. A POCD model was developed in middle-aged (MA) rats by inducing a tibia fracture via orthopaedic surgery. Control MA rats did not undergo any surgery and only received isoflurane anaesthesia. We demonstrated that cognitive decline and increased allodynia following surgery was prevented in paracetamol-treated animals, but not in animals which were exposed to anesthesia alone or underwent the surgery and received buprenorphine. Behavioral alterations were associated with different peripheral cytokine changes between buprenorphine and paracetamol treated animals. Buprenorphine showed no central effects, while paracetamol showed modulatory effects on hippocampal cytokines and markers of microtubule dynamics which were suggestive of neuroprotection. Our data provide the first experimental evidence corroborating the use of paracetamol as first-choice analgesic in POCD.

Burden of disease and clinical targets in adult patients with X-linked hypophosphatemia. A comprehensive review.

X-linked hypophosphataemia (XLH) is a lifelong condition. Despite the mounting clinical evidence highlighting the long-term multi-organ sequelae of chronic phosphate wasting and consequent hypophosphatemia over the lifetime and the morbidities associated with adult age, XLH is still perceived as a paediatric disease. INTRODUCTION: Children who have XLH need to transition from paediatric to adult healthcare as young adults. While there is general agreement that all affected children should be treated (if the administration and tolerability of therapy can be adequately monitored), there is a lack of consensus regarding therapy in adults. METHODS: To provide guidance in both diagnosis and treatment of adult XLH patients and promote better provision of care for this potentially underserved group of patients, we review the available clinical evidence and discuss the current challenges underlying the transition from childhood to adulthood care to develop appropriate management and follow-up patterns in adult XLH patients. RESULTS AND CONCLUSIONS: Such a multi-systemic lifelong disease would demand that the multidisciplinary approach, successfully experienced in children, could be transitioned to adulthood care with an integration of specialized sub-disciplines to efficiently control musculoskeletal symptoms while optimizing patients' QoL. Overall, it would be desirable that transition to adulthood care could be a responsibility shared by the paediatric and adult XLH teams. Pharmacological management should require an adequate balance between the benefits derived from the treatment itself with complicated and long-term monitoring and the potential risks, as they may differ across age strata.

Cranial osteopathic treatment and stress-related effects on autonomic nervous system measured by salivary markers: A pilot study.

BACKGROUND: Variations in the concentration of salivary alpha amylase (sAA) may indicate a change in the autonomic nervous system functionality. In osteopathic medicine it has long been stated that the osteopathic manipulative treatment (OMT) can modulate the autonomic nervous system. Studies carried out on the compression of the fourth ventricle (CV4) have shown a positive effect in reducing the sympathetic tone. The goal of this pilot study is measuring the physiological response of the sAA levels after CV4 technique. METHODS: 90 subjects were randomly assigned to a sham, a control or a CV4 group. Randomization accounted for sex and score in the STAI-2 (form Y) questionnaire. Each subject completed the STAI-1 (form Y) questionnaire to evaluate the anxiety of the moment. sAA activity and saliva flow rate were measured. Saliva was collected before, immediately after and 30 min after treatment. RESULTS: Within group analysis revealed that sAA activity increased significantly immediately after the technique application only in the CV4 group (p = 0,05). Between groups analysis show a significant difference of the sAA activity in the CV4 group respect the control group (p < 0,05), but no significant difference between CV4 and sham group (p > 0,05). The effect in the CV4 group after the intervention is highly variable and appeared to be related to the level of stress measured with the STAI-Y1 questionnaire (p = 0,002). CONCLUSIONS: This study shows a positive effect of the CV4 procedure on sAA activity even if not significantly different from the sham procedure, probably due to the confounding effect of stress variability between groups.

Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

BACKGROUND: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). PATIENTS AND METHODS: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. RESULTS: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. CONCLUSIONS: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

Causes and Pathology of Equine Pneumonia and Pleuritis in Southern Brazil.

We document the causes and pathological findings in 50 cases of equine pneumonia and pleuritis in Southern Brazil. Suppurative (17/50), pyogranulomatous (14/50), aspiration (5/50), mycotic (4/50), bronchointerstitial (3/50), embolic (3/50) and eosinophilic granulomatous pneumonia (1/50) and pleuritis (3/50) were the main conditions identified. Streptococcus spp. were identified in 11 cases of suppurative pneumonia. Suppurative pneumonia was further divided into acute (8/17), subacute (6/17) and chronic (3/17) based on the morphological pattern of lesions. Rhodococcus equi was identified in all cases of pyogranulomatous pneumonia and exclusively affected young foals.

Radiation therapy technologists' involvement and opinion in research: A national survey in Italy.

INTRODUCTION: This survey describes Italian RTTs' involvement and opinions in research activities related to radiation oncology. Primary aim was to assess the degree of involvement of the national RTTs community in research and to describe how RTTs can integrate their skills collaborating with other professionals. MATERIALS AND METHODS: A ten-items multiple-choice questionnaire, with 2-8 possible responses, was developed by a steering committee and generated on a survey platform. Links were sent via email to Italian RTTs.The questions were divided in 3 domains: demographic data; scientific research and activity; opinions about RTTs role in scientific research. The survey started on October 1, 2018 and ended on January 31, 2019. RESULTS: One hundred thirty-five out of 509 (26.5%) RTTs responded to the questionnaire at its expiring date; 97.73% think to be valid contributors in radiation oncology research, expressing clear interest in "data collection" tasks (52.71%); 38.64% feel unsupported by other professionals in the research team and 59.85% of the respondents are not members in any scientific society. CONCLUSIONS: The role of Italian RTTs in research is heterogeneous. Mainly RTTs in the age range from 30 to 40 years responded to the survey showing their interest in scientific research. This might be related to different informatics and educational skills as well as to personal attitudes. RTTs particular skills, like data management and technical hypothesis generation abilities, are of benefit to realize research projects. Therefore, engaging RTTs in research activities is strongly suggested.

Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Time- and momentum-resolved photoemission studies using time-of-flight momentum microscopy at a free-electron laser.

Time-resolved photoemission with ultrafast pump and probe pulses is an emerging technique with wide application potential. Real-time recording of nonequilibrium electronic processes, transient states in chemical reactions, or the interplay of electronic and structural dynamics offers fascinating opportunities for future research. Combining valence-band and core-level spectroscopy with photoelectron diffraction for electronic, chemical, and structural analyses requires few 10 fs soft X-ray pulses with some 10 meV spectral resolution, which are currently available at high repetition rate free-electron lasers. We have constructed and optimized a versatile setup commissioned at FLASH/PG2 that combines free-electron laser capabilities together with a multidimensional recording scheme for photoemission studies. We use a full-field imaging momentum microscope with time-of-flight energy recording as the detector for mapping of 3D band structures in (kx, ky, E) parameter space with unprecedented efficiency. Our instrument can image full surface Brillouin zones with up to 7 Å-1 diameter in a binding-energy range of several eV, resolving about 2.5 × 105 data voxels simultaneously. Using the ultrafast excited state dynamics in the van der Waals semiconductor WSe2 measured at photon energies of 36.5 eV and 109.5 eV, we demonstrate an experimental energy resolution of 130 meV, a momentum resolution of 0.06 Å-1, and a system response function of 150 fs.

The occupied electronic structure of ultrathin boron doped diamond.

Using angle-resolved photoelectron spectroscopy, we compare the electronic band structure of an ultrathin (1.8 nm) δ-layer of boron-doped diamond with a bulk-like boron doped diamond film (3 µm). Surprisingly, the measurements indicate that except for a small change in the effective mass, there is no significant difference between the electronic structure of these samples, irrespective of their physical dimensionality, except for a small modification of the effective mass. While this suggests that, at the current time, it is not possible to fabricate boron-doped diamond structures with quantum properties, it also means that nanoscale boron doped diamond structures can be fabricated which retain the classical electronic properties of bulk-doped diamond, without a need to consider the influence of quantum confinement.

[Pharmaceutical care for older adults. Application of STOPP-START criteria]. / Atención farmacéutica de adultos mayores. Aplicación de los criterios STOPP-START.

INTRODUCTION: Drug-related problems can be caused by potentially inappropriate prescribing (PIP), one of the most used tools for its identification are the STOPP (Older Persons' potentially inappropriate Prescriptions) - START (Screening Tool to Alert doctors to Right Treatment) criteria. The objective of this study is to determine PIP in older adults who receive pharmaceutical care in the Pharmacotherapy Optimization Unit (POU)-Rosario. MATERIALS AND METHODS: Pharmacoepidemiological observational study, which evaluates the quality of medication use. Workplace: POU-Rosario. Population under study: adults over 60 years of age, who received pharmacotherapy follow-up during the period March 2017 to February 2018. PIPs were identified using the STOPP-START criteria, 2014 version; selecting the most appropriate criteria to assess outpatient pharmacotherapy. Prevalence of PIP and amount of PIP per active principle were estimated. RESULTS: 50 patients older than 60 years received pharmacotherapy follow-up in the POU; 47 patients (94.0%) had at least one PIP corresponding to a STOPP criterion; 17 STOPP criteria were found among the 41 initially selected, leading to 145 PIPs identified. And 7 START criteria among the 11 initially selected, leading to 50 PIPs identified. Medications with a higher amount of PIPs: benzodiazepines and proton pump inhibitors. CONCLUSIONS: This study allowed the identification of a high prevalence of PIP. The data obtained show the usefulness of these criteria. The STOPP-START criteria have been included to support decision making during pharmacotherapy follow-up to propose pharmaceutical interventions, in order to enhance pharmacotherapy. These activities contribute to patient safety, a dimension of health quality.

Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the onset of CDKL5 Deficiency Disorder (CDD), a neurological pathology characterised by severe infantile seizures, intellectual disability, impairment of gross motor skills, sleep and gastrointestinal disturbances. CDKL5 is a serine/threonine kinase the molecular network of which is not yet fully understood. Loss of CDKL5 both in vitro and in vivo leads to altered neuronal morphology including axon specification and outgrowth, dendritic arborisation and spine morphology suggesting a link between CDKL5 and the regulation of proper cytoskeleton functioning. Recently, we found that CDKL5 regulates the binding of CLIP170 to microtubules (MT). CLIP170 is a MT-plus end tracking protein (+TIP) that associates with MTs when present in its open, active conformation. Here we present evidence suggesting CLIP170 contributes to neuronal CDKL5-dependent defects and that it represents an important novel druggable target for CDD; indeed, CLIP170 is directly targeted by the neuroactive steroid pregnenolone (PREG), which induces the active conformation of the protein thus promoting MT-dynamics. We here show that PREG and a synthetic derivative pregnenolone-methyl-ether (PME) can restore the MT association of CLIP170 and revert morphological and molecular defects in Cdkl5-KO neurons at different stages of maturation. All together, these findings identify CLIP170 as possible novel druggable target for CDKL5 related disorders providing an intriguing prospective for future disease-modifying drug-based therapies.

Influence of an Anomalous Temperature Dependence of the Phase Coherence Length on the Conductivity of Magnetic Topological Insulators.

Magnetotransport constitutes a useful probe to understand the interplay between electronic band topology and magnetism in spintronic devices. A recent theory of Lu and Shen [Phys. Rev. Lett. 112, 146601 (2014)PRLTAO0031-900710.1103/PhysRevLett.112.146601] on magnetically doped topological insulators predicts that quantum corrections Δκ to the temperature dependence of conductivity can change sign across the Curie transition. This phenomenon has been attributed to a suppression of the Berry phase of the topological surface states at the Fermi level, caused by a magnetic energy gap. Here, we demonstrate experimentally that Δκ can reverse its sign even when the Berry phase at the Fermi level remains unchanged. The contradictory behavior to theory predictions is resolved by extending the model by Lu and Shen to a nonmonotonic temperature scaling of the inelastic scattering length showing a turning point at the Curie transition.