Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis

Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions

Observation of Mixed Valence Ru Components in Zn Doped Y2Ru2O7 Pyrochlores

We present a study of Y2 12xZnxRu2O7 pyrochlores as a function of the Zn doping level x. X-ray diffraction measurements show that single-phase samples could be obtained for x < 0.2. Within the allowed range for x, dc conductivity measurements revealed a sizable decrease in resistivity at all the investigated temperatures for Zn doped samples with respect to undoped ones. Neutron diffraction data of the x = 0.2 sample showed that replacing Y3+ by Zn2+ does not result in the formation of oxygen vacancies. X-ray photoemission spectroscopy measurements revealed that part of the Ru ions are in the 5+ oxidation state to balance, in terms of electronic charge, the incorporation of Zn2+. The results give experimental evidence that the heterovalent doping promotes the increase of conductivity in the Y2Ru2O7 pyrochlores, making these systems promising as intermediate temperature solid oxide fuel cell cathodes

Increased gyrification in schizophrenia and non affective first episode of psychosis

Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. Methods: Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. Results: Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p. <. 0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. Conclusions: Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits

EPSILoN score: Validation cohort of a prognostic score in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy

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Language production impairments in patients with a first episode of psychosis

Language production has often been described as impaired in psychiatric diseases such as in psychosis. Nevertheless, little is known about the characteristics of linguistic difficulties and their relation with other cognitive domains in patients with a first episode of psychosis (FEP), either affective or non-affective. To deepen our comprehension of linguistic profile in FEP, 133 patients with FEP (95 non-affective, FEP-NA; 38 affective, FEP-A) and 133 healthy controls (HC) were assessed with a narrative discourse task. Speech samples were systematically analyzed with a well-established multilevel procedure investigating both micro- (lexicon, morphology, syntax) and macro-linguistic (discourse coherence, pragmatics) levels of linguistic processing. Executive functioning and IQ were also evaluated. Both linguistic and neuropsychological measures were secondarily implemented with a machine learning approach in order to explore their predictive accuracy in classifying participants as FEP or HC. Compared to HC, FEP patients showed language production difficulty at both micro- and macro-linguistic levels. As for the former, FEP produced shorter and simpler sentences and fewer words per minute, along with a reduced number of lexical fillers, compared to HC. At the macro-linguistic level, FEP performance was impaired in local coherence, which was paired with a higher percentage of utterances with semantic errors. Linguistic measures were not correlated with any neuropsychological variables. No significant differences emerged between FEP-NA and FEP-A (p≥0.02, after Bonferroni correction). Machine learning analysis showed an accuracy of group prediction of 76.36% using language features only, with semantic variables being the most impactful. Such a percentage was enhanced when paired with clinical and neuropsychological variables. Results confirm the presence of language production deficits already at the first episode of the illness, being such impairment not related to other cognitive domains. The high accuracy obtained by the linguistic set of features in classifying groups support the use of machine learning methods in neuroscience investigations

Evidence of local structural order and spin-lattice coupling in the frustrated pyrochloreY2Ru2O7

We present an extended x-ray absorption fine structure study of the pyrochlore Y2Ru2O7 (8-298 K). We find evidence, on a local scale, of a significant magnetoelastic coupling at the Neel temperature T-N similar to 77 K pointed out by a huge Debye-Waller sigma(2) factor deviation from a correlated temperature dependent Debye-like local order behavior plus a temperature independent static contribution. Moreover, we notice the occurrence of a potential local order-disorder structural phase transition at T* = 150 K. This anomalous behavior is consistent with the pyrochlore's predisposition towards structural disorder and with a strong spin-phonon correlation. Remarkably the low-temperature order competes with the tendency of magnetic frustration to induce a less symmetric local structure

Real-world survival outcomes of wedge resection versus lobectomy for cT1a/b cN0 cM0 non-small cell lung cancer: a single center retrospective analysis

BackgroundJCOG0802/WJOG4607L showed benefits in overall survival (OS) of segmentectomy. CALGB 140503 confirmed that sublobar resection was not inferior to lobectomy concerning recurrence-free survival (RFS) but did not provide specific OS and RFS according to the techniques of sublobar resections. Hence, we retrospectively analyze the survival differences between wedge resection and lobectomies for stage IA lung cancer.MethodsWe reviewed the clinical records of patients with clinical stage IA NSCLC over 20 years. The inclusion criteria were: preoperative staging with CT scan and whole body CT/PET; tumor size &lt;20 mm; wedge resections or lobectomies with or without lymph node dissection; NSCLC as the only primary tumor during the follow-up period. We excluded: multiple invasive lung cancer; positive resection margin; preoperative evidence of nodal disease; distant metastasis at presentation; follow-up time &lt;5 years. The reverse Kaplan – Meier method estimated the median OS and PFS and compared them by the log-rank test. The stratified backward stepwise Cox regression model was employed for multivariable survival analyses.Results539 patients were identified: 476 (88.3%) lobectomies and 63 (11.7%) wedge resections. The median OS time for the whole cohort was 189.7 months (range: 173.7 – 213.9 months). The 5-year wedge resection and lobectomy OS were 82.2% and 87.0%. The 5-year RFS of wedge resection and lobectomy were 17.8% and 28.9%. The log-rank test showed no significant differences (p = 0.39) between wedge resections and lobectomies regarding OS and RFS (p = 0.23).ConclusionsLobectomy and wedge resection are equivalent oncologic treatments for individuals with cN0/cM0 stage IA NSCLC &lt;20 mm. Validating the current findings requires a prospective, randomized comparison between wedge resection and standard lobectomy to establish the prognostic significance of wedge resection