Enhancement of Phase Formation and Critical Current Density in (Bi,Pb)-2223 Superconductor by Boron Addition and Ball Milling

The effects of crystalline boron addition and ball milling on the phase formation and transport properties of (Bi,Pb)-2223 HTS have been studied. Samples with nominal composition Bi1.7Pb0.3Sr2Ca2Cu3BxOy, x=0 - 0.5, were prepared via a solid state reaction route. Superconducting properties of undoped (reference) and boron-added (Bi,Pb)-2223 compounds were investigated through X-ray diffraction (XRD), scanning electron microscopy (SEM), resistivity and transport critical current density (Jc) measurements. Obtained results have shown that boron additive leads to the acceleration of high-Tc phase formation and enhancement of Jc in (Bi,Pb)-2223 superconductor. The estimated volume fraction of (Bi,Pb)-2223 phase increases from ~25 % for reference specimen to ~75 % for x=0.15. Moreover, strong increase in the Jc was observed for the x=0.15 sample (Jc=340 A/cm2), compared to a reference sample (Jc=115 A/cm2). We have studied the effect of high-energy ball milling on Jc in reference and x=0.15 samples. Addition of B in combination with the ball milling leads to the further enhancement of Jc up to 490 A/cm2, whereas the ball milling of reference specimen causes the marked decrease in both Jc and Tc values. Improvement of superconducting properties in (Bi,Pb)-2223 superconductor can be attributed to the acceleration of high-Tc phase formation along with the enhancement of intergrain coupling due to the elemental boron addition

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Synthesis and preliminary evaluation of 3-thiocyanato-1H-indoles as potential anticancer agents

A novel series of twenty 3-thiocyanato-1H-indoles, carrying diversification at positions N-1, C-2 and C-5 of the heterocyclic core, were synthesized; their antiproliferative activity against four human cancer cell lines (HL60, HEP-2, NCI-H292 and MCF-7) was evaluated, employing doxorubicin as positive control. Indole, N-methylindole and 2-(4-chlorophenyl)-N-methylindole demonstrated to be essentially inactive, whereas several of their congener 3-thiocyanato-1H-indoles displayed good to excellent levels of potency (IC50 ≤ 6 μM), while being non-hemolytic. N-Phenyl-3-thiocyanato-1H-indole and 1-methyl-2-(4-chlorophenyl)-3-thiocyanato-1H-indole showed good to high potency against all the cell lines. On the other side, the N-(4-chlorophenyl)-, 2-(4-chlorophenyl)- and 2-phenyl- 3-thiocyanato-1H-indole derivatives were slightly less active against the test cell lines. Overall, these results suggest that the indole-3-thiocyanate motif can be suitably decorated to afford highly cytotoxic compounds and that the substituted indole can be employed as a useful scaffold toward more potent compounds.Fil: Fortes, Margiani P.. Universidade Federal de Santa Maria; BrasilFil: da Silva, Paulo B. N.. Universidade Federal de Pernambuco; BrasilFil: Da Silva, Teresinha G.. Universidade Federal de Pernambuco; BrasilFil: Kaufman, Teodoro Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Militão, Gardenia C. G.. Universidade Federal de Pernambuco; BrasilFil: Silveira, Claudio C.. Universidade Federal de Santa Maria; Brasi

Stimulation OF IN VIVO dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid

The synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)-indole (JWH-018) has been detected in about 140 samples of a smokable herbal mixture termed "Spice". JWH-018 is a CB1 and CB2 agonist with a higher affinity than Δ(9)-THC. In order to investigate the neurobiological substrates of JWH-018 actions, we studied by microdialysis in freely moving rats the effect of JWH-018 on extracellular dopamine (DA) levels in the nucleus accumbens (NAc) shell and core and in the medial prefrontal cortex (mPFC). JWH-018, at the dose of 0.25 mg/kg i.p., increased DA release in the NAc shell but not in the NAc core and mPFC. Lower (0.125 mg/kg) and higher doses (0.50 mg/kg) were ineffective. These effects were blocked by CB1 receptor antagonists (SR-141716A and AM 251) and were absent in mice lacking the CB1 receptor. Ex vivo whole cell patch clamp recordings from rat ventral tegmental area (VTA) DA neurons showed that JWH-018 decreases GABAA-mediated post-synaptic currents in a dose-dependent fashion suggesting that the stimulation of DA release observed in vivo might result from disinhibition of DA neurons. In addition, on the "tetrad" paradigm for screening cannabinoid-like effects (i.e., hypothermia, analgesia, catalepsy, hypomotility), JWH-018, at doses of 1 and 3 mg/kg, i.p., produced CB1 receptor-dependent behavioural effects in rats. Finally, under appropriate experimental conditions, rats (20 μg/kg/inf iv, FR3; nose-poking) and mice (30 μg/kg/inf iv, FR1; lever-pressing) self-administer intravenously JWH-018. In conclusion, JWH-018 shares with the active ingredient of Marijuana, Δ(9)-THC, CB1-dependent reinforcing and DA stimulant actions

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (&gt;50 days) while having unaltered recent memories (&lt;24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC

Serotonergic signaling controls input-specific synaptic plasticity at striatal circuits

Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca2+signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes. Cavaccini and Gritti et al. combine chemogenetic and optogenetic approaches to show that serotonergic signaling provides a control mechanism of synaptic plasticity at thalamic inputs to the striatum