Measurement of adsorption of a single component from the liquid phase : modelling investigation and sensitivity analysis

In this work, we consider an alternative approach for the measurement of adsorption from the liquid phase. Consider a mixture consisting of a non-adsorbed component (B) and an adsorbed component (A) present at some low concentration. Initially, a feed of component B only flows through a column packed with an adsorbent. Then, the feed is switched to the mixture of A and B. As soon as the mixture enters the column, there will be a reduction in the outlet flow rate as component A leaves the liquid phase and passes into the adsorbed phase. There are three stages to this work. The first is to develop overall and component balances to show how the amount adsorbed of component A can be determined from the variation in the column outlet flow rate. The second is to determine the actual variation in the column outlet flow rate for both plug flow and axial-dispersed plug flow. The final stage is to consider the suitability of a gravity-fed system to deliver the feed to the column. An analysis of the results shows that the experimental arrangement should be able to accurately monitor adsorption from the liquid phase where the mass fraction of the solute is of the order of 1%: the limiting experimental factor is how constant the volumetric flow rate of the liquid feed can be maintained

ROLE OF EXCITATORY SEROTONERGIC SIGNALING IN THE PATHWAY-SPECIFIC NEUROMODULATION OF STRIATAL SYNAPTIC PLASTICITY

The dorsolateral striatum (DLS) of the basal ganglia plays a critical role in action selection and motor control. The DLS receives cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Dopamine and 5-HT act as circuit neuromodulators by activating both stimulatory (Gs) and inhibitory (Gi) protein-coupled receptors that regulate synaptic mechanisms of plasticity. On a system level, 5-HT signal has been classically associated with learning of negative events, acting as an opponent of dopamine regulation of rewarding processes. Recent evidence has challenged this view, suggesting that 5HT signaling can synergize with dopamine signaling to shape reward-guided behavior. However, the molecular and synaptic correlates of this behavioral role of 5-HT at striatal circuits remain to be established. To address this hypothesis, we investigated the role of serotonergic signaling in regulating the strength of glutamatergic synaptic connections to the Medium Spiny Neurons of the direct pathway (dMSNs), which mediate movement, reward and reinforcement. Specifically, we focused on the regulation of distinct forms of long-term synaptic plasticity that depend on both the relative timing of a neuron output and an input spike (Spike timing-dependent plasticity, STDP), and on the pattern of neuronal stimulation (high-frequency stimulation, HFS). Upon a STDP protocol, the chemo-genetic inhibition of 5-HT release resulted in a long lasting depression (STDP-LTD) of glutamatergic afferents to the dMSNs of the DLS. The synaptic effects of chemo-genetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R). This form of LTD was independent from presynaptic CB1 receptor (CB1R) activation, it showed a postsynaptic locus of expression, and it was associated with an increased dendritic Ca2+ signal. We obtained similar results upon HFS; antagonism of 5-HT4R resulted in a CB1R independent form of HFS-LTD, which was associated with enhanced dendritic Ca2+ levels. Collectively, these data provide molecular and synaptic insights on the neuromodulatory role of 5-HT at striatal circuits. Dysfunctional serotonergic modulation of striatal circuits has been associated with repetitive behaviors in obsessive-compulsive disorders (OCD). Thus, elucidating how 5-HT4R manipulation affects aspects of reward-guided behavior, and how this is causally relevant for defined cognitive processes implicated in action control, could facilitate the development of new pharmacological approaches to treat OCD symptoms

Modelling RT-qPCR cycle-threshold using digital PCR data for implementing SARS-CoV-2 viral load studies

Objectives To exploit the features of digital PCR for implementing SARS-CoV-2 observational studies by reliably including the viral load factor expressed as copies/μL. Methods A small cohort of 51 Covid-19 positive samples was assessed by both RT-qPCR and digital PCR assays. A linear regression model was built using a training subset, and its accuracy was assessed in the remaining evaluation subset. The model was then used to convert the stored cycle threshold values of a large dataset of 6208 diagnostic samples into copies/μL of SARSCoV- 2. The calculated viral load was used for a single cohort retrospective study. Finally, the cohort was randomly divided into a training set (n = 3095) and an evaluation set (n = 3113) to establish a logistic regression model for predicting case-fatality and to assess its accuracy. Results The model for converting the Ct values into copies/μL was suitably accurate. The calculated viral load over time in the cohort of Covid-19 positive samples showed very low viral loads during the summer inter-epidemic waves in Italy. The calculated viral load along with gender and age allowed building a predictive model of case-fatality probability which showed high specificity (99.0%) and low sensitivity (21.7%) at the optimal threshold which varied by modifying the threshold (i.e. 75% sensitivity and 83.7% specificity). Alternative models including categorised cVL or raw cycle thresholds obtained by the same diagnostic method also gave the same performance. Conclusion The modelling of the cycle threshold values using digital PCR had the potential of fostering studies addressing issues regarding Sars-CoV-2; furthermore, it may allow setting up predictive tools capable of early identifying those patients at high risk of case-fatality already at diagnosis, irrespective of the diagnostic RT-qPCR platform in use. Depending upon the epidemiological situation, public health authority policies/aims, the resources available and the thresholds used, adequate sensitivity could be achieved with acceptable low specificity

Chemical, Electrochemical, and Surface Morphological Studies of the Corrosion Behavior of the AZ31 Alloy in Simulated Body Fluid: Effect of NaOH and H2O2Surface Pretreatments on the Corrosion Resistance Property

Magnesium and its alloys have attracted attention for biomedical implant materials in dental and orthopedic applications because of their biodegradability and similar properties to human bones. The very high rate of degradation in the physiological systems is, however, a major setback to their utilization. Chemical modification is one of the approaches adopted to enhance the corrosion resistance property of Mg and its alloys. In this work, NaOH and H2O2were used as a pretreatment procedure to improve the corrosion resistance of the AZ31 Mg alloy in simulated body fluid (SBF). Advanced techniques such as dynamic electrochemical impedance spectroscopy (dynamic-EIS), atomic force microscopy, and optical profilometry were used in addition to the classical mass loss, hydrogen evolution, EIS, and polarization techniques to study the corrosion resistance property of the alloy in SBF for 30 h. Results obtained show that the surface treatment significantly enhanced the corrosion resistance property of the alloy. From dynamic-EIS at 30 h, the charge transfer resistance of the untreated AZ31 Mg alloy is 432.6 ω cm2, whereas 822.7 and 2617.3 ω cm2are recorded for NaOH- and H2O2-treated surfaces, respectively. H2O2is a better treatment reagent than NaOH. The mechanism of corrosion of both untreated and treated samples in the studied corrosive medium has been discussed. © 2022 American Chemical Society. All rights reserved

Novel bicistronic lentiviral vectors correct beta-Hexosaminidase deficiency in neural and hematopoietic stem cells and progeny: implications for in vivo and ex vivo gene therapy of GM2 gangliosidosis

The favorable outcome of in vivo and ex vivo gene therapy approaches in several Lysosomal Storage Diseases suggests that these treatment strategies might equally benefit GM2 gangliosidosis. Tay-Sachs and Sandhoff disease (the main forms of GM2 gangliosidosis) result from mutations in either the HEXA or HERB genes encoding, respectively, the alpha- or beta-subunits of the lysosomal beta-Hexosaminidase enzyme. In physiological conditions, alpha- and beta-subunits combine to generate beta-Hexosaminidase A (HexA, alpha beta) and beta-Hexosaminidase B (HexB, 1313). A major impairment to establishing in vivo or ex vivo gene therapy for GM2 gangliosidosis is the need to synthesize the alpha- and beta-subunits at high levels and with the correct stoichiometric ratio, and to safely deliver the therapeutic products to all affected tissues/organs. Here, we report the generation and in vitro validation of novel bicistronic lentiviral vectors (LVs) encoding for both the murine and human codon optimized Hexa and Hex!) genes. We show that these LVs drive the safe and coordinate expression of the alpha- and beta-subunits, leading to supranormal levels of beta-Hexosaminidase activity with prevalent formation of a functional HexA in SD murine neurons and glia, murine bone marrow-derived hematopoietic stem/progenitor cells (HSPCs), and human SD fibroblasts. The restoration/overexpression of beta-Hexosaminidase leads to the reduction of intracellular GM2 ganglioside storage in transduced and in cross-corrected SD murine neural progeny, indicating that the transgenic enzyme is secreted and functional. Importantly, bicistronic LVs safely and efficiently transduce human neurons/glia and CD34 + HSPCs, which are target and effector cells, respectively, in prospective in vivo and ex vivo GT approaches. We anticipate that these bicistronic LVs may overcome the current requirement of two vectors co-delivering the alpha- or beta-subunits genes. Careful assessment of the safety and therapeutic potential of these bicistronic LVs in the SD murine model will pave the way to the clinical development of LV-based gene therapy for GM2 gangliosidosis

Multinational evaluation of the measurement invariance of the level of personality functioning scale–brief form 2.0: comparison of student and community samples across seven countries

DSM-5’s Level of Personality Functioning Scale (LPFS) was introduced as a dimensional rating of impairments in self- and interpersonal functioning, and the LPFS – Brief Form (LPFS-BF) was the first published corresponding self-report. The updated LPFS-BF 2.0 has been translated into several languages and international research supports many of the instrument’s psychometric properties; however, its measurement invariance has only been evaluated across a few countries. This study expands previous studies as an introductory step in a global evaluation of the LPFS-BF 2.0’s measurement invariance. Archival data (N = 5,618, 57% female) from seven countries (Canada, Chile, Denmark, Germany, Italy, United Arab Emirates, United States of America) were used for this study. Participants were recruited from both community (n = 4,677) and student (n = 941) populations. After confirming adequate model fit separately in the community and student samples, we evaluated a series of increasingly stringent model comparisons to test three aspects of measurement invariance (configural, metric, scalar) and then examined latent mean differences across countries. Full scalar invariance was supported in the community sample and partial scalar invariance was supported in the student sample. Evaluation of latent mean differences revealed multiple significant differences. Overall, the LPFS-BF 2.0 appears to assess self- and interpersonal functioning impairment similarly across the included countries. Findings are discussed through the lenses of the cultures from which participants were recruited, as well as in the context of alternative explanations. Limitations, plans for future research, and implications for both research and clinical practice are offered

Behaviour and Degenerative Changes in the Basal Forebrain Systems of Aged Rats (12 Months Old) after Levo-Acetyl-Carnitine Treatments

One group of six male control rats [12 months old] and one group of six male rats of the same age, singularly maintained in a cage, and treated with acetyl-L-carnitine-HCl [(gamma-trimethyl-beta-acetyl-butyrobetaine-HCl: Sigma-Tau code ST200 or ALCAR: 60 mg/kg/day[7]/po)] for six months were tested in the spatial learning/memory Morris mazewater task and for atrophy and cell loss in seven myelo- and cytostructurally defined basal forebrain (BF) cholinergic regions [Freddi et al., 2009]. Coronal sections 25 ?m thick were cut through the BF regions and processed every 200 ?m for choline acetyltransferase (ChAT) immunohistochemistry. The ALCAR-treated rats had significantly shorter exit times on the Morris maze-water task test than the control rats (average \ub1 SD 28.3 \ub1 12.4 s vs. 61.16 \ub1 4.67 s; t = 6.07, DOF = 10, P = 0.0001). Degenerative morphological changes in the BF ChAT-positive cells were observed in the substantia innominata pars anterior of the control rats but not in the treated animals (P < 0.05). In the BF, the counted and estimated average number of ChAT + cells in the 12-month-old ALCAR-treated rats (ChAT-ALCAR-12+ [Nos. 2,3,4]) was higher but not significantly (15.288 \ub1 3281) than that counted and estimated in the 12-month-old control rats [(ChAT-CT-12 [Nos. 1,2,3]) (11.508 \ub1 3868), t = 1.82, DOF = 10, P = 0.319]. In the substantia innominata pars posterior, the ChAT+ cells were significantly more numerous (P < 0.05) in the 12-month-old ALCAR-treated rats (ChAT-ALCAR-12 + [Nos. 2,3,4]) than in the control rats (ChAT-CT-12 [Nos. 1,2,3]). Above all, these results dem-onstrate that treatment with ALCAR from the age of 6 up to 12 months significantly attenuated spatial learning/memory impairment on the Morris maze-water behavioral task (P < 0.001) and also importantly reduced degeneration in size and number of cholinergic cells in the nucleus basalis magnocellularis of the BF. Accordingly, the surviving cholinergic neurons found in the BF of the ALCAR-treated rats might play an important role in modulating cortical activity and facilitating processes of attention, learning and memory

Electroencephalographic Changes after a Marathon at 4300 M of Altitude

Running at altitude is gaining greater popularity but it may expose participants to the risk of acute mountain sickness (AMS). The study investigated electroencephalographic (EEG) changes and eventual symptoms suggestive of AMS in 5 well-trained lowland native male runners (average age, 38.2 \uf0b1 4.6 years; VO2 peak 61.4 \uf0b1 2.7 mL\ub7kg\u20131\ub7min\u20131 at sea level; best marathon performance at sea level under 3 hours), who completed a marathon at 4300 m altitude. EEG, per-centage of peripheral arterial oxygen saturation (% SpaO2) and heart rate (HR) were recorded during wakefulness at rest (supine position) and in comfort: 1) at sea level; 2) at 3600 m after 32 - 38 hours of acute acclimatization; 3) at 4300 m after 145 - 153 hours of chronic acclimatization; and 4) at 4300 m immediately after a marathon race. Symptoms of AMS were evaluated with the Lake Louise questionnaire before any ECG recording. There was a significant decrease in low-voltage high-frequency activities at rest after acute hypoxic-hypobaric exposure at 3600 m as compared to sea level. After six days of acclimatization at 4300 m there was a significant increase in the power of low-voltage high-frequency activities, particularly beta and gamma, indicating an aroused waking state and an integrated activity across widely dis-tributed cortical regions. An increase in the power of low-voltage high-frequency activities over the entire cortex was observed, particularly after completion of the marathon at 4300 m. The increase in the high-frequency activities was probably due to direct and indirect reflex activation of the forebrain and reticular activating system involved in behav-ioral and metabolic integration of autonomic control and arousal and due to residual activation of the somatomotor and parietal cortex after the end of the marathon. Lake Louise score always resulted lower than 3, indicating no signs of AMS in all the runners. The results of this study indicate that in well-trained and acclimatized athletes, arousal has a protective role in preventing excessive oxygen deprivation also after an endurance exercise performed at high altitude. The absence of AMS fond in our study bear out that well trained and acclimatized runners, can safely participate in a marathon at high altitude that gives rise to temporary EEG changes without inducing paroxysmal phenomena

Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer

Cisplatin-based combinations are efficacious in increasing the overall survival of patients with non-small cell lung cancer (NSCLC), but their toxicity makes them unsuitable for elderly and unfit patients. The primary objective of this non-randomized phase II study was to evaluate the feasibility and activity of the gemcitabine plus vinorelbine combination in previously untreated elderly and/or unfit patients with measurable stage III or IV NSCLC. Forty-three patients aged ≥ 65 years or with contraindications against cisplatin treatment (36 males and seven females: median age 66 years; range 48–75: PS 0 = 11, PS 1 = 19, PS 2 = 13) received intravenous (i.v.) gemcitabine 1000 mg m–2, followed by vinorelbine 25 mg m–2i.v. on day 1 and 8 every 21 days. Fifteen patients (34.9%) achieved partial remission (confidence interval: 27.6–42.2%) for a median duration of 6 months; the median survival of these patients has not yet been reached. A further 15 had stable disease for a median of 4 months and a median survival of 7 months. The 10 patients (23.2%) who experienced disease progression had a median survival of 4 months. Three patients are not evaluable. The 1-year actuarial survival rate is 31.1%. The treatment was well tolerated: only 35% of the patients had grade 3 or 4 granulocytopenia on day 14, none experienced episodes of neutropenic fever, and there was no evidence of severe haematological toxicity upon recycling. Only 9% of the patients suffered from gastrointestinal toxicity (grade 3); increased but reversible transaminase levels were observed in 11.6%. In conclusion, the results of this phase II study show that the combination of gemcitabine and vinorelbine is active and well tolerated in NSCLC, and thus encourage its use in elderly or unfit patients. © 2000 Cancer Research Campaig