Modeling and Control of Layer Height in Laser Wire Additive Manufacturing

Laser Wire Additive Manufacturing (LWAM) is a flexible and fast manufacturing method used to produce variants of high metal geometric complexity. In this work, a physics-based model of the bead geometry including process parameters and material properties was developed for the LWAM process of large-scale products. The developed model aimed to include critical process parameters, material properties and thermal history to describe the relationship between the layer height with different process inputs (i.e., the power, the standoff distance, the temperature, the wire-feed rate, and the travel speed). Then, a Model Predictive Controller (MPC) was designed to keep the layer height trajectory constant taking into consideration the constraints faced in the LWAM technology. Experimental validation results were performed to check the accuracy of the proposed model and the results revealed that the developed model matches the experimental data. Finally, the designed MPC controller was able to track a predefined layer height reference signal by controlling the temperature input of the system.     

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The β₂-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of −31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.     

A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide,ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease.Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.Subject terms: Drug development, Drug safety     

Large Electrocaloric Responsivity and Energy Storage Response in the Lead-Free Ba(GexTi1−x)O3 Ceramics

Ferroelectric property that induces electrocaloric effect was investigated in Ba(Ge_xTi_1−x)O₃ ceramics, known as BTGx. X-ray diffraction analysis shows pure perovskite phases in tetragonal symmetry compatible with the P4mm (No. 99) space group. Dielectric permittivity exhibits first-order ferroelectric-paraelectric phase transition, confirmed by specific heat measurements, similar to that observed in BaTiO₃ (BTO) crystal. Curie temperature varies weakly as a function of Ge-content. Using the direct and indirect method, we confirmed that the adiabatic temperature change ΔT reached its higher value of 0.9 K under 8 kV/cm for the composition BTG6, corresponding to an electrocaloric responsivity ΔT/ΔE of 1.13 × 10⁻⁶ K.m/V. Such electrocaloric responsivity significantly exceeds those obtained so far in other barium titanate-based lead-free electrocaloric ceramic materials. Energy storage investigations show promising results: stored energy density of ~17 mJ/cm³ and an energy efficiency of ~88% in the composition BTG5. These results classify the studied materials as candidates for cooling devices and energy storage applications.     

Investigation of Structural,Physical, and Attenuation Parameters of Glass: TeO2-Bi2O3-B2O3-TiO2-RE2O3 (RE: La,Ce, Sm,Er, and Yb), and Applications Thereof

A novel series of glass, consisting of B₂O₃, Bi₂O₃, TeO₂, and TiO₂ (BBTT) containing rare earth oxide RE₂O₃, where RE is La, Ce, Sm, Er, and Yb, was prepared. We investigated the structural, optical, and gamma attenuation properties of the resultant glass. The optical energy bands, the linear refractive indices, the molar refractions, the metallization criteria, and the optical basicity were all determined for the prepared glass. Furthermore, physical parameters such as the density, the molar volume, the oxygen molar volume, and the oxygen packing density of the prepared glass, were computed. Both the values of density and optical energy of the prepared glass increased in the order of La₂O₃, Ce₂O₃, Sm₂O₃, Er₂O₃, and then Yb₂O₃. In addition, the glass doped with Yb₂O₃ had the lowest refractive index, electronic polarizability, and optical basicity values compared with the other prepared glass. The structures of the prepared glass were investigated by the deconvolution of infrared spectroscopy, which determined that TeO₄, TeO₃, BO₄, BO₃, BiO₆, and TiO₄ units had formed. Furthermore, the structural changes in glass are related to the ratio of the intensity of TeO₄/TeO₃, depending on the type of rare earth. It is also clarified that the resultant glass samples are good attenuators against low-energy radiation, especially those that modified by Yb₂O₃, which exhibited superior shielding efficiency at energies of 622, 1170, and 1330 keV. The optical and gamma ray spectroscopy results of the prepared glass show that it is a good candidate for nonlinear optical fibers, laser solid material, and optical shielding protection.     

Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways

Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.     

Antiproliferative triterpenes from Melaleuca ericifolia

Three new 28-norlupane triterpenes, 28-norlup-20(29)-en-3beta-hydroxy-17beta-hydroperoxide (1), 28-norlup-20(29)-en-3beta-hydroxy-17alpha-hydroperoxide (2), and 20 S-17beta,29-epoxy-28-norlupan-3beta-ol (3), were isolated from the leaves of Melaleuca ericifolia along with eight known pentacyclic triterpenes. The structures of the new compounds were elucidated by spectroscopic methods including 1D and 2D NMR spectroscopy and mass spectrometry. The isolated triterpenes were evaluated for antiproliferative activity against the malignant +SA mammary epithelial cell line.     

Anti-HIV-1 protease activity of lanostane triterpenes from the vietnamese mushroom Ganoderma colossum

Four new lanostane triterpenes, colossolactone V (1), colossolactone VI (2), colossolactone VII (3), and colossolactone VIII (4), were isolated from the fruiting bodies of the Vietnamese mushroom Ganoderma colossum, together with the known compound colossolactone E (5). The structures of 1- 4 were assigned on the basis of spectroscopic evidence, and their absolute configurations were determined by CD spectroscopy and the Mosher ester method. Compounds 1- 5, as well as two previously isolated compounds [schisanlactone A (6) and colossolactone G (7)] from the same mushroom, were evaluated for inhibition of HIV-1 protease, with IC 50 values for the most potent compounds ranging from 5 to 13 microg/mL.     

Meroditerpenoids and derivatives from the brown alga Cystoseira baccata and their antifouling properties

The brown alga Cystoseira baccata harvested along the Atlantic coasts of Morocco yielded seven new meroditerpenoids (1-4) and derivatives (5-7), whose chemical structures were elucidated mainly by 2D NMR and mass spectrometry. Surprisingly, for all these compounds, which possess a bicyclo[4.3.0]nonane ring system, a trans fusion of the bicyclic system was deduced by stereochemical studies even though such compounds isolated from Cystoseira species are known to have a typical cis orientation for the bridgehead methyls. The antifouling and antibacterial activities of compounds 1-5 and 7 were evaluated, as well as their toxicity toward nontarget species. Compounds 4, 5, and 7 showed antifouling activities against growth of microalgae, macroalgal settlement, and mussel phenoloxidase activity, while being nontoxic to larvae of sea urchins and oysters.