Wire Arc Additive Manufacturing of Aluminum Foams Using TiH2-Laced Welding Wires.

Composite materials made from aluminum foam are increasingly used in aerospace and automotive industries due to their low density, high energy absorption capacity, and corrosion resistance. Additive manufacturing processes offer several advantages over conventional manufacturing methods, such as the ability to produce significantly more geometrically complex components without the need for expensive tooling. Direct Energy Deposition processes like Wire Arc Additive Manufacturing (WAAM) enable the additive production of near-net-shape components at high build rates. This paper presents a technology for producing aluminum foam structures using WAAM. This paper's focus is on the development of welding wires that are mixed with a foaming agent (TiH2) and produce a foamed weld metal as well as their processing using MIG welding technology.

Dysregulation of cell state dynamics during early stages of serous endometrial carcinogenesis.

Serous endometrial carcinoma (SEC) constitutes about 10% of endometrial carcinomas and is one of the most aggressive and lethal types of uterine cancer. Due to the rapid progression of SEC, early detection of this disease is of utmost importance. However, molecular and cellular dynamics during the pre-dysplastic stage of this disease remain largely unknown. Here, we provide a comprehensive census of cell types and their states for normal, pre-dysplastic, and dysplastic endometrium in a mouse model of SEC. This model is associated with inactivation of tumor suppressor genes Trp53 and Rb1 , whose pathways are altered frequently in SEC. We report that pre-dysplastic changes are characterized by an expanded and increasingly diverse immature luminal epithelial cell populations. Consistent with transcriptome changes, cells expressing the luminal epithelial marker TROP2 begin to substitute FOXA2+ cells in the glandular epithelium. These changes are associated with a reduction in number and strength of predicted interactions between epithelial and stromal endometrial cells. By using a multi-level approach combining single-cell and spatial transcriptomics paired with screening for clinically relevant genes in human endometrial carcinoma, we identified a panel of 44 genes suitable for further testing of their validity as early diagnostic and prognostic markers. Among these genes are known markers of human SEC, such as C DKN2A, and novel markers, such as OAS2 and OASL, members of 2-5A synthetase family that is essential for the innate immune response. In summary, our results suggest an important role of the luminal epithelium in SEC pathogenesis, highlight aberrant cell-cell interactions in pre-dysplastic stages, and provide a new platform for comparative identification and characterization of novel, clinically relevant prognostic and diagnostic markers and potential therapeutic modalities.

Study of Precipitates in Oxide Dispersion-Strengthened Steels by SANS, TEM, and APT.

In this work, the nanostructure of oxide dispersion-strengthened steels was studied by small-angle neutron scattering (SANS), transmission electron microscopy (TEM), and atom probe tomography (APT). The steels under study have different alloying systems differing in their contents of Cr, V, Ti, Al, and Zr. The methods of local analysis of TEM and APT revealed a significant number of nanosized oxide particles and clusters. Their sizes, number densities, and compositions were determined. A calculation of hardness from SANS data collected without an external magnetic field, or under a 1.1 T field, showed good agreement with the microhardness of the materials. The importance of taking into account two types of inclusions (oxides and clusters) and both nuclear and magnetic scattering was shown by the analysis of the scattering data.

AMPK activation protects against prostate cancer by inducing a catabolic cellular state.

Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.

Tribological Properties of Ti-TiC Composite Coatings on Titanium Alloys.

The application of titanium and its alloys under friction conditions is severely restricted, owing to their poor wear resistance. The paper presents the results of studies of the composition, microstructure, and tribological properties of Ti-TiC-based composite coatings formed on titanium alloys by the electroarc treatment in an aqueous electrolyte using a graphite anode. It has been found that TiC grains have a different stoichiometry and do not contain oxygen. The grain size varies from hundreds of nanometers to tens of micrometers, and the micro-hardness of the treated surface reached the value of 29.5 GPa. The wear resistance of the treated surface increased approximately 40-fold, and the friction coefficient with steel decreased to 0.08-0.3 depending on the friction conditions. The formation of a composite material based on Ti-TiC will contribute to the effective protection of titanium alloys from frictional loads in engineering.

A Novel Model of Ultrasonic Fatigue Test in Pure Bending.

The very high cycle fatigue (VHCF) failure of in-service components is mainly caused by the vibration of thin-wall elements at a high frequency. In this work, a novel model of ultrasonic fatigue test was developed to test thin-wall material in bending up to VHCF with an accelerated frequency. The theoretical principle and finite element analysis were introduced for designing a sample that resonated at the frequency of 20 kHz in flexural vibration. In the advantage of the second-order flexural vibration, the gauge section of the sample was in the pure bending condition which prevented the intricate stress condition for thin-wall material as in the root of cantilever or the contact point of three points bending. Moreover, combining the constraint and the loading contact in one small section significantly reduced heating that originated from the friction at an ultrasonic frequency. Both strain gauge and deflection angle methods were applied to verify the controlling of stress amplitude. The fractography observation on Ti6Al4V samples indicated that the characterized fracture obtained from the novel model was the same as that from the conventional bending test.

Severe Intraoperative Hyperglycemia and Infectious Complications After Elective Brain Neurosurgical Procedures: Prospective Observational Study.

BACKGROUND: Postoperative infections after brain surgery are a serious complication potentially worsening the outcome of surgical treatment. Severe intraoperative hyperglycemia (SIH) contributes to both infectious and noninfectious postoperative complications. However, there are a lack of data on the incidence of SIH in patients undergoing elective neurosurgical brain procedures and its association with the risk of postoperative infections. METHODS: A total of 514 patients were prospectively enrolled in this single-center observational cohort clinical study to assess the incidence of SIH (blood glucose concentration [BGC] ≥180 mg/dL) in adult patients undergoing elective brain neurosurgical procedures and its association with postoperative infections. Both nondiabetic and diabetic patients were included in the study. BGC was determined by whole-blood analyses taken at the beginning and at the end of the surgery. Diagnosis of infection (wound, pulmonary, blood stream, urinary tract infection, or central nervous system infection) was established according to US Centers for Disease Control and Prevention (CDC) criteria within the first postoperative week. RESULTS: SIH was recorded in at least 1 blood sample in 23 patients (4.5%). Infectious complications within the first postoperative week were diagnosed in 40 patients (7.8%). Five of 23 patients (22%) with SIH had postoperative infections, compared with 35 of 491 patients (7%) without SIH (odds ratio [OR] = 3.71; 95% confidence interval [CI], 1.24-11.09; P = .018 after fitting a multiple logistic regression model to adjust for age, body mass index [BMI], and surgery duration). Intraoperative BGC >140 mg/dL was also associated with an increased risk of postoperative infections (OR = 3.10; 95% CI, 1.43-6.75; P = .004). Elevated preoperative glycated hemoglobin (HbA1c) concentration was also associated with postoperative infections in the study population (OR = 2.4; 95% CI, 1.02-6.00; P = .045). Age, BMI, American Society of Anesthesiologists (ASA) physical status, type of surgery, and duration of intervention had no significant association with the postoperative infection rate. CONCLUSIONS: SIH is associated with a higher risk of infections within the first postoperative week in patients undergoing elective brain neurosurgical procedures. Preoperative HbA1c is a reliable marker of the potential risk both of SIH and postoperative infections in the selected cohort. Future studies need to assess possible improvements in outcome under more precise monitoring and tighter control of perioperative hyperglycemia.

Synthesis, inhibitory activity and oral dosing formulation of AV5124, the structural analogue of influenza virus endonuclease inhibitor baloxavir.

BACKGROUND: The development and clinical implementation of the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil was a breakthrough in influenza therapy, but it was associated with the emergence of drug-resistant variants. OBJECTIVES: To design and synthesize structural analogues of CEN inhibitors and evaluate their safety, pharmacokinetics and antiviral potency in vitro and in vivo. METHODS: The drug candidate AV5124 and its active metabolite AV5116 were synthesized based on pharmacophore modelling. Stability in plasma and microsomes, plasma protein binding, cytotoxicity and antiviral activities were assessed in vitro. Pharmacokinetics after IV or oral administration were analysed in CD-1 mice. Acute toxicity and protective efficacy against lethal A(H1N1)pdm09 influenza virus challenge were examined in BALB/c mice. RESULTS: Pharmacophore model-assisted, 3D molecular docking predicted key supramolecular interactions of the metal-binding group and bulky hydrophobic group of AV5116 with the CEN binding site (Protein Data Bank code: 6FS6) that are essential for high antiviral activity. AV5116 inhibited influenza virus polymerase complexes in cell-free assays and replication of oseltamivir-susceptible and -resistant influenza A and B viruses at nanomolar concentrations. Notably, AV5116 was equipotent or more potent than baloxavir acid (BXA) against WT (I38-WT) viruses and viruses with reduced BXA susceptibility carrying an I38T polymerase acidic (PA) substitution. AV5116 exhibited low cytotoxicity in Madin-Darby canine kidney cells and lacked mitochondrial toxicity, resulting in favourable selective indices. Treatment with 20 or 50 mg/kg AV5124 prevented death in 60% and 100% of animals, respectively. CONCLUSIONS: Overall, AV5124 and A5116 are promising inhibitors of the influenza virus CEN and warrant further development as potent anti-influenza agents.

Real-time 1.5 kHz adaptive optical system to correct for atmospheric turbulence.

Problems of constructing an adaptive optical system intended for correcting the wavefront of laser radiation that has passed through a turbulent atmosphere are considered. To ensure high-quality wavefront correction, the frequency of the discrete system should be at least 1 kHz or more. This performance can be achieved by using FPGA as the main control element of the system. The results of a laboratory experiments of the laser beam phase fluctuations caused by turbulence, produced by the airflow of a fan heater, correction by means of the FPGA-based adaptive optical system are presented. The system efficiency was evaluated at various correction frequencies up to 1875 Hz.

Laser beam focusing through a moderately scattering medium using a bimorph mirror.

The rarely considered case when the optical radiation passes through the weakly scattering medium, e.g. mid-density atmospheric fog with the number of scattering events up to 10 was investigated in this paper. We demonstrated an improvement of focusing of a laser beam (λ=0.65 µm) passed through the 5 mm-thick layer of scattering suspension of 1 µm polystyrene microbeads diluted in a distilled water. For the first time the low-order aberration corrector - wide aperture bimorph deformable mirror with 48 electrodes configured in 6 rings was used to optimize a far-field focal spot. We compared efficiencies of the algorithm that optimized the positions of the focal spots on Shack-Hartmann type sensor and the algorithm that optimized the peak brightness and the diameter of the far-field focal spot registered with a CCD. We experimentally demonstrated the increase of the peak brightness of the far-field focal spot by up to 60% due to the use of the bimorph deformable mirror for beam focusing through the scattering medium with concentration values of scatterers ranged from 105 to 106 mm-3.

Influence of Titanium Surface Porosity on Adhesive Strength of Coatings Containing Calcium Silicate.

Titanium-based alloys are widely used in aerospace engineering. They have good mechanical and corrosion properties but, in some cases, the material itself or the coating should meet some additional requirements. For example, it may be a requirement of high reflectance to provide effective temperature control. Wollastonite is a promising component for reflective coatings because it improves both their whiteness and mechanical properties. This paper presents the results of studying the composition, the structure and the adhesive strength of wollastonite-containing silicate coatings to titanium substrate. The surface of titanium samples was pre-treated by laser cladding with TiC and etching to provide surface porosity. It has been shown that such treatment allows a significantly increase in the adhesive strength of the coating to the substrate. A decrease in the adhesive strength was observed on titanium samples with an excess of TiO2 on the surface. This is caused by the formation of crystalline PbTiO3 at the interface.

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.

Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8+ epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. Inactivation of the tumor suppressor genes Trp53 and Rb1 in PAX8+ cells, but not in FOXJ1+ cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8+ cells represents the main source of regeneration of the adult endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma and suggest that PAX8+ cells represent the cell of origin of this neoplasm.

Most Commonly Mutated Genes in High-Grade Serous Ovarian Carcinoma Are Nonessential for Ovarian Surface Epithelial Stem Cell Transformation.

High-grade serous ovarian carcinoma (HGSOC) is the fifth leading cause of cancer-related deaths of women in the United States. Disease-associated mutations have been identified by the Cancer Genome Atlas Research Network. However, aside from mutations in TP53 or the RB1 pathway that are common in HGSOC, the contributions of mutation combinations are unclear. Here, we report CRISPR mutagenesis of 20 putative HGSOC driver genes to identify combinatorial disruptions of genes that transform either ovarian surface epithelium stem cells (OSE-SCs) or non-stem cells (OSE-NSs). Our results support the OSE-SC theory of HGSOC initiation and suggest that most commonly mutated genes in HGSOC have no effect on OSE-SC transformation initiation. Our results indicate that disruption of TP53 and PTEN, combined with RB1 disruption, constitutes a core set of mutations driving efficient transformation in vitro. The combined data may contribute to more accurate modeling of HGSOC development.

Non-rigid Diarylmethyl Analogs of Baloxavir as Cap-Dependent Endonuclease Inhibitors of Influenza Viruses.

4-Substituted 2,4-dioxobutanoic acids inhibit influenza virus cap-dependent endonuclease (CEN) activity. Baloxavir marboxil, 4, is approved for treating influenza virus infections. We describe here the synthesis and biological evaluation of active compounds, 5a-5g, and their precursors (6a, 6b, 6d, and 6e) with flexible bulky hydrophobic groups instead of the rigid polyheterocyclic moieties. In silico docking confirmed the ability of 5a-5g to bind to the active site of influenza A CEN (PDB code: 6FS6) like baloxavir acid, 3. These novel compounds inhibited polymerase complex activity, inhibited virus replication in cells, prevented death in a lethal influenza A virus mouse challenge model, and dramatically lowered viral lung titers. 5a and 5e potently inhibited different influenza genera in vitro. Precursors 6a and 6d demonstrated impressive mouse oral bioavailability with 6a, providing effective in vivo protection. Thus, these novel compounds are potent CEN inhibitors with in vitro and in vivo activity comparable to baloxavir.

WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations.

Many high-grade serous carcinomas (HGSCs) likely originate in the distal region of the Fallopian tube's epithelium (TE) before metastasizing to the ovary. Unfortunately, molecular mechanisms promoting malignancy in the distal TE are obfuscated, largely due to limited primary human TE gene expression data. Here we report an in depth bioinformatic characterization of 34 primary TE mRNA-seq samples. These samples were prepared from proximal and distal TE regions of 12 normal Fallopian tubes. Samples were segregated based on their aldehyde dehydrogenase (ALDH) activity. Distal cells form organoids with higher frequency and larger size during serial organoid formation assays when compared to proximal cells. Consistent with enrichment for stem/progenitor cells, ALDH+ cells have greater WNT signaling. Comparative evaluation of proximal and distal TE cell population's shows heightened inflammatory signaling in distal differentiated (ALDH-) TE. Furthermore, comparisons of proximal and distal TE cell populations finds that the distal ALDH+ TE cells exhibit pronounced expression of gene sets characteristic of HGSC sub-types. Overall, our study indicates increased organoid forming capacity, WNT/inflammatory signaling, and HGSC signatures underlie differences between distal and proximal regions of the human TE. These findings provide the basis for further mechanistic studies of distal TE susceptibility to the malignant transformation.

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells.

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency and delay growth of human prostate cancer xenografts by reducing the number of cancer-propagating cells. In sum, our study provides a definitive proof of tumor-suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer-propagating cells in prostate cancers with MME downregulation.

Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5-CD44+ cells.

Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5-CD44+ cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.

Physical confinement induces malignant transformation in mammary epithelial cells.

The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics.

CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis.

: New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) ß1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer. SIGNIFICANCE: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.