The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD+ to ADP-ribose and nicotinamide, CD38 governs organismal NAD+ homeostasis and the activity of NAD+-dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD+ decline underlying adverse metabolic states, frailty and reduced health span. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by fibrosis in multiple organs. We sought to test the hypothesis that inhibition of the CD38 ecto-enzymatic activity using a heavy-chain monoclonal antibody Ab68 will, via augmenting organismal NAD+, prevent fibrosis in a mouse model of SSc characterized by NAD+ depletion. Here we show that treatment of mice with a non-cytotoxic heavy-chain antibody that selectively inhibits CD38 ectoenzyme resulted in NAD+ boosting that was associated with significant protection from fibrosis in multiple organs. These findings suggest that targeted inhibition of CD38 ecto-enzymatic activity could be a potential pharmacological approach for SSc fibrosis treatment.

<div class="section abstract"><div class="htmlview paragraph">Hydrogen internal combustion engines are a robust and cost-efficient solution to decarbonize the heavy- duty on- and off-highway vehicle sectors. Mature base technology, low additional system costs, and no dependence on expensive raw materials will enable a fast market penetration and thus a rapid reduction of CO2 emissions, provided customer expectations for performance, driving range and total cost of ownership as well as regulatory requirements such as ultra-low pollutant emissions can be met.</div><div class="htmlview paragraph">The power density of a hydrogen engine is currently limited by uncontrolled combustion events such as knocking, pre-ignition and backfiring. Tenneco, TME and FEV show in this paper how the optimization of components and combustion strategies minimizes these risks such that Diesel-like performance can be reached.</div></div>

In this work, dissimilar rotary inertia friction welds between 422 martensitic stainless steel and 4140 martensitic low-alloy steel were made to fabricate prototype heavy-duty diesel engine pistons. The influence of the inertia friction welding process and post weld heat treatment (PWHT) temperature on the interfacial microstructure evolutions and corresponding effects on mechanical properties of the 422/4140 welds were evaluated in detail. Carbon diffused from the 4140 side to the 422 side during PWHT at 650 °C for 1.5 h, causing the formation of a hard carbide-rich layer on the 422 side, and a softer but discontinuous C-depleted layer the 4140 side. PWHT at 700 °C for 1.5 h greatly accelerated C diffusion across the interface relative to 650 °C, resulting in a thicker hard carbide-rich layer and a relatively thick and continuous layer of coarse C-depleted grains (ferrite) on the 4140 side. In addition, the PWHT temperature greatly influenced the tensile properties and fracture behavior of the welds, with the 650 °C PWHT-ed samples failing predominately in a ductile manner in the 4140 heat affected zone during tensile testing. Conversely, the 700 °C PWHT specimens exhibited a strength reduction compared with the 650 °C PWHT specimens because of additional coarsening of the interfacial ferrite layer and softening of the base materials during PWHT, with brittle fracture between the hard and soft layers the predominate failure mechanism. Based on the findings, a reduced PWHT temperature and/or time, minimizing the hardness differential of the base metals, and pre-heating the 422 steel prior to welding are the potential pathways to achieve a more optimal balance between desirable tempering and stress relief of the weld microstructure and undesirable C migration across the weld interface, and to reduce the strength mismatch across the weld.

Abstract This article reviews the analytical techniques used for phase identification in components, including x-ray diffraction, metallography/microscopy, electron backscatter diffraction, trasmission electron microscopy,and atom probe tomography. The article addresses the advantages and disadvantages of each technique compared to the other approaches.

ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

ABSTRACT The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density cells. TNB-928B induces preferential effector T-cell activation, proliferation, and selective cytotoxic activity on high FRα expressing cells while sparing low FRα expressing cells. In addition, TNB-928B induces minimal cytokine release compared to a positive control TCE containing OKT3. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T-cells and robust tumor clearance in vivo, promoting T-cell infiltration and antitumor activity in mouse models of ovarian cancer. TNB-928B exhibits pharmacokinetics similar to conventional antibodies, which are projected to enable favorable administration in humans. TNB-928B is a novel TCE with enhanced safety and specificity for the treatment of ovarian cancer.

ABSTRACT Cluster of differentiation 38 (CD38) is an ecto-enzyme expressed primarily on immune cells that metabolizes nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose or cyclic ADP-ribose and nicotinamide. Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate and nicotinamide mononucleotide, a critical NAD+ precursor in the salvage pathway. NAD+ is an important coenzyme involved in several metabolic pathways and is a required cofactor for the function of sirtuins (SIRTs) and poly (adenosine diphosphate-ribose) polymerases. Declines in NAD+ levels are associated with metabolic and inflammatory diseases, aging, and neurodegenerative disorders. To inhibit CD38 enzyme activity and boost NAD+ levels, we developed TNB-738, an anti-CD38 biparatopic antibody that pairs two non-competing heavy chain-only antibodies in a bispecific format. By simultaneously binding two distinct epitopes on CD38, TNB-738 potently inhibited its enzymatic activity, which in turn boosted intracellular NAD+ levels and SIRT activities. Due to its silenced IgG4 Fc, TNB-738 did not deplete CD38-expressing cells, in contrast to the clinically available anti-CD38 antibodies, daratumumab, and isatuximab. TNB-738 offers numerous advantages compared to other NAD-boosting therapeutics, including small molecules, and supplements, due to its long half-life, specificity, safety profile, and activity. Overall, TNB-738 represents a novel treatment with broad therapeutic potential for metabolic and inflammatory diseases associated with NAD+ deficiencies. Abbreviations: 7-AAD: 7-aminoactinomycin D; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cell-mediated phagocytosis; ADPR: adenosine diphosphate ribose; APC: allophycocyanin; cADPR: cyclic ADP-ribose; cDNA: complementary DNA; BSA: bovine serum albumin; CD38: cluster of differentiation 38; CDC: complement dependent cytotoxicity; CFA: Freund’s complete adjuvant; CHO: Chinese hamster ovary; CCP4: collaborative computational project, number 4; COOT: crystallographic object-oriented toolkit; DAPI: 4′,6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; DSC: differential scanning calorimetry; 3D: three dimensional; εNAD+: nicotinamide 1,N6-ethenoadenine dinucleotide; ECD: extracellular domain; EGF: epidermal growth factor; FACS: fluorescence activated cell sorting; FcγR: Fc gamma receptors; FITC: fluorescein isothiocyanate; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IgG: immunoglobulin; IFA: incomplete Freund’s adjuvant; IFNγ: Interferon gamma; KB: kinetic buffer; kDa: kilodalton; KEGG: kyoto encyclopedia of genes and genomes; LDH: lactate dehydrogenase; M: molar; mM: millimolar; MFI: mean fluorescent intensity; NA: nicotinic acid; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NAM: nicotinamide; NGS: next-generation sequencing; NHS/EDC: N-Hydroxysuccinimide/ ethyl (dimethylamino propyl) carbodiimide; Ni-NTA: nickel-nitrilotriacetic acid; nL: nanoliter; NK: natural killer; NMN: nicotinamide mononucleotide; OD: optical density; PARP: poly (adenosine diphosphate-ribose) polymerase; PBS: phosphate-buffered saline; PBMC: peripheral blood mononuclear cell; PDB: protein data bank; PE: phycoerythrin; PISA: protein interfaces, surfaces, and assemblies: PK: pharmacokinetics; mol: picomolar; RNA: ribonucleic acid; RLU: relative luminescence units; rpm: rotations per minute; RU: resonance unit; SEC: size exclusion chromatography; SEM: standard error of the mean; SIRT: sirtuins; SPR: surface plasmon resonance; µg: microgram; µM: micromolar; µL: microliter

Copper-cobalt deposits in the Central African Copperbelt belong to the Sediment-Hosted Stratiform Copper (SHSC) type and are situated in the Neoproterozoic Katanga Supergroup. This paper describes in detail the geology, geochemistry and hydrometallurgy of cobalt, with a special focus on the Black Ore Mineralised Zone (BOMZ) unit from the Ruashi Cu-Co deposit as a case study. Based on results from fieldwork and laboratory testing, it was concluded that the BOMZ consists of a succession of massive and stratified dolostones, which are weathered into carbonaceous clay dolostones and clays. The Lower “Calcaire à Minéreaux Noirs Formation” (Lower CMN Formation) consists of stratified and finely laminated dolostones, which are weathered at the surface into clayey to siliceous dolostones. The cobalt concentration in the weathering zone is due to supergene enrichment, a process that is linked to the formation of a cobalt cap. The ore consists of heterogenite associated with minor amounts of chrysocolla and malachite. Minor carrollite, chalcopyrite, chalcocite and bornite are present in unweathered fragments. The cobalt grade in both the BOMZ and Lower CMN decreases within depth while the copper grade increases. These grade changes reflect the variation in mineralogy with depth from heterogenite with minor amounts of malachite and chrysocolla to malachite, chrysocolla with traces of heterogenite, spherocobaltite, chalcocite, chalcopyrite, carrollite and bornite. Based on the Cu (100xAS Cu/TCu) and Co ratio (100 xAS Co/TCo), which is related to the ore mineralogy, oxide ores (Cu ratio ≥ 75%) and oxide dominant mixed ores (Cu ratio < 75%, containing the copper sulphide chalcocite) can be differentiated in both the BOMZ and Lower CMN. The absence of talc and the low concentration of Ni, Mn and Fe, on the one hand, and the high-grade Cu in the BOMZ, on the other hand, facilitate the hydrometallurgy of cobalt but require a specific processing. Consequently, the recovery of Co from the BOMZ requires the application of a processing method that is based on sulphuric acid (30 g/L) leaching under reducing conditions (300–350 mV) and the removal of impurities (Cu > 95% and Mn ≈ 99%) from the pregnant leach solution (PLS) by solvent extraction (SX) prior to the precipitation of cobalt as a high-grade hydroxide (40.5%). The sulphuric acid leaching of the BOMZ enabled achieving, after 8 h of magnetic stirring (500 rpm), a highest yield of 93% Co, with other major elements Mn (84%) and Cu (40%). The latter forms a main co-product of the Co exploitation. In contrast, the highest leaching yield for Fe remained smaller than 5%.