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Intestinal fibrosis, a severe complication of Crohn's disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset [FAP.sup.+] fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that [CD81.sup.+] [Pi.sup.16] fibroblasts exhibited transcriptomic and functional similarities to human [FAP.sup.+] fibroblasts. Consistently, [FAP.sup.+] fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by [FAP.sup.+] fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by [CXCL9.sup.+] macrophages enriched in fibrotic tissues via IL- 1[beta] and TGF-[beta] signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment., Introduction Crohn's disease (CD) is a chronic gastrointestinal inflammatory disease with limited effective pharmacological treatments and several clinical complications like strictures and fistulas. Approximately 50% of patients with CD develop [...]

To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications. [ABSTRACT FROM AUTHOR]

The Altaids is generally considered to be the largest Phanerozoic accretionary orogen on Earth, but it is unclear whether it was associated with extensive continental crustal growth and whether there is a link between the crustal growth and ore mineralization. This paper reviews whole-rock Nd and zircon Hf isotope data for felsic–intermediate–mafic igneous rocks in the Altaids and presents Nd + Hf isotopic contour maps for this region. The maps highlight the 3D lithospheric compositional architecture of the Altaids and make it possible to quantitatively evaluate the crustal growth and its relationship with ore deposits. The Altaids hosts ∼4 107 350 km2 and ∼184 830 750 km3 (assuming a crustal thickness of 40–50 km) juvenile crust (ϵ Nd(t) > 0), accounting for 58% by isotope-mapped area (∼7 010 375 km2) of almost all outcrops of the Altaids (∼8 745 000 km2) and formed during 1000–150 Ma (mainly 600–150 Ma). The juvenile crustal, slightly juvenile-reworked crustal and slightly reworked crustal provinces controlled the Cu–Au, the Pb–Zn–Ag and the Li–Be, Nb–Ta and W–Sn ore deposits. According to the crustal architecture and background of deep compositions, we propose that the ore deposits can be grouped into three types: juvenile crust-related, mixed-source (or slightly juvenile crust)-related and reworked crust-related. This highlights the close relationship between accretion, continental growth and mineralization, and will facilitate exploration for specific ore-deposit types in the Altaids. [ABSTRACT FROM AUTHOR]

The widespread occurrence of voluminous granitoids is a typical characteristic of the Central Asian Orogenic Belt (CAOB) in the central and eastern parts of Central Asia. The granitoids occupy a total area more than 8 million km 2 , with three major area peaks at Cambro-Ordovician, Carboniferous-Permian, and Jurassic. Six zircon age peaks at ca. 500, 430–370, 330–300, 290–260, 210–170 and 145–110 Ma. The early Paleozoic granitoids (540–440 Ma, with age peak at ca. 500 Ma) mainly occur in the northwestern CAOB, and are of calc-alkaline I-type. They probably formed in a subduction setting (500–480 Ma) within the Paleo-Asian Ocean (PAO) and subsequent microcontinental-collision (ca. 460 Ma). The middle Paleozoic granitoids (430–370 Ma) predominately occur in the NW and southern CAOB, and are characterized by a high-K calc-alkaline affinity, suggesting an accretionary and/or a collisional setting. The late Paleozoic (350–260 Ma) granitoids are widespread in the CAOB and formed in variable tectonic settings within an intra-continental regime or active continental margins in the PAO and in the evolving Mongol-Okhotsk Ocean (MOO). Carboniferous granitoids (350–300 Ma) in the northern and northwestern CAOB exhibit A-type, alkaline features and formed in a post-accretionary settings, whereas granitoids in the southern CAOB show I-type, calc-alkaline features and were generated in an arc setting. Permian granitoids (290–270 Ma) are predominantly of I-A, A-type with alkaline signatures, associated with coeval mafic magmatism and suggesting a post-collisional or intraplate setting, contemporaneous with a Large Igneous Province (LIP) in the Tarim Craton. Some 270–250 Ma calc-alkaline granitoids also occur in the southernmost CAOB. Combined with 250–245 Ma high Sr/Y granitoids, these rocks reflect final closure of the PAO during 270–250 Ma. Early Mesozoic (mainly Triassic) granitoids occur mainly in the eastern CAOB or eastern Central Asia. The early-phase granitoids (250–230 Ma) are of I- and S-types, whereas the mid- and late-phase granitoids (ca. 230–190 Ma) are of A-type and transitional I-A type or highly fractionated I-type. All these granitoids occur in variable settings (intraplate, post-orogenic, and continental arc) related to three tectonics regimes, namely the Paleo-Asian Ocean (PAO), the Mongol-Okhotsk Ocean (MOO), and the Paleo-Pacific Ocean (PPO). Late Mesozoic granitoids mainly occur in eastern Central Asia and were emplaced during 6 major magmatic events at 190–180, 180–165, 165–145, 145–135, 135–100 and 100–60 Ma. The 190–165 Ma granitoids are of I-type, calc-alkaline/high-K calc-alkaline, and evolved along active margins related to the Mongol-Okhotsk and Paleo-Pacific ocean domains. The 145–120 Ma granitoids are highly fractionated I-, transitional I-A or, A-types, with high-K calc-alkaline/shoshonitic signatures. The magmatic evolution from the Late Jurassic to Early Cretaceous coincided with a tectonic transition from contractional, thickened crust to extensional thinning. The 120–65 Ma granitoid magmatism displays a southeastward younging trend, suggesting a roll-back of the Paleo-Pacific oceanic plate. The granitoids in the CAOB of eastern Central Asia show variable whole-rock Nd and Hf-in-zircon isotopic compositions, and most have juvenile signatures. In some regions (e.g., Altai-Junggar and Great Xing’an), the volume of juvenile and slightly juvenile crust (<1.0 Ga) is much higher than that of other orogens (such as the Qinling in Central China. The proportion of juvenile vs. old crust may be a marker to identify a typical accretionary orogen from a collisional orogen. [ABSTRACT FROM AUTHOR]

The southern boundary of the central segment of the Central Asian Orogenic Belt (CAOB) with the Precambrian Alxa Block is not well constrained due to poor recognition of deep crust. Statistical analysis of zircon xenocrysts within igneous rocks from the northern Alxa and its adjacent regions was applied to resolve this problem. We compiled new and previously published geochronological zircon age data obtained by SHRIMP, SIMS, TIMS, and LA-ICP-MS for 316 igneous rock samples of which 61 samples contain zircon xenocrysts. New and previously published Hf isotopic compositions of these zircon xenocrysts are combined with zircon ages in this study. The zircon xenocrysts are mainly contained within Permian rocks from the Yabulai–Nurgong–Honggueryulin (YNH) zone and igneous rocks from the northwestern margin of the North China Craton (WNCC). A few xenocrysts were also found in Permian igneous rocks from the Zongnaishan–Shalazhashan (ZS) zone, Neo-proterozoic and Paleo-proterozoic intrusive rocks in the YNH zone, as well as Devonian to Carboniferous granitoids and volcanic rocks from southern Mongolia. Altogether we analyzed more than 270 zircon xenocrysts and considered only ages that are less than 10% discordant. Xenocryst ages within the Permian igneous rocks from the ZS zone are mainly around ca. 350 Ma, ca. 600 Ma and ca. 1400 Ma. The oldest age of zircon xenocrysts in this zone is similar to those of zircon xenocrysts from the CAOB (∼1.1 Ga). By contrast, abundant zircon xenocrysts within Permian igneous rocks from the YNH zone show highly variable age populations at ca. 2.6–2.1 Ga, 1.8–1.6 Ga, 930–750 Ma and 460–300 Ma. Zircon xenocrysts from the ZS zone have positive ε Hf ( t ) values of +6.3 to +13.9, whereas those from the YNH zone display highly variable ε Hf ( t ) values from −16.1 to +11.6. From the southern CAOB and the ZS zone to the YNH zone, the zircon xenocrysts show a significant shift from juvenile to crustal Hf isotopic compositions, suggesting that the area between the ZS and the YNH zones constitutes the southern boundary of the CAOB in the deep crust within this region. Our study indicates that statistical analysis (or isotopic mapping) of zircon xenocrysts is an effective method to trace the nature of the deep continental crust and to separate between newly-formed orogenic domain and ancient cratons. [ABSTRACT FROM AUTHOR]

Intestinal fibrosis, a severe complication of Crohn's disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81+Pi16- fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.

Sodium and potassium-ion batteries are promising for energy storage owing to their source abundance and low cost; however, most active materials still suffer from sluggish kinetics, huge volume variations, and poor conductivity and cycle stability. It remains a great challenge to explore appropriate electrode materials for scaled practical applications. Herein, mesoporous FeCo-incorporated MoS 2 nanosheets encapsulated into a porous carbon framework (FeCo@C@MoS 2 ) are smartly designed, artistically fabricated and evaluated for sodium and potassium storage. The FeCo@C@MoS 2 electrode displays high reversible capacities of 380 mA h g -1 and 147 mA h g -1 at 500 mA g -1 for sodium and potassium storage, respectively. FeCo derived from a Prussian blue analogue promotes fast reaction kinetics of Na + /K + transport, introduces the formation of a stable solid electrolyte interphase layer (SEI) in both the interior and exterior of the cube-like porous nanostructure and controls the Na + /K + fluxes, suppressing the growth of metal dendrites. The porous carbon framework with large interstitial voids can effectively buffer volume variations and mitigate mechanical stress, contributing significantly to alleviate strain intensification on the surface layer between MoS 2 and FeCo during repeated plating/stripping processes. Density functional theoretical calculations (DFT) further confirm that the synthesized nanostructure shows an intensified electron state, elevated anti-stress ability, high-quality SEI film and preferable Na + /K + adsorption energies. This in-depth investigation of the electrochemical performance and the extended energy storage mechanism based on metal alloy/sulfide nanostructures for sodium and potassium storage provides guidance for the smart design of heterojunctions for remarkable energy storage.