Alteration of Innate Immunity by Donor IL-6 Deficiency in a Presensitized Heart Transplant Model

Engraftment of IL-6 deficient donor into wild-type recipient could significantly improve allograft survival through T cell lineage particularly regulatory T cells (Tregs) in non-sensitized transplant host. However, its effect on innate immune responses remains uncertain. Our data revealed that donor IL-6 deficiency significantly increased infiltration of two subsets of MDSCs (CD11b+Gr1+myeloid-derived suppressor cells), CD11b+Gr1-low and CD11b+Gr1-int with strong immunosuppression activity in the transplanted graft. It resulted in a dramatic increase of CD11b+Gr1-low frequency and a significant decrease of the frequency of CD11b+Gr1-high and CD4-CD8-NK1.1+ cells in the recipient’s spleen. Unexpectedly, donor IL-6 deficiency could not significantly reduce macrophage frequency irrespective of in the host’s spleen or graft. Taken together, suppression of innate immune effector cells and enhanced activity of regulatory MDSCs contributed to tolerance induction by blockade of IL-6 signaling pathway. The unveiled novel mechanism of targeting IL-6 might shed light on clinical therapeutic application in preventing accelerated allograft rejection for those pre-sensitized transplant recipients

Can Large Language Models Understand Real-World Complex Instructions?

Large language models (LLMs) can understand human instructions, showing their potential for pragmatic applications beyond traditional NLP tasks. However, they still struggle with complex instructions, which can be either complex task descriptions that require multiple tasks and constraints, or complex input that contains long context, noise, heterogeneous information and multi-turn format. Due to these features, LLMs often ignore semantic constraints from task descriptions, generate incorrect formats, violate length or sample count constraints, and be unfaithful to the input text. Existing benchmarks are insufficient to assess LLMs' ability to understand complex instructions, as they are close-ended and simple. To bridge this gap, we propose CELLO, a benchmark for evaluating LLMs' ability to follow complex instructions systematically. We design eight features for complex instructions and construct a comprehensive evaluation dataset from real-world scenarios. We also establish four criteria and develop corresponding metrics, as current ones are inadequate, biased or too strict and coarse-grained. We compare the performance of representative Chinese-oriented and English-oriented models in following complex instructions through extensive experiments. Resources of CELLO are publicly available at https://github.com/Abbey4799/CELLO

Additive manufacturing of bio-inspired ceramic bone scaffolds: structural design, mechanical properties and biocompatibility

Ideal bone scaffolds require good biocompatibility and moderate mechanical properties, so as to promote the proliferation and differentiation of osteoblast cells, and achieve the good bone repair. Inspired by the porous structure of cancellous bone, 15 groups of bone scaffolds with variable irregularity (Ir1-5) and porosity (35.53-61.75%) were designed and fabricated by ceramic digital light processing (DLP) using 20 wt.% hydroxyapatite doped zirconia as the matrix material. The effects of structural parameters and material on mechanical properties and biocompatibility were studied. The shrinkage test results showed that the density of scaffolds was mainly affected by the porosity. The mechanical test results showed that Ir2 and Ir3 scaffolds had better compressive behaviors, and the compressive strength could be increased by 30% by regulating the irregularity. All scaffolds showed comparable mechanical properties to that of cancellous bone. Cell experiments showed that the effect of structure on cell proliferation, differentiation, and mineralization was most evident at the early stage of implantation. Meanwhile, the biocompatibility variation with the irregularity was consistent with mechanical properties. This study proved that a bio-inspired bone scaffold with excellent comprehensive properties could be obtained through reasonable design

Star formation in bright-rimmed clouds and cluster associated with W5 E H{\sc ii} region

The aim of this paper is to present the results of photometric investigations of the central cluster of the W5 E region as well as a follow-up study of the triggered star formation in and around bright-rimmed clouds (BRCs). We have carried out wide field $UBVI_c$ and deep $VI_c$ photometry of the W5 E H{\sc ii} region. A distance of $\sim$2.1 kpc and a mean age of $\sim$1.3 Myr have been obtained for the central cluster. The young stellar objects (YSOs) associated with the region are identified on the basis of near-infrared and mid-infrared observations. We confirmed our earlier results that the average age of the YSOs lying on/inside the rim are younger than those lying outside the rim. The global distribution of the YSOs shows an aligned distribution from the ionising source to the BRCs. These facts indicate that a series of radiation driven implosion processes proceeded from near the central ionising source towards the periphery of the W5 E H{\sc ii} region. We found that, in general, the age distributions of the Class II and Class III sources are the same. This result is apparently in contradiction with the conclusion by Bertout, Siess & Cabrit (2007) and Chauhan et al. (2009) that classical T Tauri stars evolve to weak-line T Tauri stars. The initial mass function of the central cluster region in the mass range $0.4 \le M/M_\odot \le 30$ can be represented by $\Gamma = -1.29 \pm 0.03$. The cumulative mass functions indicate that in the mass range $0.2 \le M/M_\odot \le 0.8$, the cluster region and BRC NW have more low mass YSOs in comparison to BRCs 13 and 14.Comment: 43 pages, 17 figures, accepted for publication in MNRA

Zn-doped chitosan/alginate multilayer coatings on porous hydroxyapatite scaffold with osteogenic and antibacterial properties

Porous hydroxyapatite (HA) scaffolds prepared by three-dimensional (3D) printing have wide application prospects owing to personalized structural design and excellent biocompatibility. However, the lack of antimicrobial properties limits its widespread use. In this study, a porous ceramic scaffold was fabricated by digital light processing (DLP) method. The multilayer chitosan/alginate composite coatings prepared by layer-by-layer method were applied to scaffolds and Zn2+ was doped into coatings in the form of ion crosslinking. The chemical composition and morphology of coatings were characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). Energy dispersive spectroscopy (EDS) analysis demonstrated that Zn2+ was uniformly distributed in the coating. Besides, the compressive strength of coated scaffolds (11.52 ± 0.3 MPa) was slightly improved compared with that of bare scaffolds (10.42 ± 0.56 MPa). The result of soaking experiment indicated that coated scaffolds exhibited delayed degradation. In vitro experiments demonstrated that within the limits of concentration, a higher Zn content in the coating has a stronger capacity to promote cell adhesion, proliferation and differentiation. Although excessive release of Zn2+ led to cytotoxicity, it presented a stronger antibacterial effect against Escherichia coli (99.4%) and Staphylococcus aureus (93%)

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

Computing the Performance of A New Adaptive Sampling Algorithm Based on The Gittins Index in Experiments with Exponential Rewards

Designing experiments often requires balancing between learning about the true treatment effects and earning from allocating more samples to the superior treatment. While optimal algorithms for the Multi-Armed Bandit Problem (MABP) provide allocation policies that optimally balance learning and earning, they tend to be computationally expensive. The Gittins Index (GI) is a solution to the MABP that can simultaneously attain optimality and computationally efficiency goals, and it has been recently used in experiments with Bernoulli and Gaussian rewards. For the first time, we present a modification of the GI rule that can be used in experiments with exponentially-distributed rewards. We report its performance in simulated 2-armed and 3-armed experiments. Compared to traditional non-adaptive designs, our novel GI modified design shows operating characteristics comparable in learning (e.g. statistical power) but substantially better in earning (e.g. direct benefits). This illustrates the potential that designs using a GI approach to allocate participants have to improve participant benefits, increase efficiencies, and reduce experimental costs in adaptive multi-armed experiments with exponential rewards.JKH thanks the University of Cambridge MRC Biostatistics Unit Summer Internship Program for the support and training that made this research possible. LM and SSV acknowledge funding and support from the UK Medical Research Council (MC UU 00002/15)

Plastic rod as a promising feed material for enhanced performance of ultrasonic plasticization microinjection molding: Plasticization rate, mechanical and thermal properties

A polymer plasticization rate measurement method is proposed for ultrasonic plasticization microinjection molding. The effect of ultrasonic amplitude on the plasticization rate of polypropylene (PP) rods was comprehensively investigated, and the mechanical and thermal properties of PP rods were studied using tensile tests, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Results show that the plasticization rate of PP rods increased from 67.25 mg/s to 192.41 mg/s with increase of ultrasonic amplitude, an increase of 186%. The mechanical properties of the PP samples remained stable under different ultrasonic amplitudes, with tensile strength around 21 MPa and elongation at break about 21%. DSC and TGA results showed that PP samples exhibit improved thermal properties after ultrasonic plasticization compared with pure PP. The melting point of the PP sample decreased from 171.7 °C to 164.0 °C and the crystallinity increased from 26.1% to 38.7%. The temperatures corresponding to 1% and 5% weight loss of PP increased from 283.63 °C to 350.30 °C without ultrasonic amplitude to 393.70 °C and 420.13 °C, respectively. The studies have great significance to further understand the influence of ultrasonic plasticization process parameters on the plasticization rate and material properties of polymers

La(Ca)CrO₃-Filled SiCN Precursor Thin Film Temperature Sensor Capable to Measure up to 1100 °C High Temperature

Thin-film sensors are regarded as advanced technologies for in situ condition monitoring of components operating in harsh environments, such as aerospace engines. Nevertheless, these sensors encounter challenges due to the high-temperature oxidation of materials and intricate manufacturing processes. This paper presents a simple method to fabricate high temperature-resistant oxidized SiCN precursor and La(Ca)CrO3 composite thin film temperature sensors by screen printing and air annealing. The developed sensor demonstrates a broad temperature response ranging from 200 °C to 1100 °C with negative temperature coefficients (NTC). It exhibits exceptional resistance to high-temperature oxidation and maintains performance stability. Notably, the sensor’s resistance changes by 3% after exposure to an 1100 °C air environment for 1 h. This oxidation resistance improvement surpasses the currently reported SiCN precursor thin-film sensors. Additionally, the sensor’s temperature coefficient of resistance (TCR) can reach up to −7900 ppm/°C at 200 °C. This strategy is expected to be used for other high-temperature thin-film sensors such as strain gauges, heat flux sensors, and thermocouples. There is great potential for applications in high-temperature field monitoring