Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors.

The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells. Here, we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment. Our study reveals that intratumor injection of E.

ACL reconstruction combined with anterolateral structures reconstruction for treating ACL rupture and knee injuries: a finite element analysis.

The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v.

Emerging chemophysiological diversity of gut microbiota metabolites.

Human physiology is profoundly influenced by the gut microbiota, which generates a wide array of metabolites. These microbiota-derived compounds serve as signaling molecules, interacting with various cellular targets in the gastrointestinal tract and distant organs, thereby impacting our immune, metabolic, and neurobehavioral systems. Recent advancements have unveiled unique physiological functions of diverse metabolites derived from tryptophan (Trp) and bile acids (BAs).

Oxidative Tandem Cyclization of Aromatic Acids with (Benzo)thiophenes: One-Pot Access to Planar Sulfur-Containing Polycyclic Heteroarenes for Lipid-Droplet-Targeted Probes.

The efficient construction of π-conjugated polycyclic heteroarenes represents a significant task in the field of functional materials. A one-step oxidative tandem cyclization of aromatic acids with (benzo)thiophenes was developed to access planar sulfur-containing polycyclic heteroarenes. This protocol undergoes intermolecular cross-dehydrogenative coupling followed by intramolecular Friedel-Crafts acylation and provides a facile pathway to planar polycyclic compounds from inexpensive reactants.

In situ formed depot of elastin-like polypeptide-hirudin fusion protein for long-acting antithrombotic therapy.

Thrombosis, induced by abnormal coagulation or fibrinolytic systems, is the most common pathology associated with many life-threatening cardio-cerebrovascular diseases. However, first-line anticoagulant drugs suffer from rapid drug elimination and risk of hemorrhagic complications. Here, we developed an in situ formed depot of elastin-like polypeptide (ELP)-hirudin fusion protein with a prodrug-like feature for long-term antithrombotic therapy.

Amino acid formula induces microbiota dysbiosis and depressive-like behavior in mice.

Amino acid formula (AAF) is increasingly consumed in infants with cow's milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior.

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment.

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells' insufficient infiltration and rapid dysfunction.

Gasdermin D licenses MHCII induction to maintain food tolerance in small intestine.

The intestinal epithelial cells (IECs) constitute the primary barrier between host cells and numerous foreign antigens; it is unclear how IECs induce the protective immunity against pathogens while maintaining the immune tolerance to food. Here, we found IECs accumulate a less recognized 13-kD N-terminal fragment of GSDMD that is cleaved by caspase-3/7 in response to dietary antigens. Unlike the 30-kD GSDMD cleavage fragment that executes pyroptosis, the IEC-accumulated GSDMD cleavage fragment translocates to the nucleus and induces the transcription of CIITA and MHCII molecules, which in turn induces the Tr1 cells in upper small intestine.

Microbial sensing in the intestine.

The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system.

Hourglass-shaped grafts are superior to conventional grafts for restoring knee stability and graft force at knee flexion angle of 30° following anterior cruciate ligament reconstruction: A finite element analysis.

Anterior cruciate ligament reconstruction (ACLR) using a generally columnar graft is considered the gold standard for treating anterior cruciate ligament ruptures, but such grafts cannot replicate the geometry and mechanical properties of the native anterior cruciate ligament. To evaluate the effectiveness of an innovative hourglass-shaped graft versus a traditional columnar graft for restoring joint stability and graft force, while avoiding notch impingement following anterior cruciate ligament reconstruction. Finite element models of a human knee were developed to simulate ① An intact state, ② anterior cruciate ligament reconstruction using columnar grafts with different diameters (7.

Graft Diameter Should Reflect the Size of the Native Anterior Cruciate Ligament (ACL) to Improve the Outcome of ACL Reconstruction: A Finite Element Analysis.

The size of the anterior cruciate ligament (ACL) often varies between individuals, but such variation is not typically considered during ACL reconstruction (ACLR). This study aimed to explore how the size of the ACL affects the selection of a suitable graft diameter. A finite element model of a human knee was implanted with intact ACLs of different dimensions (0.

The comfort assessment in healthy adults during constant-flow mode in noninvasive ventilator.

Background: From the point of view of machine construction and hydrodynamics, this paper innovatively proposes that the essence of high-flow nasal cannula (HFNC) is a constant-flow mode in noninvasive ventilator (NIVCFM). This study enrolled healthy adults as study subjects to assess the subjective comfort assessed by visual analog scoring scale of NIVCFM/HFNC and objective comfort measured by the noise level generated by NIVCFM/HFNC, aiming to provide a scientific basis for the rational clinical application of NIVCFM/HFNC.

Methods: Forty-four healthy adults participated in this study.

Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome.

NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6 mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity.

The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells.

RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases.

Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells.

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells.

The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression.

Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway.