Browse Articles

Promises and potential pitfalls of in vivo CAR gene therapy

Abstract Genetically modified T cells expressing chimeric antigen receptors (CARs) manufactured ex vivo have demonstrated high efficacy in patients with lymphoid hematologic malignancies, but their logistic complexity limits patient access. In vivo approaches generate the CAR-expressing T cells within the body but may have their own challenges. Recent clinical reports provide proof of concept for the feasibility and therapeutic potential of in vivo CAR gene delivery. We summarize clinical evidence and discuss the critical technical, biological, and safety considerations of this approach.

To deplete or not to deplete: that is the question

Neonatal platelets: MDSC-ooling the monocytes

Neonatal platelets differentiate monocytes to a myeloid-derived suppressor cell phenotype

Abstract Adult platelets are relatively enriched in immune-related molecules compared with neonatal platelets, but neonatal platelets express some growth factors and enzymes at comparatively higher levels. This makes a prediction of platelet-immune cell interaction outcomes in neonates a challenge, as they are likely dependent on the cell type and tissue environment at the time of injury or infection. Our previous studies revealed that the transfusion of adult but not neonatal platelets into thrombocytopenic neonatal mice led to an acute increase in monocyte trafficking. We have now found that neonatal but not adult platelets induce monocytes to a myeloid-derived suppressor cell phenotype, typified by increased programmed death ligand 1, that limits T-cell activation in vitro and in vivo. Monocytes previously incubated with neonatal but not adult platelets or platelet releasates limited T-cell activation in vitro. Using an in vivo asthma-like model we also found that the treatment of mice with monocytes before incubation with neonatal platelet releasates limited T-cell activation in a asthma-like model. Platelet-driven effects were dependent on neonatal platelets producing more prostaglandin E2 that signaled through monocyte prostaglandin EP4 receptor. These studies indicate that neonatal platelets have immune-limiting roles in the postnatal period by indirectly limiting T-cell responses, perhaps contributing to the adverse outcomes of platelet transfusions to neonates.

Domostegui A, Peddigari S, Mercer CA, et al. Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death. <i>Blood</i> . 2021;137(24):3351-3364.

Tunneling nanotube–mediated intercellular filamin A transport mechanosensitively programs osteoclastogenesis in myeloma bone disease

Abstract Intercellular communication between multiple myeloma (MM) cells and osteoclast precursor cells (pre-OCs) contributes extensively to the occurrence and development of myeloma-related bone destruction. However, key interacting modes and the exchanged substances involved in this communication remain unclear. In this study, we discover that tunneling nanotubes (TNTs) directly connect MM and pre-OCs. Using the stable isotope labeling with amino acids in cell culture assay and a positive-negative double selection strategy, we identify filamin A (FLNA) as a major protein transported from MM to pre-OCs. FLNA acts as a molecular clutch linking extracellular matrix–bound MAC1 to the cytoskeleton, activating Rho and MAPK signaling pathways and promoting F-actin polymerization, which subsequently enhances osteoclast differentiation by modulating cellular stiffness, traction force, and deformability. In addition, FLNA directly binds vinculin and promotes its recruitment to podosomes, thereby enhancing the functions of podosomes and the bone resorption capacity of osteoclasts. The conditional depletion of Flna in mice suppresses podosome activity and reduces stiffness, traction force, and deformability in pre-OCs, leading to significantly impaired osteoclast differentiation and increased bone mass. In the Vk∗MYC mouse model of myeloma, the administration of the TNT inhibitor latrunculin B disrupts FLNA transport to osteoclasts and alleviates osteolytic bone disease. These findings highlight the critical role of MM-transferred FLNA in osteoclastogenesis and suggest that targeting TNTs may represent a therapeutic strategy to limit pathological bone resorption associated with MM.

Lipids drive chronic sickle cell disease pain

Nanotube trafficking fuels myeloma bone loss

Epigenetic toggling between multipotency and differentiation

CD19 CAR T-cell therapy is feasible for patients with pemphigus vulgaris treated without lymphodepletion in the RESET-PV trial

Abstract Lymphodepleting preconditioning (LD) is essential for the efficacy of chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies. However, in the setting of autoimmune diseases (ADs), the contribution of LD for efficacy is unclear. Here, we report on the early safety, efficacy, and correlative data of the first 4 patients with pemphigus vulgaris (PV) who received resecabtagene autoleucel (rese-cel), a fully human CD19 CAR T-cell therapy, without LD in the RESET-PV trial, a substudy of the DesCAARTes trial. Following infusion, pemphigus disease area index scores improved significantly in all patients. A favorable safety profile was observed, with a single episode of grade 1 cytokine release syndrome. Immune effector cell–associated neurotoxicity was not observed. Rese-cel expansion was similar in patients with PV compared with other rese-cel–treated patients with AD who received LD. B-cell depletion was observed in all patients with PV, with 3 of 4 patients achieving B-cell aplasia. Elevations in serum B-cell activating factor (BAFF) level were observed, with 3 of 4 patients achieving levels within the lowest end of the range exhibited in rese-cel–treated patients with AD who received LD. PV autoantibodies decreased in 2 of 4 patients. These preliminary data suggest that LD may be dispensable for humanized CAR T-cell efficacy in patients with AD. This trial was registered at www.clinicaltrials.gov as NCT04422912.

The roles of pre-season immunity, age, viral shedding, and community exposures in shaping influenza household transmission dynamics

Abstract Protective immunity against influenza transmission remains poorly understood due to the high prevalence of undetected asymptomatic infections. To address this, we analyze 1518 individuals and 623 infection episodes from a three-year, rural and urban, South African household cohort study that combines pre-season serum collection with twice-weekly virological testing regardless of symptoms. By developing a subtype/lineage-specific household transmission model and incorporating time-resolved viral shedding kinetics for all observed infections, we disentangle household and community exposure, pre-season immunity, and age effects. After adjusting for exposure intensity, pre-season hemagglutination inhibition (HAI) titers ≥1:40 are associated with a reduced infection risk for A(H1N1)pdm09, A(H3N2), and B/Victoria, but not B/Yamagata. However, children exhibit higher susceptibility and longer viral shedding durations than adults across all subtypes/lineages, even after accounting for pre-season HAI titers. Here, we show persistent age-related effects on influenza susceptibility and viral shedding, underscoring the need to explore immune mechanisms beyond HAI-based correlates of protection.

Controlled parity of cooper pair tunneling in a hybrid superconducting qubit

Low-intensity pulsed ultrasound-mediated nose-to-brain co-delivery of β-blockers and aPD-L1 enhances glioblastoma immunotherapy

Abstract Intranasal delivery offers a direct route to the brain, circumventing the blood-brain barrier (BBB) and minimizing systemic toxicity. However, its efficiency is mainly limited by the nasal mucosal barrier (NMB). Here, low-intensity pulsed ultrasound (LIPUS) without depending on the microbubbles (MBs) to amplify energy, is directly used to reversibly open the NMB by disrupting tight junction proteins. A bionic nanovesicle (iRGD-anti-programmed cell death ligand 1 (aPD-L1) &amp; carvedilol (β-blocker) @ macrophage-derived extracellular vesicles, iMPC) is designed to co-deliver carvedilol for β-receptor blockade to reduce T-cell exhaustion, and aPD-L1 to enhance T-cell anti-tumor activity in orthotopic glioblastoma (GBM) mice during the two-hour window for NMB opening. Consequently, compared to free aPD-L1, up to a 33.38-fold increase of aPD-L1 in the GBM region is obtained with LIPUS-mediated intranasal delivery of iMPC. Reactivating T cells significantly enhances immunotherapy, leading to a 40% tumor reduction, extended survival, and long-term immune memory in orthotopic GBM mice. Overall, the LIPUS-mediated NMB opening strategy notably enhances nose-to-brain drug delivery efficiency, offering a promising platform for treating brain diseases.

Life course trajectory segregation and political polarization in contemporary Sweden

Abstract Understanding how and why places differ geographically has long been central to human geography—a question sharpened by the growing geographical polarization of political views. Spatial polarization can result from an uneven geographical distribution of life-course trajectories, trajectories that emerge from individuals’ successive positions across interconnected, possibly spatially differentiated social fields such as education, employment, family, and housing. Here we show that the uneven geographical distribution of such trajectories produces landscapes where contrasting life experiences, opportunities, and aspirations become inscribed in geographical space. A key finding is that segregation intensifies over the life-course, with young adults substantially less segregated than older adults, particularly after homeownership transitions. Moreover, studies relying on single indicators such as income and education may underestimate residential segregation strength. Homeownership is a major segregation driver, creating highly separated residential areas in later life phases. The spatial concentration of trajectory types also corresponds with geographical patterns in political polarization.

Northward expansion of high-stature vegetation reveals net surface-cooling feedbacks in the majority of Canadian Boreal-Tundra ecozones

Tracking the catastrophic collapse of hybrid exciton-phonon order in a quantum material

Abstract Revealing the hidden interactions that bind electronic and lattice components of cooperative quantum order is central to sculpting new states of matter. This challenge is epitomized by the charge density wave material 1 T -TiSe 2 , where photoexcitation disrupts its presumed hybrid exciton-phonon order: the electronic component collapses within femtoseconds, while the periodic lattice distortion persists, challenging the definition of hybrid order. Here we resolve this paradox by uncovering a low-frequency mode (~0.13 THz) that emerges only in the ordered state and signals exciton-phonon coupling. This mode is consistent with a locked phason, a collective excitation arising when excitonic and lattice degrees of freedom share a coupled potential landscape. At a critical photoexcitation threshold, the collapse of the excitonic order flattens this potential, causing the locked phason to disappear, the charge density wave phonon to selectively overheat, and the surviving lattice distortion to become a trapped non-thermal remnant.

Protonated portlandite precursor unlocks enhanced nucleation and growth for cement hydration

Circularly polarized electroluminescence from topologically chiral [2]catenane-based neutral radicals with tunable deep-red emission

Screening of amphipathic helices identifies features linked to inner nuclear membrane properties

Abstract Inner nuclear membrane (INM) proteins control numerous nuclear functions, yet properties governing peripheral INM-association remain poorly defined. Here, we perform an image-based screen to identify features in candidate and established amphipathic helices (AHs) that mediate INM association. AHs that localize to ER/Golgi membranes become INM-associated when directed to the nucleus, whereas mitochondrial-localized AHs become largely nucleoplasmic. Mutating a mitochondrial-localized AH to increase its preference for membranes with lipid packing defects enables INM-association upon nuclear targeting. Structural studies of an INM-associated AH in TMEM214 show folding upon binding to lipid packing defects, and full-length TMEM214 localizes to nuclear pores. Consistently across multiple AHs, INM binding depends primarily on sensitivity to lipid packing defects, with a minor electrostatic contribution. Highlighting distinct effects of different mechanical inputs, nuclear swelling, but not cell stretching, enhances INM association of select AHs. These findings define AH features that promote INM association, with implications for nucleo-mechanical responses.

Directional thermal emission enables efficient energy savings

Abstract Thermal radiation, a fundamental heat transfer mechanism, is crucial for energy exchange across various applications. However, conventional radiative heat transfer systems rely on omnidirectional thermal radiation, causing energy dissipation in undesired directions and limiting radiative heat transfer efficiency. Here, we show that perfectly matched directional thermal emission between an emitter and absorber can reach a theoretical efficiency up to 100%. In a parallel-plate configuration, replacing a conventional system with a customized directional system raises efficiency from 29% to 100%. We further experimentally demonstrate directional radiative heat transfer realizes substantial energy savings of 67.8% in vacuum and 28.7% in non-vacuum conditions. Moreover, directional radiative heat transfer enables efficient heating in diverse scenarios, including vehicle heating, car paint drying, human body heating, and rail car thawing, achieving 17–46% energy savings. Our work highlights the broad applicability and energy-saving potential of directional radiative heat transfer, opening new avenues for efficient energy utilization.