Exploring caspase functions in mouse models.

Caspases are enzymes with protease activity. Despite being known for more than three decades, caspase investigation still yields surprising and fascinating information. Initially associated with cell death and inflammation, their functions have gradually been revealed to extend beyond, targeting pathways such as cell proliferation, migration, and differentiation. These processes are also associated with disease mechanisms, positioning caspases as potential targets for numerous pathologies including inflammatory, neurological, metabolic, or oncological conditions. While in vitro studies play a crucial role in elucidating molecular pathways, they lack the context of the body's complexity. Therefore, laboratory animals are an indispensable part of successfully understanding and applying caspase networks. This paper aims to summarize and discuss recent knowledge, understanding, and challenges in caspase knock-out mice.

Vascular architecture regulates mesenchymal stromal cell heterogeneity via P53-PDGF signaling in the mouse incisor.

Mesenchymal stem cells (MSCs) reside in niches to maintain tissue homeostasis and contribute to repair and regeneration. Although the physiological functions of blood and lymphatic vasculature are well studied, their regulation of MSCs as niche components remains largely unknown. Using adult mouse incisors as a model, we uncover the role of Trp53 in regulating vascular composition through THBS2 to maintain mesenchymal tissue homeostasis. Loss of Trp53 in GLI1+ progeny increases arteries and decreases other vessel types. Platelet-derived growth factors from arteries deposit in the MSC region and interact with PDGFRA and PDGFRB. Significantly, PDGFRA+ and PDGFRB+ cells differentially contribute to defined cell lineages in the adult mouse incisor. Collectively, our results highlight Trp53's importance in regulating the vascular niche for MSCs. They also shed light on how different arterial cells provide unique cues to regulate MSC subpopulations and maintain their heterogeneity. Furthermore, they provide mechanistic insight into MSC-vasculature crosstalk.

ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling.

ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.

Bioinspired In-Sensor Multimodal Fusion for Enhanced Spatial and Spatiotemporal Association.

Multimodal perception can capture more precise and comprehensive information compared with unimodal approaches. However, current sensory systems typically merge multimodal signals at computing terminals following parallel processing and transmission, which results in the potential loss of spatial association information and requires time stamps to maintain temporal coherence for time-series data. Here we demonstrate bioinspired in-sensor multimodal fusion, which effectively enhances comprehensive perception and reduces the level of data transfer between sensory terminal and computation units. By adopting floating gate phototransistors with reconfigurable photoresponse plasticity, we realize the agile spatial and spatiotemporal fusion under nonvolatile and volatile photoresponse modes. To realize an optimal spatial estimation, we integrate spatial information from visual-tactile signals. For dynamic events, we capture and fuse in real time spatiotemporal information from visual-audio signals, realizing a dance-music synchronization recognition task without a time-stamping process. This in-sensor multimodal fusion approach provides the potential to simplify the multimodal integration system, extending the in-sensor computing paradigm.

Green moisture-electric generator based on supramolecular hydrogel with tens of milliamp electricity toward practical applications.

Moisture-electric generators (MEGs) has emerged as promising green technology to achieve carbon neutrality in next-generation energy suppliers, especially combined with ecofriendly materials. Hitherto, challenges remain for MEGs as direct power source in practical applications due to low and intermittent electric output. Here we design a green MEG with high direct-current electricity by introducing polyvinyl alcohol-sodium alginate-based supramolecular hydrogel as active material. A single unit can generate an improved power density of ca. 0.11 mW cm-2, a milliamp-scale short-circuit current density of ca. 1.31 mA cm-2 and an open-circuit voltage of ca. 1.30 V. Such excellent electricity is mainly attributed to enhanced moisture absorption and remained water gradient to initiate ample ions transport within hydrogel by theoretical calculation and experiments. Notably, an enlarged current of ca. 65 mA is achieved by a parallel-integrated MEG bank. The scalable MEGs can directly power many commercial electronics in real-life scenarios, such as charging smart watch, illuminating a household bulb, driving a digital clock for one month. This work provides new insight into constructing green, high-performance and scalable energy source for Internet-of-Things and wearable applications.

Electrochromic Devices Based on 2D MoO3-x/PEDOT:PSS Composite Film with Boosted Ion Transport.

Electrochromic materials allow for optical modulation and have attracted much attention due to their bright future in applications such as smart windows and energy-saving displays. Two-dimensional (2D) molybdenum oxide nanoflakes with combined advantages of high active specific surface area and natural layered structure should be highly potential candidates for electrochromic devices. However, the efficient top-down preparation of 2D MoO3 nanoflakes is still a huge challenge and the sluggish ionic kinetics hinder its electrochromic performance. Herein, we demonstrated a feasible thiourea-assisted exfoliation procedure, which can not only increase the yield but also reduce the thickness of 2D MoO3-x nanoflakes down to a few nanometers. Furthermore, electrophoretic-deposited MoO3-x nanoflakes were combined with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)-conjugated polymer to simultaneously enhance the ionic kinetics and electronic conductivity, with a diffusion coefficient of 3.09 × 10-10 cm2 s-1 and a charge transport resistance of 33.7 Ω. The prepared 2D MoO3-x/PEDOT:PSS composite films exhibit improved electrochromic performance, including fast switching speed (7 s for bleaching, 5 s for coloring), enhanced coloration efficiency (87.1 cm2 C-1), and large transmittance modulation (ΔT = 65%). This study shows outstanding potential for 2D MoO3-x nanoflakes in electrochromic applications and opens new avenues for optimizing the ion transport in inorganic-organic composites, which will be possibly inspired for other electrochemical devices.

Identifying atomically thin isolated-band channels for intrinsic steep-slope transistors by high-throughput study.

Developing low-power FETs holds significant importance in advancing logic circuits, especially as the feature size of MOSFETs approaches sub-10 nanometers. However, this has been restricted by the thermionic limitation of SS, which is limited to 60 mV per decade at room temperature. Herein, we proposed a strategy that utilizes 2D semiconductors with an isolated-band feature as channels to realize sub-thermionic SS in MOSFETs. Through high-throughput calculations, we established a guiding principle that combines the atomic structure and orbital interaction to identify their sub-thermionic transport potential. This guides us to screen 192 candidates from the 2D material database comprising 1608 systems. Additionally, the physical relationship between the sub-thermionic transport performances and electronic structures is further revealed, which enables us to predict 15 systems with promising device performances for low-power applications with supply voltage below 0.5 V. This work opens a new way for the low-power electronics based on 2D materials and would inspire extensive interests in the experimental exploration of intrinsic steep-slope MOSFETs.

Optoelectronic Synapses Based on MXene/Violet Phosphorus van der Waals Heterojunctions for Visual-Olfactory Crossmodal Perception.

The crossmodal interaction of different senses, which is an important basis for learning and memory in the human brain, is highly desired to be mimicked at the device level for developing neuromorphic crossmodal perception, but related researches are scarce. Here, we demonstrate an optoelectronic synapse for vision-olfactory crossmodal perception based on MXene/violet phosphorus (VP) van der Waals heterojunctions. Benefiting from the efficient separation and transport of photogenerated carriers facilitated by conductive MXene, the photoelectric responsivity of VP is dramatically enhanced by 7 orders of magnitude, reaching up to 7.7 A W-1. Excited by ultraviolet light, multiple synaptic functions, including excitatory postsynaptic currents, paired-pulse facilitation, short/long-term plasticity and "learning-experience" behavior, were demonstrated with a low power consumption. Furthermore, the proposed optoelectronic synapse exhibits distinct synaptic behaviors in different gas environments, enabling it to simulate the interaction of visual and olfactory information for crossmodal perception. This work demonstrates the great potential of VP in optoelectronics and provides a promising platform for applications such as virtual reality and neurorobotics.

Controllable van der Waals gaps by water adsorption.

Van der Waals (vdW) gaps with ångström-scale heights can confine molecules or ions to an ultimately small scale, providing an alternative way to tune material properties and explore microscopic phenomena. Modulation of the height of vdW gaps between two-dimensional (2D) materials is challenging due to the vdW interaction. Here we report a general approach to control the vdW gap by preadsorption of water molecules on the material surface. By controlling the saturation vapour pressure of water vapour, we can precisely control the adsorption level of water molecules and vary the height of the vdW gaps of MoS2 homojunctions from 5.5 Å to 53.6 Å. This technique can be further applied to other homo- and heterojunctions, constructing controlled vdW gaps in 2D artificial superlattices and in 2D/3D and 3D/3D heterojunctions. Engineering the vdW gap has great practical potential to modulate the device performance, as evidenced by the vdW-gap-dependent diode characteristics of the MoS2/gap/MoS2 junction. Our work introduces a general strategy of molecular preadsorption that can extend to various precursors, creating more tunability and variability in vdW material systems.

A Calvarial Defect Model to Investigate the Osteogenic Potential of Umbilical Cord Stem Cells in Bone Regeneration.

BACKGROUND: The standard graft material for alveolar cleft repair (ACR) is autogenous iliac crest. A promising alternative potential graft adjunct-newborn human umbilical cord mesenchymal stem cells (h-UCMSCs)-has yet to be explored in vivo. Their capacity for self-renewal, multipotent differentiation, and proliferation allows h-UCMSCs to be harnessed for regenerative medicine. This study sought to evaluate the efficacy of using tissue-derived h-UCMSCs and their osteogenic capabilities to improve ACR in a murine model. METHODS: Foxn1 mice were separated into three groups with the following calvarial defects: no treatment (empty defect; n = 6), poly(D,L-lactide-co-glycolide) (PLGA) scaffold ( n = 6), or h-UCMSCs with PLGA ( n = 4). Bilateral 2-mm-diameter parietal bone critical-sized defects were created using a dental drill. Microcomputed tomography (microCT) imaging was performed 1, 2, 3, and 4 weeks postoperatively. The mice were euthanized 4 weeks postoperatively for RNAScope, immunohistochemical, and histological analysis. RESULTS: No mice experienced complications during the follow-up period. MicroCT imaging and histological analysis demonstrated that the no-treatment and PLGA-only defects remained patent without significant defect size differences across groups. In contrast, the h-UCMSCs with PLGA group had significantly greater bone fill on microCT and histological analysis. CONCLUSIONS: This study demonstrates a successful calvarial defect model for the investigation of h-UCMSC-mediated osteogenesis and bone repair. Evidence reveals that PLGA alone has neither short-term effects on bone formation nor any unwanted side effects, making it an attractive scaffold. Further investigation using h-UCMSCs with PLGA in larger animals is warranted to advance future translation to patients requiring ACR. CLINICAL RELEVANCE STATEMENT: The authors' results demonstrate a successful murine calvarial defect model for the investigation of h-UCMSC-mediated osteogenesis and bone repair, and they provide preliminary evidence for the safe and efficacious use of this graft adjunct in alveolar cleft repair.

Introducing the Reversible Reaction of CO2 with Diamines into Nonisocyanate Polyurethane Synthesis.

Nonisocyanate polyurethanes (NIPUs) are considered greener alternatives to traditional polyurethanes, and the preparation of NIPUs considerably depends on the design and synthesis of suitable monomers. Herein, we propose a toolbox for in situ capturing and conversion of CO2 into α,ω-diene-functionalized carbamate monomers by taking advantage of the facile reversible reaction of CO2 with diamines in the presence of organic superbases. The activation of CO2 into carbamate intermedia was demonstrated by NMR and in situ FTIR, and the optimal conditions to prepare α,ω-diene-functionalized carbamate monomers were established. Thiol-ene and acyclic diene metathesis (ADMET) polymerization of these monomers under mild conditions yielded a series of poly(thioether urethane)s and unsaturated aromatic-aliphatic polyurethanes with high yield and glass transition temperatures ranging from -26.8 to -1.1 °C. These obtained NIPUs could be further modified via postpolymerization oxidation or hydrogenation to yield poly(sulfone urethane) and saturated polyurethane with tunable properties.

Generation of tamoxifen-inducible Tfap2b-CreERT2 mice using CRISPR-Cas9.

Tfap2b, a pivotal transcription factor, plays critical roles within neural crest cells and their derived lineage. To unravel the intricate lineage dynamics and contribution of these Tfap2b+ cells during craniofacial development, we established a Tfap2b-CreERT2 knock-in transgenic mouse line using the CRISPR-Cas9-mediated homologous direct repair. By breeding with tdTomato reporter mice and initiating Cre activity through tamoxifen induction at distinct developmental time points, we show the Tfap2b lineage within the key neural crest-derived domains, such as the facial mesenchyme, midbrain, cerebellum, spinal cord, and limbs. Notably, the migratory neurons stemming from the dorsal root ganglia are visible subsequent to Cre activity initiated at E8.5. Intriguingly, Tfap2b+ cells, serving as the progenitors for limb development, show activity predominantly commencing at E10.5. Across the mouse craniofacial landscape, Tfap2b exhibits a widespread presence throughout the facial organs. Here we validate its role as a marker of progenitors in tooth development and have confirmed that this process initiates from E12.5. Our study not only validates the Tfap2b-CreERT2 transgenic line, but also provides a powerful tool for lineage tracing and genetic targeting of Tfap2b-expressing cells and their progenitor in a temporally and spatially regulated manner during the intricate process of development and organogenesis.

Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.

Skull progenitor cell-driven meningeal lymphatic restoration improves neurocognitive functions in craniosynostosis.

The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate remains largely unknown. We found that impaired meningeal lymphatics and brain perfusion drive neurocognitive defects in Twist1+/- mice, an animal model of craniosynostosis recapitulating human Saethre-Chotzen syndrome. Loss of SPCs leads to skull deformities and elevated intracranial pressure (ICP), whereas transplanting SPCs back into mutant mice mitigates lymphatic and brain defects through two mechanisms: (1) decreasing elevated ICP by skull correction and (2) promoting the growth and migration of lymphatic endothelial cells (LECs) via SPC-secreted vascular endothelial growth factor-C (VEGF-C). Treating Twist1+/- mice with VEGF-C promotes meningeal lymphatic growth and rescues defects in ICP, brain perfusion, and neurocognitive functions. Thus, the skull functionally integrates with the brain via meningeal lymphatics, which is impaired in craniosynostosis and can be restored by SPC-driven lymphatic activation via VEGF-C.

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria.

The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.

Symmetry or asymmetry: which one is the platform of nitrogen vacancies for alkaline hydrogen evolution.

Conventional nitrogen vacancies with a symmetric coordination of metal cations (i.e., M1-Nv-M1) play a crucial role in tuning the local environment of the metal sites in metal nitrides and improving their electrochemical activity in the hydrogen evolution reaction (HER). However, the symmetric Nv sites, which feature a uniform charge distribution on adjacent metal sites, suffer from sluggish water dissociation kinetics and a poor capability for hydrogen desorption. Here, we fabricated Cr-doped and Nv-rich Co4N nanorods grown on a Ni foam (Cr-Co4N-Nv/NF) with asymmetric Cr-Nv-Co sites to effectively catalyze hydrogen evolution under alkaline conditions, with a low overpotential of 33 mV at a current density of 10 mA cm-2 and a small Tafel slope of 37 mV dec-1. The experimental characterizations and theoretical simulations collectively reveal that the construction of asymmetric Cr-Nv-Co sites gives rise to the upshift of the d-band center, thus promoting water adsorption and activation. Moreover, asymmetric Nv sites allow a balance between hydrogen adsorption and desorption, which avoids the limited desorption process over the symmetric Co-Nv-Co sites.

MFSD2A potentiates gastric cancer response to anti-PD-1 immunotherapy by reprogramming the tumor microenvironment to activate T cell response.

BACKGROUND: The efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC (AGC). METHODS: The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice. Cytometry by Time-of-Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics. RESULTS: Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8+ T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor ß1 (TGFß1) release from GC cells by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, which consequently reprogrammed TME to promote anti-tumor T cell activation. CONCLUSIONS: MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.

Recent Advances and Future Prospects for Memristive Materials, Devices, and Systems.

Memristive technology has been rapidly emerging as a potential alternative to traditional CMOS technology, which is facing fundamental limitations in its development. Since oxide-based resistive switches were demonstrated as memristors in 2008, memristive devices have garnered significant attention due to their biomimetic memory properties, which promise to significantly improve power consumption in computing applications. Here, we provide a comprehensive overview of recent advances in memristive technology, including memristive devices, theory, algorithms, architectures, and systems. In addition, we discuss research directions for various applications of memristive technology including hardware accelerators for artificial intelligence, in-sensor computing, and probabilistic computing. Finally, we provide a forward-looking perspective on the future of memristive technology, outlining the challenges and opportunities for further research and innovation in this field. By providing an up-to-date overview of the state-of-the-art in memristive technology, this review aims to inform and inspire further research in this field.

Two-dimensional semiconducting SnP2Se6 with giant second-harmonic-generation for monolithic on-chip electronic-photonic integration.

Two-dimensional (2D) layered semiconductors with nonlinear optical (NLO) properties hold great promise to address the growing demand of multifunction integration in electronic-photonic integrated circuits (EPICs). However, electronic-photonic co-design with 2D NLO semiconductors for on-chip telecommunication is limited by their essential shortcomings in terms of unsatisfactory optoelectronic properties, odd-even layer-dependent NLO activity and low NLO susceptibility in telecom band. Here we report the synthesis of 2D SnP2Se6, a van der Waals NLO semiconductor exhibiting strong odd-even layer-independent second harmonic generation (SHG) activity at 1550 nm and pronounced photosensitivity under visible light. The combination of 2D SnP2Se6 with a SiN photonic platform enables the chip-level multifunction integration for EPICs. The hybrid device not only features efficient on-chip SHG process for optical modulation, but also allows the telecom-band photodetection relying on the upconversion of wavelength from 1560 to 780 nm. Our finding offers alternative opportunities for the collaborative design of EPICs.

Electrochemical Production of Glycolate Fuelled By Polyethylene Terephthalate Plastics with Improved Techno-Economics.

Electrochemical valorization of polyethylene terephthalate (PET) waste streams into commodity chemicals offers a potentially sustainable route for creating a circular plastic economy. However, PET wastes upcycling into valuable C2 product remains a huge challenge by the lack of an electrocatalyst that can steer the oxidation economically and selectively. Here, it is reported a catalyst comprising Pt nanoparticles hybridized with γ-NiOOH nanosheets supported on Ni foam (Pt/γ-NiOOH/NF) that favors electrochemical transformation of real-word PET hydrolysate into glycolate with high Faradaic efficiency (> 90%) and selectivity (> 90%) across wide reactant (ethylene glycol, EG) concentration ranges under a marginal applied voltage of 0.55 V, which can be paired with cathodic hydrogen production. Computational studies combined with experimental characterizations elucidate that the Pt/γ-NiOOH interface with substantial charge accumulation gives rise to an optimized adsorption energy of EG and a decreased energy barrier of potential determining step. A techno-economic analysis demonstrates that, with the nearly same amount of resource investment, the electroreforming strategy towards glycolate production can raise revenue by up to 2.2 times relative to conventional chemical process. This work may thus serve as a framework for PET wastes valorization process with net-zero carbon footprint and high economic viability.