Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age.

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

C. elegans ageing is accelerated by a self-destructive reproductive programme.

In post-reproductive C. elegans, destructive somatic biomass repurposing supports production of yolk which, it was recently shown, is vented and can serve as a foodstuff for larval progeny. This is reminiscent of the suicidal reproductive effort (reproductive death) typical of semelparous organisms such as Pacific salmon. To explore the possibility that C. elegans exhibits reproductive death, we have compared sibling species pairs of the genera Caenorhabditis and Pristionchus with hermaphrodites and females. We report that yolk venting and constitutive, early pathology involving major anatomical changes occur only in hermaphrodites, which are also shorter lived. Moreover, only in hermaphrodites does germline removal suppress senescent pathology and markedly increase lifespan. This is consistent with the hypothesis that C. elegans exhibit reproductive death that is suppressed by germline ablation. If correct, this would imply a major difference in the ageing process between C. elegans and most higher organisms, and potentially explain the exceptional plasticity in C. elegans ageing.

Blocking LAIR1 signaling in immune cells inhibits tumor development.

The current immune checkpoint blockade therapy has been successful in treating some cancers but not others. New molecular targets and therapeutic approaches of cancer immunology need to be identified. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) is an immune inhibitory receptor expressing on most immune cell types. However, it remains a question whether we can specifically and actively block LAIR1 signaling to activate immune responses for cancer treatment. Here we report the development of specific antagonistic anti-LAIR1 monoclonal antibodies and studied the effects of LAIR1 blockade on the anti-tumor immune functions. The anti-LAIR1 antagonistic antibody stimulated the activities of T cells, natural killer cells, macrophages, and dendritic cells in vitro. The single-cell RNA sequencing analysis of intratumoral immune cells in syngeneic human LAIR1 transgenic mice treated with control or anti-LAIR1 antagonist antibodies indicates that LAIR1 signaling blockade increased the numbers of CD4 memory T cells and inflammatory macrophages, but decreased those of pro-tumor macrophages, regulatory T cells, and plasmacytoid dendritic cells. Importantly, the LAIR1 blockade by the antagonistic antibody inhibited the activity of immunosuppressive myeloid cells and reactivated T cells from cancer patients in vitro and impeded tumor metastasis in a humanized mouse model. Blocking LAIR1 signaling in immune cells represents a promising strategy for development of anti-cancer immunotherapy.

Single-Step Fabrication of Au-Fe-BaTiO3 Nanocomposite Thin Films Embedded with Non-Equilibrium Au-Fe Alloyed Nanostructures.

Nanocomposite thin film materials present great opportunities in coupling materials and functionalities in unique nanostructures including nanoparticles-in-matrix, vertically aligned nanocomposites (VANs), and nanolayers. Interestingly the nanocomposites processed through a non-equilibrium processing method, e.g., pulsed laser deposition (PLD), often possess unique metastable phases and microstructures that could not achieve using equilibrium techniques, and thus lead to novel physical properties. In this work, a unique three-phase system composed of BaTiO3 (BTO), with two immiscible metals, Au and Fe, is demonstrated. By adjusting the deposition laser frequency from 2 Hz to 10 Hz, the phase and morphology of Au and Fe nanoparticles in BTO matrix vary from separated Au and Fe nanoparticles to well-mixed Au-Fe alloy pillars. This is attributed to the non-equilibrium process of PLD and the limited diffusion under high laser frequency (e.g., 10 Hz). The magnetic and optical properties are effectively tuned based on the morphology variation. This work demonstrates the stabilization of non-equilibrium alloy structures in the VAN form and allows for the exploration of new non-equilibrium materials systems and their properties that could not be easily achieved through traditional equilibrium methods.

Reducing leakage current and enhancing polarization in multiferroic 3D super-nanocomposites by microstructure engineering.

Multiferroic materials have generated great interest due to their potential as functional device materials. Nanocomposites have been increasingly used to design and generate new functionalities by pairing dissimilar ferroic materials, though the combination often introduces new complexity and challenges unforeseeable in single-phase counterparts. The recently developed approaches to fabricate 3D super-nanocomposites (3D-sNC) open new avenues to control and enhance functional properties. In this work, we develop a new 3D-sNC with CoFe2O4(CFO) short nanopillar arrays embedded in BaTiO3(BTO) film matrix via microstructure engineering by alternatively depositing BTO:CFO vertically-aligned nanocomposite layers and single-phase BTO layers. This microstructure engineering method allows encapsulating the relative conducting CFO phase by the insulating BTO phase, which suppress the leakage current and enhance the polarization. Our results demonstrate that microstructure engineering in 3D-sNC offers a new bottom-up method of fabricating advanced nanostructures with a wide range of possible configurations for applications where the functional properties need to be systematically modified.

Life Cycle Assessment on Environmental Sustainability of Food Processing.

Food processing represents a critical part of the food supply chain that converts raw materials into safe and nutritious food products with high quality. However, the fast-growing food processing industry has imposed enormous burdens on the environment. Life cycle assessment (LCA) is widely used for evaluating the sustainability of food systems; nonetheless, current attention mainly concentrates on the agricultural production stage. This article reviews recent LCA studies on dairy, fruits and vegetables, and beverage products, with a particular emphasis on their processing stage. The environmental impacts of various foods are summarized, and the hotspots in their processing lines as well as potential remediation strategies are highlighted. Moreover, an outlook on the environmental performance of nonthermal processing, modified atmosphere packaging, and active packaging is provided, and future research directions are recommended. This review enables quantitative assessments and comparisons to be made by food manufacturers that are devoted to implementing sustainable processing technologies.

Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes.

Within primates, the great apes are outliers both in terms of body size and lifespan, since they include the largest and longest-lived species in the order. Yet, the molecular bases underlying such features are poorly understood. Here, we leveraged an integrated approach to investigate multiple sources of molecular variation across primates, focusing on over 10,000 genes, including approximately 1,500 previously associated with lifespan, and additional approximately 9,000 for which an association with longevity has never been suggested. We analyzed dN/dS rates, positive selection, gene expression (RNA-seq), and gene regulation (ChIP-seq). By analyzing the correlation between dN/dS, maximum lifespan, and body mass, we identified 276 genes whose rate of evolution positively correlates with maximum lifespan in primates. Further, we identified five genes, important for tumor suppression, adaptive immunity, metastasis, and inflammation, under positive selection exclusively in the great ape lineage. RNA-seq data, generated from the liver of six species representing all the primate lineages, revealed that 8% of approximately 1,500 genes previously associated with longevity are differentially expressed in apes relative to other primates. Importantly, by integrating RNA-seq with ChIP-seq for H3K27ac (which marks active enhancers), we show that the differentially expressed longevity genes are significantly more likely than expected to be located near a novel "ape-specific" enhancer. Moreover, these particular ape-specific enhancers are enriched for young transposable elements, and specifically SINE-Vntr-Alus. In summary, we demonstrate that multiple evolutionary forces have contributed to the evolution of lifespan and body size in primates.

Effectiveness of Intrathecal Baclofen for Intractable Stiffperson Syndrome: a Case Report.

BACKGROUND: Intrathecal baclofen is considered an adjuvant therapy for patients with intractable spasms due to stiff-person syndrome. There is increasing evidence to support the use of intrathecal baclofen in the management of symptomatic stiffperson syndrome, with improvement in function. CASE REPORT: A 38-year-old woman with stiff- person syndrome initially presented to inpatient rehabilitation for intractable muscle spasms. The symptoms made her non-ambulatory and limited her tolerance to wheelchair use for mobility. The patient underwent up-titration of oral baclofen and diazepam, with concurrent intravenous immunoglobulin cycles, leading to transient symptom relief. She agreed to explore intrathecal baclofen therapy. An initial trial of a single bolus of 50 µg intrathecal baclofen resulted in a significant decrease in spontaneous spasms, enabling modified independence in transfers and ambulation. The patient was subsequently implanted with a permanent intrathecal delivery system. To date, the intrathecal baclofen had been titrated to 186 µg per day with simple continuous delivery. The patient was weaned off oral baclofen. She attained complete functional independence with ambulation without the need for assistive devices, and has had no lasting post-procedural complications to date. CONCLUSION: This case report adds to the increasing evidence of cases of refractory stiff-person syndrome managed successfully using intrathecal baclofen therapy.

Mutation of daf-2 extends lifespan via tissue-specific effectors that suppress distinct life-limiting pathologies.

In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF-1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf-2 insulin/IGF-1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf-2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS-regulated DAF-16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF-16 also promotes p Age in class 2 daf-2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf-2 interactions with the daf-12 steroid receptor implies that previously described opposing effects of daf-12 on daf-2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF-1 and steroid signaling. These findings support the view that wild-type IIS acts through multiple distinct mechanisms which promote different life-limiting pathologies, each of which contribute to late-life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan.

Gross ways to live long: Parasitic worms as an anti-inflammaging therapy?

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore 'old friend' microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?

Multifunctional Metal-Oxide Nanocomposite Thin Film with Plasmonic Au Nanopillars Embedded in Magnetic La0.67Sr0.33MnO3 Matrix.

Searching for multifunctional materials with tunable magnetic and optical properties has been a critical task toward the implementation of future integrated optical devices. Vertically aligned nanocomposite (VAN) thin films provide a unique platform for multifunctional material designs. Here, a new metal-oxide VAN has been designed with plasmonic Au nanopillars embedded in a ferromagnetic La0.67Sr0.33MnO3 (LSMO) matrix. Such Au-LSMO nanocomposite presents intriguing plasmon resonance in the visible range and magnetic anisotropy property, which are functionalized by the Au and LSMO phase, respectively. Furthermore, the vertically aligned nanostructure of metal and dielectric oxide results in the hyperbolic property for near-field electromagnetic wave manipulation. Such optical and magnetic response could be further tailored by tuning the composition of Au and LSMO phases.

Hybrid Ag-LiNbO3 nanocomposite thin films with tailorable optical properties.

Ag nanostructures exhibit extraordinary optical properties, which are important for photonic device integration. Herein, we deposited Ag-LiNbO3 (LNO) nanocomposite thin films with Ag nanoparticles (NPs) embedded into the LNO matrix by the co-deposition of Ag and LNO using a pulsed laser deposition (PLD) method. The density and size of Ag NPs were tailored by varying the Ag composition. Low-density and high-density Ag-LNO nanocomposite thin films were deposited and their optical properties, such as transmittance spectra, ellipsometry measurement, as well as angle-dependent and polarization-resolved reflectivity spectra, were explored. The Ag-LNO films show surface plasmon resonance (SPR) in the visible range, tunable optical constants and optical anisotropy, which are critical for photonic device applications.

The Writers, Readers, and Erasers in Redox Regulation of GAPDH.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme, which is crucial for the breakdown of glucose to provide cellular energy. Over the past decade, GAPDH has been reported to be one of the most prominent cellular targets of post-translational modifications (PTMs), which divert GAPDH toward different non-glycolytic functions. Hence, it is termed a moonlighting protein. During metabolic and oxidative stress, GAPDH is a target of different oxidative PTMs (oxPTM), e.g., sulfenylation, S-thiolation, nitrosylation, and sulfhydration. These modifications alter the enzyme's conformation, subcellular localization, and regulatory interactions with downstream partners, which impact its glycolytic and non-glycolytic functions. In this review, we discuss the redox regulation of GAPDH by different redox writers, which introduce the oxPTM code on GAPDH to instruct a redox response; the GAPDH readers, which decipher the oxPTM code through regulatory interactions and coordinate cellular response via the formation of multi-enzyme signaling complexes; and the redox erasers, which are the reducing systems that regenerate the GAPDH catalytic activity. Human pathologies associated with the oxidation-induced dysregulation of GAPDH are also discussed, featuring the importance of the redox regulation of GAPDH in neurodegeneration and metabolic disorders.

Au-Encapsulated Fe Nanorods in Oxide Matrix with Tunable Magneto-Optic Coupling Properties.

Materials with magneto-optic coupling properties are highly coveted for their potential applications ranging from spintronics and optical switches to sensors. In this work, a new, three-phase Au-Fe-La0.5Sr0.5FeO3 (LSFO) hybrid material grown in a vertically aligned nanocomposite (VAN) form has been demonstrated. This three-phase hybrid material combines the strong ferromagnetic properties of Fe and the strong plasmonic properties of Au and the dielectric nature of the LSFO matrix. More interestingly, the immiscible Au and Fe phases form Au-encapsulated Fe nanopillars, embedded in the LSFO matrix. Multifunctionalities including anisotropic optical dielectric properties, plasmonic properties, magnetic anisotropy, and room-temperature magneto-optic Kerr effect coupling are demonstrated. The single-step growth method to grow the immiscible two-metal nanostructures (i.e., Au and Fe) in the complex hybrid material form opens exciting new potential opportunities for future three-phase VAN systems with more versatile metal selections.

Strain Effects on the Growth of La0.7Sr0.3MnO3 (LSMO)-NiO Nanocomposite Thin Films via Substrate Control.

Oxide-oxide-based vertically aligned nanocomposites (VANs) have demonstrated a new material platform for enhanced and/or combined functionalities because of their unique vertical geometry and strain coupling. Various factors contribute to the growth of VANs, including deposition parameters, phase composition, phase ratios, crystallography, etc. In this work, substrate strain effects are explored through growing a two-phase oxide-oxide La0.7Sr0.3MnO3 (LSMO):NiO system, combining antiferromagnetic NiO and ferromagnetic LSMO, on various substrates with different lattice parameters. The X-ray diffraction (XRD), transmission electron microscopy (TEM), and magnetic property measurements all suggest that substrate strain plays a critical role in the epitaxial growth of a VAN structure and their two-phase separation, and thus results in different physical properties. This work sheds light on the fundamental nucleation and growth mechanisms of the two-phase VAN systems and the effects of substrate strain on the overall orientation and growth quality of the VAN films.

Ceramic Material Processing Towards Future Space Habitat: Electric Current-Assisted Sintering of Lunar Regolith Simulant.

In situ utilization of available resources in space is necessary for future space habitation. However, direct sintering of the lunar regolith on the Moon as structural and functional components is considered to be challenging due to the sintering conditions. To address this issue, we demonstrate the use of electric current-assisted sintering (ECAS) as a single-step method of compacting and densifying lunar regolith simulant JSC-1A. The sintering temperature and pressure required to achieve a relative density of 97% and microhardness of 6 GPa are 700 °C and 50 MPa, which are significantly lower than for the conventional sintering technique. The sintered samples also demonstrated ferroelectric and ferromagnetic behavior at room temperature. This study presents the feasibility of using ECAS to sinter lunar regolith for future space resource utilization and habitation.

Induced ferroelectric phases in SrTiO3 by a nanocomposite approach.

Inducing new phases in thick films via vertical lattice strain is one of the critical advantages of vertically aligned nanocomposites (VANs). In SrTiO3 (STO), the ground state is ferroelastic, and the ferroelectricity in STO is suppressed by the orthorhombic transition. Here, we explore whether vertical lattice strain in three-dimensional VANs can be used to induce new ferroelectric phases in SrTiO3:MgO (STO:MgO) VAN thin films. The STO:MgO system incorporates ordered, vertically aligned MgO nanopillars into a STO film matrix. Strong lattice coupling between STO and MgO imposes a large lattice strain in the STO film. We have investigated ferroelectricity in the STO phase, existing up to room temperature, using piezoresponse force microscopy, phase field simulation and second harmonic generation. We also serendipitously discovered the formation of metastable TiO nanocores in MgO nanopillars embedded in the STO film matrix. Our results emphasize the design of new phases via vertical epitaxial strain in VAN thin films.

Integration of highly anisotropic multiferroic BaTiO3-Fe nanocomposite thin films on Si towards device applications.

Integration of highly anisotropic multiferroic thin films on silicon substrates is a critical step towards low-cost devices, especially high-speed and low-power consumption memories. In this work, an oxide-metal vertically aligned nanocomposite (VAN) platform has been used to successfully demonstrate self-assembled multiferroic BaTiO3-Fe (BTO-Fe) nanocomposite films with high structural anisotropy on Si substrates. The effects of various buffer layers on the crystallinity, microstructure, and physical properties of the BTO-Fe films have been explored. With an appropriate buffer layer design, e.g. SrTiO3/TiN bilayer buffer, the epitaxial quality of the BTO matrix and the anisotropy of the Fe nanopillars can be improved greatly, which in turn enhances the physical properties, including the ferromagnetic, ferroelectric, and optical response of the BTO-Fe thin films. This unique combination of properties integrated on Si offers a promising approach in the design of multifunctional nanocomposites for Si-based memories and optical devices.

Tuning magnetic anisotropy in Co-BaZrO3 vertically aligned nanocomposites for memory device integration.

Ferromagnetic nanostructures with strong anisotropic properties are highly desired for their potential integration into spintronic devices. Several anisotropic candidates, such as CoFeB and Fe-Pt, have been previously proposed, but many of them have limitations such as patterning issues or thickness restrictions. In this work, Co-BaZrO3 (Co-BZO) vertically aligned nanocomposite (VAN) films with tunable magnetic anisotropy and coercive field strength have been demonstrated to address this need. Such tunable magnetic properties are achieved through tuning the thickness of the Co-BZO VAN structures and the aspect ratio of the Co nanostructures, which can be easily integrated into spintronic devices. As a demonstration, we have integrated the Co-BZO VAN nanostructure into tunnel junction devices, which demonstrated resistive switching alluding to Co-BZO's immense potential for future spintronic devices.

Self-assembled vertically aligned Ni nanopillars in CeO2 with anisotropic magnetic and transport properties for energy applications.

Self-assembled vertically aligned metal-oxide (Ni-CeO2) nanocomposite thin films with novel multifunctionalities have been successfully deposited by a one-step growth method. The novel nanocomposite structures presents high-density Ni-nanopillars vertically aligned in a CeO2 matrix. Strong and anisotropic magnetic properties have been demonstrated, with a saturation magnetization (Ms) of ∼175 emu cm-3 and ∼135 emu cm-3 for out-of-plane and in-plane directions, respectively. Such unique vertically aligned ferromagnetic Ni nanopillars in the CeO2 matrix have been successfully incorporated in high temperature superconductor YBa2Cu3O7 (YBCO) coated conductors as effective magnetic flux pinning centers. The highly anisotropic nanostructures with high density vertical interfaces between the Ni nanopillars and CeO2 matrix also promote the mixed electrical and ionic conductivities out-of-plane and thus demonstrate great potential as nanocomposite anode materials for solid oxide fuel cells and other potential applications requiring anisotropic ionic transport properties.