Intrinsic Ability Research Articles

Co-continuous structure enhanced magnetic responsive shape memory PLLA/TPU blend fabricated by 4D printing

ABSTRACT Combining poly (L-lactic acid) (PLLA) with thermoplastic polyurethane elastomer (TPU) can integrate the advantages of excellent biocompatibility and intrinsic shape memory ability of PLLA and high elasticity and excellent shape memory properties of TPU in the application of minimally invasive surgery for bone tissue engineering. However, TPU easily forms a sea-island-like structure in PLLA matrix, decreasing shape memory properties. In this study, a co-continuous structure of TPU phase in PLLA matrix was constructed by adding Fe3O4 nanoparticles due to the changed interfacial tension and flow behavior of TPU, which endowed the TPU/PLLA/Fe3O4 blend fabricated via selective laser sintering (SLS) with excellent shape memory properties. As a result, the morphology of TPU in the blend changed from sea-island-like structure to complete co-continuous structure with increasing Fe3O4 content (0 to 10wt%), and shape recovery ratios in 50 °C water increased from 66.67 to 95.92%. The introduction of Fe3O4 endowed the blend with magnetic responsive shape memory in alternating magnetic field because Fe3O4 could heat it by generating heat from relative friction and particle collisions. Besides, the tensile modulus and hardness of the specimen with 10wt% Fe3O4 nanoparticles increased. In addition, the blend demonstrated excellent biocompatibility by promoting cell adhesion, spreading, and proliferation.

Modulation of terpenoid indole alkaloid pathway via elicitation with phytosynthesized silver nanoparticles for the enhancement of ajmalicine, a pharmaceutically important alkaloid.

The use of silver nanoparticles as elicitors in cell cultures of Rauwolfia serpentina resulted in increased levels of ajmalicine, upregulated structural and regulatory genes, elevated MDA content, and reduced activity of antioxidant enzymes. These findings hold potential for developing a cost-effective method for commercial ajmalicine production. Plants possess an intrinsic ability to detect various stress signals, prompting the activation of defense mechanisms through the reprogramming of metabolites to counter adverse conditions. The current study aims to propose an optimized bioprocess for enhancing the content of ajmalicine in Rauwolfia serpentina callus through elicitation with phytosynthesized silver nanoparticles. Initially, callus lines exhibiting elevated ajmalicine content were established. Following this, a protocol for the phytosynthesis of silver nanoparticles using seed extract from Rauwolfia serpentina was successfully standardized. The physicochemical attributes of the silver nanoparticles were identified, including their spherical shape, size ranging from 6.7 to 28.8nm in diameter, and the presence of reducing-capping groups such as amino, carbonyl, and amide. Further, the findings indicated that the presence of 2.5mg L-1 phytosynthesized silver nanoparticles in the culture medium increased the ajmalicine content. Concurrently, structural genes (TDC, SLS, STR, SGD, G10H) and regulatory gene (ORCA3) associated with the ajmalicine biosynthetic pathway were observed to be upregulated. A notable increase in MDA content and a decrease in the activities of antioxidant enzymes were observed. A notable increase in MDA content and a decrease in the activities of antioxidant enzymes were also observed. Our results strongly recommend the augmentation of ajmalicine content in the callus culture of R. serpentina through supplementation with silver nanoparticles, a potential avenue for developing a cost-effective process for the commercial production of ajmalicine.

The SVZ stem cell niche-components, functions, and in vitro modelling.

Neocortical development depends on the intrinsic ability of neural stem and progenitor cells to proliferate and differentiate to generate the different kinds of neurons in the adult brain. These progenitor cells can be distinguished into apical progenitors, which occupy a stem cell niche in the ventricular zone and basal progenitors, which occupy a stem cell niche in the subventricular zone (SVZ). During development, the stem cell niche provided in the subventricular zone enables the increased proliferation and self-renewal of basal progenitors, which likely underlie the expansion of the human neocortex. However, the components forming the SVZ stem cell niche in the developing neocortex have not yet been fully understood. In this review, we will discuss potential components of the SVZ stem cell niche, i.e., extracellular matrix composition and brain vasculature, and their possible key role in establishing and maintaining this niche during fetal neocortical development. We will also emphasize the potential role of basal progenitor morphology in maintaining their proliferative capacity within the stem cell niche of the SVZ. Finally, we will focus on the use of brain organoids to i) understand the unique features of basal progenitors, notably basal radial glia; ii) study components of the SVZ stem cell niche; and iii) provide future directions on how to improve brain organoids, notably the organoid SVZ, and make them more reliable models of human neocortical development and evolution studies.

INTRINSIC CAPACITY OF OLDER ADULTS IN SINGAPORE USING WHO INTEGRATED CARE FOR OLDER PEOPLE (ICOPE) FRAMEWORK

Abstract The World Health Organization (WHO) proposed the Integrated Care for Older People (ICOPE) approach to guide health systems in better supporting the intrinsic capacity and functional ability of older adults to enable healthy aging (Briggs et al., 2018; de Carvalho et al., 2019). This approach is aligned with Singapore’s Healthier SG initiative, which aims to build a good healthcare system that promotes better health and quality of life for everyone. Recent studies have shown that older adults experience intrinsic capacity decline in various countries, including Singapore, highlighting the importance of targeted interventions to maintain functionality and quality of life in old age (Beard et al., 2019; Liu et al., 2021; Tay et al., 2022). In this cross-sectional study, 367 participants were assessed by 43 ICOPE assessors, of whom 77.4% (n=284) had impairments in intrinsic capacity. The three most prevalent intrinsic capacity impairments were visual impairment (42%), hearing loss (33.5%), and cognitive decline (31.3%), followed by limited mobility (24.3%), malnutrition (16.1%), and depressive symptoms (16.1%). Furthermore, 22.6% of participants were unaware of any elderly care services available in the community, and 8.2% did not know where to seek help in case of problems. These findings emphasize the need for ICOPE assessments at the community level to promote early detection of intrinsic capacity impairments and interventions. More discussion of the care pathway, together with health professionals, older adults, and caregivers, should be the next step to offer diagnostic assessment and guide self-management of intrinsic capacity impairment for among older adults.

Intrinsic factors driving mosquito vector competence and viral evolution: a review.

Mosquitoes are responsible for the transmission of numerous viruses of global health significance. The term "vector competence" describes the intrinsic ability of an arthropod vector to transmit an infectious agent. Prior to transmission, the mosquito itself presents a complex and hostile environment through which a virus must transit to ensure propagation and transmission to the next host. Viruses imbibed in an infectious blood meal must pass in and out of the mosquito midgut, traffic through the body cavity or hemocoel, invade the salivary glands, and be expelled with the saliva when the vector takes a subsequent blood meal. Viruses encounter physical, cellular, microbial, and immunological barriers, which are influenced by the genetic background of the mosquito vector as well as environmental conditions. Collectively, these factors place significant selective pressure on the virus that impact its evolution and transmission. Here, we provide an overview of the current state of the field in understanding the mosquito-specific factors that underpin vector competence and how each of these mechanisms may influence virus evolution.

Synthesis of thermoset elastomer from microbial oil derived from the fermentation of sugarcane

AbstractIn the context of the 21st century, the integration of diverse perspectives within the circular economy framework, encompassing waste management, economic growth, and environmental sustainability, stands out as a paramount challenge. Addressing this challenge, an innovative avenue emerges through the application of microbial oil to replace traditional petroleum in the synthesis of essential commodity chemicals. This groundbreaking study takes a significant step toward this goal by introducing a pioneering polyester material boasting an exceptionally high renewable content. This material is synthesized through melt polycondensation, utilizing a novel primary feedstock derived from the oily residue extracted post‐distillation of β‐farnesene (FDR). The ingenious approach involves fermenting sugarcane syrup using a genetically engineered yeast strain of Saccharomyces cerevisiae. The outcome of this study reveals the creation of an amorphous polymer with rubber‐like attributes. These attributes include a Young's modulus of 3.9 MPa, with a maximum elastic strain and tensile stress values of 185.4% and 510 KPa, respectively, along with distinctive strain‐hardening characteristics. Remarkably, this material also exhibits indications of shape memory behavior in a temperature range spanning from −47 to 12°C, as discerned from dynamic mechanical analysis. Evidently, this novel polymer demonstrates exceptional promise in the realm of low‐temperature applications. Its intrinsic ability to uphold mechanical integrity, even when subjected to substantial deformations within its service conditions, positions it as an invaluable resource for various components requiring resilience in challenging environments.

Applications of Ionic Liquids in the Field of Agriculture: A Review

This review delves into the diverse applications of ionic liquids (ILs) in modern agriculture, focusing on their pivotal roles in the extraction of natural products and pesticides, as well as their substantial significance in sustainable pesticide delivery systems. The reported extraction methods include ILs and their modified materials as solvents in dispersive liquid–liquid microextraction, solid-phase dispersion, and solid-phase microextraction. The study categorizes ILs according to their utility as herbicides, microbicides, food repellents, and plant growth regulators. This review investigates the use of ILs as plant immunity inducers to elevate the systemic acquired resistance in crops, thereby augmenting their intrinsic ability to defend against plant pathogens. Furthermore, the review explores the application of ILs in pesticide delivery systems, emphasizing their ability to enhance efficacy while promoting environmental sustainability. The biodegradability and toxicity aspects of ILs are also discussed, shedding light on their potential as eco-friendly alternatives in agricultural practices. In conclusion, this comprehensive overview underscores the multifaceted contributions of ILs in agriculture, from efficient extraction methods to the development of innovative and sustainable pesticide delivery systems. As the agricultural landscape evolves towards environmentally conscious practices, the integration of ILs presents a promising avenue for enhancing productivity while minimizing ecological impact. As the agricultural industry seeks innovative and sustainable solutions, the nuanced exploration of ILs in this review highlights their potential to address multiple challenges in modern farming practices.

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement.

Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.

Altered apoptosis and proliferation in milk cells and PBMc from BLV-infected bovines with different proviral loads: Possible role of the BCL-2 family proteins, TNF-alpha, and receptors

Bovines infected by bovine leukemia virus (BLV) are characterized by presenting low proviral load (LPL) or high proviral load (HPL). It is reported that animals with HPL in peripheral blood mononuclear cells (PBMCs) present a decrease in apoptosis, an increase in viability and the proliferation rate, while animals that maintain an LPL have an intrinsic ability to control the infection, presenting an increased apoptosis rate of their PBMCs. However, there is little information on the effect of BLV on these mechanisms when the virus infects somatic milk cells (SC). This study investigates the mechanisms underlying apoptosis in milk and blood from BLV-infected animals with HPL and LPL. Relative levels of mRNA of tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNF-RI), TNF receptor 2 (TNF-RII), anti-apoptotic B-cell lymphoma 2 protein (Bcl-2), and pro-apoptotic Bcl-2-like protein 4 (Bax) were measured in SC and PBMCs using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. A significant decrease in the expression of TNF-α in SC from HPL animals vs non-infected bovines was observed, but the infection in SC with BLV did not show a modulation on the expression of TNF receptors. A significant increase in TNF-RI expression in PBMCs from HPL bovines compared to LPL bovines was observed. No significant differences in PBMCs between HPL and LPL compared to non-infected animals concerning TNF-α, TNF-RI, and TNF-RII expression were found. There was a significant increase of both Bcl-2 and Bax in SC from LPL compared to non-infected bovines, but the Bcl-2/Bax ratio showed an anti-apoptotic profile in LPL and HPL bovines compared to non-infected ones. Reduced mRNA expression levels of Bax were determined in the PBMCs from HPL compared to LPL subjects. In contrast, BLV-infected bovines did not differ significantly in the mRNA expression of Bax compared to non-infected bovines. Our data suggest that the increased mRNA expression of Bax corresponds to the late lactation state of bovine evaluated and the exacerbated increase of mRNA expression of Bcl-2 may be one of the mechanisms for the negative apoptosis regulation in the mammary gland induced by BLV infection. These results provide new insights into the mechanism of mammary cell death in HPL and LPL BLV-infected bovine mammary gland cells during lactation.

In silico identification and characterization of small molecule binding to the CD1d immunoreceptor

CD1 immunoreceptors are a non-classical major histocompatibility complex (MHC) that present antigens to T cells to elucidate immune responses against disease. The antigen repertoire of CD1 has been composed primarily of lipids until recently when CD1d-restricted T cells were shown to be activated by non-lipidic small molecules, such as phenyl pentamethyl dihydrobenzofuran sulfonate (PPBF) and related benzofuran sulfonates. To date structural insights into PPBF/CD1d interactions are lacking, so it is unknown whether small molecule and lipid antigens are presented and recognized through similar mechanisms. Furthermore, it is unknown whether CD1d can bind to and present a broader range of small molecule metabolites to T cells, acting out functions analogous to the MHC class I related protein MR1. Here, we perform in silico docking and molecular dynamics simulations to structurally characterize small molecule interactions with CD1d. PPBF was supported to be presented to T cell receptors through the CD1d F’ pocket. Virtual screening of CD1d against more than 17,000 small molecules with diverse geometry and chemistry identified several novel scaffolds, including phytosterols, cholesterols, triterpenes, and carbazole alkaloids, that serve as candidate CD1d antigens. Protein-ligand interaction profiling revealed conserved residues in the CD1d F’ pocket that similarly anchor small molecules and lipids. Our results suggest that CD1d could have the intrinsic ability to bind and present a broad range of small molecule metabolites to T cells to carry out its function beyond lipid antigen presentation. Communicated by Ramaswamy H. Sarma

Global Remodeling of Host Proteome in Response to Leishmania Infection.

The protozoan parasite Leishmania possesses an intrinsic ability to modulate a multitude of pathways in the host, toward aiding its own proliferation. In response, the host reprograms its cellular, immunological, and metabolic machinery to evade the parasite's lethal impact. Besides inducing various antioxidant signaling pathways to counter the elevated stress response proteins like heme oxygenase-1 (HO-1), Leishmania also attempts to delay host cell apoptosis by promoting anti-apoptotic proteins like Bcl-2. The downstream modulation of apoptotic proteins is regulated by effector pathways, including the PI3K/Akt survival pathway, the mitogen-activated protein kinases (MAPKs) signaling pathway, and STAT phosphorylation. In addition, Leishmania assists in its infection in a time-dependent manner by modulating the level of various proteins of autophagic machinery. Immune effector cells, such as mast cells and neutrophils, entrap and kill the pathogen by secreting various granular proteins. In contrast, the host macrophages exert their leishmanicidal effect by secreting various cytokines, such as IL-2, IL-12, etc. An interplay of various signaling pathways occurs in an organized network that is highly specific to both pathogen and host species. This Review analyzes the modulation of expression of proteins, including the cytokines, providing a realistic approach toward understanding the pathophysiology of disease and predicting some prominent markers for disease intervention and vaccine support strategies.

Board competence and green innovation—Does external governance matter?

AbstractPrevious research examining the link between board attributes and ecological strategies such as green innovation has primarily focused on structural board attributes, yielding mixed findings. Moreover, the critical contextual grounds that shape the relationship between board attributes and green innovation have often been overlooked, leading to potential biases in empirical investigations. Considering that competence drives outstanding performance, we developed a unique measure of board competence that represents the board's intrinsic ability to perform in corporate strategies. Drawing on a holistic perspective of agency, resource dependence, and stakeholder theories, we posit a strong relationship between board competence and green innovation. Furthermore, we contend that this association is moderated by external governance mechanisms, namely audit quality, media coverage, and imitative pressure. Through our analysis of publicly traded Chinese companies, we found compelling evidence to support our assertions. These findings have important implications for policymakers, practitioners, and managers.

Salmonella enterica and outer membrane vesicles are current and future options for cancer treatment.

Conventional cancer therapies have many limitations. In the last decade, it has been suggested that bacteria-mediated immunotherapy may circumvent the restrictions of traditional treatments. For example, Salmonella enterica is the most promising bacteria for treating cancer due to its intrinsic abilities, such as killing tumor cells, targeting, penetrating, and proliferating into the tumor. S. enterica has been genetically modified to ensure safety and increase its intrinsic antitumor efficacy. This bacterium has been used as a vector for delivering anticancer agents and as a combination therapy with chemotherapy, radiotherapy, or photothermic. Recent studies have reported the antitumor efficacy of outer membrane vesicles (OMVs) derived from S. enterica. OMVs are considered safer than attenuated bacteria and can stimulate the immune system as they comprise most of the immunogens found on the surface of their parent bacteria. Furthermore, OMVs can also be used as nanocarriers for antitumor agents. This review describes the advances in S. enterica as immunotherapy against cancer and the mechanisms by which Salmonella fights cancer. We also highlight the use of OMVs as immunotherapy and nanocarriers of anticancer agents. OMVs derived from S. enterica are innovative and promising strategies requiring further investigation.

Enzyme-Mediated Temporal Control over the Conformational Disposition of a Condensed Protein in Macromolecular Crowded Media.

Temporal regulation between input and output signals is one of the hallmarks of complex biological processes. Herein, we report that the conformational disposition of a protein in macromolecularly crowded media can be controlled with time using enzymes. First, we demonstrate the pH dependence of bovine serum albumin (BSA) condensation and conformational alteration in the presence of poly(ethylene glycol) as a crowder. However, by exploiting the strength of pH-modulatory enzymatic reactions (glucose oxidase and urease), the conversion time between the condensed and free forms can be tuned. Additionally, we demonstrate that the trapping of intermediate states with respect to the overall system at a particular α-helix or β-sheet composition and rotational mobility can be possible simply by altering the substrate concentration. Finally, we show that the intrinsic catalytic ability of BSA toward the Kemp elimination (KE) reaction is inhibited in the aggregated form but regained in the free form. In fact, the rate of KE reaction can also be actuated enzymatically in a temporal fashion, therefore demonstrating the programmability of a cascade of biochemical events in crowded media.

Metamorphosis as the Crux of the Character Vandiya Devan in Kalki’s Ponniyin Selvan

Human life is inherently compared. Man compares his life to other people’s lives. He has the intrinsic moral ability to balance the evil and good thoughts that bubble up from the depths of his mind. This is how literature and art have developed throughout all cultures. They have all been created in a comparative way. Literature has been a tool for teaching people about life and how it should and should not be. Images, symbols, and recurring themes from everyday life are used to illustrate the concepts. We refer to them as archetypes. They are the archaic pictures from global mythology that predominate in everyone’s minds. The journey of the hero is one such motif that has been predominating in the literary genre. This style totally maintains the hero’s quest as its foundation. They are fiercely patriotic toward their respective national identities. The great heroes of any nation are represented by their characters. Characters from the film “Ponniyin Selvan” such Aditya Karikalan, Arulmozhi Varman, and Vanthiyathevan are well-known for their quests, adventures, feuds, fights, and wars. Their quest and triumph serve as ideal illustrations of the hero archetype’s journey. In Kalki’s Ponniyin Selvan, the transformation of the character Vanthiya Devan is extra ordinary. Thus, the present paper explores Vanthiya Devan’s transformation and achievements in the novel and film.

A fatigue crack growth prediction method on small datasets based on optimized deep neural network and Delaunay data augmentation

The neural network-based prediction method has shown great potential in the field of fatigue crack growth prediction due to its powerful nonlinear processing and generalization capabilities. However, traditional deep neural network-based methods often encounter problems such as overfitting, underfitting, and instability when predicting FCG rates on small datasets. To address these issues, this study proposes a SA-DNN prediction method for metal fatigue crack growth by introducing Delaunay data augmentation and simulated annealing algorithm into the basic DNN framework. The proposed SA-DNN model is then used to predict the fatigue crack growth process of AM60B magnesium alloy and 7055 Al alloy, and the intrinsic and extrinsic generalization abilities of the model are evaluated. In both the evaluation of intrinsic and extrinsic generalization abilities, the mean squared errors of the training, validation, and testing sets rapidly converge to the target error in various epochs. The lowest mean squared errors achieved are 1.07 e-5 and 1.241 e-5, respectively. Moreover, the results also indicate that the proposed model can accurately predict the fatigue crack growth process of metal materials with varying degrees of nonlinearity.

Electron-Sponge Nature of Polyoxometalates for Next-Generation Electrocatalytic Water Splitting and Nonvolatile Neuromorphic Devices.

Designing next-generation molecular devices typically necessitates plentiful oxygen-bearing sites to facilitate multiple-electron transfers. However, the theoretical limits of existing materials for energy conversion and information storage devices make it inevitable to hunt for new competitors. Polyoxometalates (POMs), a unique class of metal-oxide clusters, have been investigated exponentially due to their structural diversity and tunable redox properties. POMs behave as electron-sponges owing to their intrinsic ability of reversible uptake-release of multiple electrons. In this review, numerous POM-frameworks together with desired features of a contender material and inherited properties of POMs are systematically discussed to demonstrate how and why the electron-sponge-like nature of POMs is beneficial to design next-generation water oxidation/reduction electrocatalysts, and neuromorphic nonvolatile resistance-switching random-access memory devices. The aim is to converge the attention of scientists who are working separately on electrocatalysts and memory devices, on a point that, although the application types are different, they all hunt for a material that could exhibit electron-sponge-like feature to realize boosted performances and thus, encouraging the scientists of two completely different fields to explore POMs as imperious contenders to design next-generation nanodevices. Finally, challenges and promising prospects in this research field are also highlighted.

Surface reconstruction of pyrite-type transition metal sulfides during oxygen evolution reaction

Reconstruction universally occurs over non-layered transition metal sulfides (TMSs) during oxygen evolution reaction (OER), leading to the formation of active species metal (oxy)hydroxide and thus significantly influences the OER performance. However, the reconstruction process and underlying mechanism quantitatively remain largely unexplored. Herein, we proposed an electrochemical reaction mechanism, namely sulfide oxidation reaction (SOR), to elucidate the reconstruction process of pyrite-type TMSs. Based on this mechanism, we evaluated the reconstruction capability of NiS2 doped with transition metals V, Cr, Mn, Fe, Co, Cu, Mo, Ru, Rh, and Ir within different doped systems. Two key descriptors were thus proposed to describe the reconstruction abilities of TMSs: USOR (the theoretical electric potential of SOR) and ΔU (the difference between the theoretical electric potential of SOR and OER), representing the initiation electric potential of reconstruction and the intrinsic reconstruction abilities of TMSs, respectively. Our finding shows that a lower USOR readily initiate reconstruction at a lower potential and a larger ΔU indicating a poorer reconstruction ability of the catalyst during OER. Furthermore, Fe-doped CoS2 was used to validate the rationality of our proposed descriptors, being consistent with the experiment findings. Our work provides a new perspective on understanding the reconstruction mechanism and quantifying the reconstruction of TMSs.

Factors Underlying Impaired Organ Recovery Despite a Deep Hematologic Response in Patients with Systemic AL Amyloidosis

Background: Amyloid-mediated organ dysfunction is the main determinant of survival for patients with light chain (AL) amyloidosis. Reducing the production of amyloidogenic light chains with plasma cell-directed therapy is a prerequisite for organ response. Despite achieving a hematologic complete response (hemCR), some patients have enduring organ dysfunction. A better grasp of the mechanisms underlying organ recovery is needed, especially as attention moves to novel therapeutics that trigger removal of existing amyloid deposits, and as graded organ response criteria to gauge improvement more precisely than traditional binary systems are adopted. Aims: We designed this study to identify the (1) rates of organ non-response and (2) possible reasons for impaired organ recovery in patients with AL amyloidosis with hemCR after treatment. Methods: Patients with biopsy confirmed AL amyloidosis who presented to our center for post-treatment assessment between February 2019 and June 2023 were included if they had major organ involvement (heart, kidney and/or liver) and were evaluable for organ response (Palladini, 2012). Graded cardiac response was assessed by validated criteria (Muchtar, 2022). We excluded patients who received amyloid fibril-targeted antibody therapies. To eliminate the possibility of insufficient hematologic response as a confounder for organ non-response, we focused only on patients with hemCR. Organ response was measured as best response >3 months from hemCR achievement. Reasons for organ non-response were postulated by our multidisciplinary team after extensive workup and review of clinical data. Results: Among 143 patients with hemCR, the median age at diagnosis was 58 years (range 30-78); 94 (66%) were male; and 24 (17%) identified as non-white race. Kidney, heart and liver involvement was present in 117 (82%), 68 (48%) and 17 (12%) patients, respectively; 54 (38%) had ≥2 major organs affected. Final treatment granting hemCR was high-dose melphalan and stem cell transplantation for 49 (34%); bortezomib-based for 37 (26%); daratumumab monotherapy for 31 (22%); daratumumab-CyBorD for 18 (13%); and an immunomodulatory drug for 8 (6%) patients; 58 (41%) required ≥2 lines of therapy to achieve hemCR. Failure to attain organ response was observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) of patients with kidney, heart and liver involvement, respectively. Of 42 patients with both kidney and heart involvement, 21 (50%) had concordant responses of both organs; 6 (14%) had concordant non-responses; and 15 (36%) had discordant responses. Among 49 heart responders, 14 (29%) attained CarCR (nadir BNP ≤80 pg/mL); 16 (33%) CarVGPR (>60% reduction); and 19 (39%) CarPR (31-60% reduction); 40/77 (52%) kidney responders attained proteinuria <500 mg/24h. Clinical features of organ non-responders in relation to responders are reported in Table 1. Notably, kidney non-responders had more advanced disease at baseline, whereas heart non-responders more often had lambda-typic amyloidogenic light chains. Among kidney non-responders, 2 had stable and another 2 had rising proteinuria level; the remaining 36 had improved proteinuria but were categorized as non-response due to >25% worsening of eGFR. Among heart non-responders, 5 had stable elevation of BNP and 14 experienced organ progression (BNP increase >30% and >50 pg/mL); 2 required heart transplantation. The two most common factors believed to underlie kidney non-response were permanent kidney damage at diagnosis needing dialysis and treatment-related toxicity (Table 2). For 10 (25%) kidney non-responders, there was no apparent explanation, 7 of whom had detectable measurable residual disease (MRD) by multiparametric flow cytometry. Most cases of heart non-response had no apparent explanation; 6 of these 8 patients had detectable MRD. Conclusions: Despite effective treatment of the plasma cell clone, a considerable number of patients with AL amyloidosis in hemCR have enduring organ dysfunction. We found that the reasons for organ non-response differed across organ systems. Response was not always concordant for all involved organs, suggesting heterogeneity in organ biology in terms of mechanisms for amyloid-mediated injury and intrinsic ability to repair. Careful scrutiny of reasons for organ non-response is warranted before providing further hematologic treatments, which may be ineffective for organ recovery.

Local H2 release remodels senescence microenvironment for improved repair of injured bone

The senescence microenvironment, which causes persistent inflammation and loss of intrinsic regenerative abilities, is a main obstacle to effective tissue repair in elderly individuals. In this work, we find that local H2 supply can remodel the senescence microenvironment by anti-inflammation and anti-senescence effects in various senescent cells from skeletally mature bone. We construct a H2-releasing scaffold which can release high-dosage H2 (911 mL/g, up to 1 week) by electrospraying polyhydroxyalkanoate-encapsulated CaSi2 nanoparticles onto mesoporous bioactive glass. We demonstrate efficient remodeling of the microenvironment and enhanced repair of critical-size bone defects in an aged mouse model. Mechanistically, we reveal that local H2 release alters the microenvironment from pro-inflammation to anti-inflammation by senescent macrophages repolarization and secretome change. We also show that H2 alleviates the progression of aging/injury-superposed senescence, facilitates the recruitment of endogenous cells and the preservation of their regeneration capability, thereby creating a pro-regenerative microenvironment able to support bone defect regeneration.