Multidimensional analysis of TMEM132A in pan-cancer: unveiling its potential as a biomarker for treatment response prediction.

Background: TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. Methods: We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. Results: First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. Conclusion: This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.

Mulberry (Morus alba L.) leaf powder modified the processing of meat alternatives: Principal component analysis from apparent properties to chemical bonds.

For texture control in plant-meat alternatives, the interrelationship between apparent characteristics and chemical bonds in high-fiber formulations remains unclear. The influence of mulberry leaf powder on apparent characteristics and chemical bonds of raw materials, block and strip products at addition amounts of 0.5-25% was analyzed. The results showed that 8% addition significantly increased the chewiness of the block by 98.12%. The strips' texture shows a downward trend, and the processing produced more redness and color difference. Additives promoted the formation of voids, lamellar and filamentous structures, and the strip produced more striped structures. Disulfide bonds significantly increased in the block, and the ß-turn in the secondary structure enhanced by 12.20%. The ß-turn transformed into a ß-sheet in strips. Principal component analysis revealed that the texture improvement was associated with producing disulfide bonds and ß-turn, providing a basis for high-fiber components to improve products' apparent characteristics by chemical bonds.

Multicomponent chitosan complex/polyvinyl alcohol blended film with full-band UV-shielding performance and excellent antioxidant property for active food packaging.

Utilizing renewable natural resources to construct multifunctional packaging materials is critical to achieving sustainable development in the food packaging industry. In this study, we crafted transparent films with comprehensive UV-shielding and antioxidant properties by blending a multicomponent chitosan complex with polyvinyl alcohol (PVA), subsequently applied to preserve peanut butter. The multicomponent chitosan complex, synthesized from chitosan, ferulic acid (FA), and 5-oxo-3,5-dihydro-2H-thiazolo [3,2-a] pyridine-7-carboxylic acid (TPCA) through direct heating in water, served as the foundation. This chitosan complex was seamlessly blended with PVA, resulting in the creation of a transparent film through the solvent casting method. A meticulous investigation into the chemical structure and physicochemical properties of the blended films was conducted. The FA and TPCA components exhibited robust ultraviolet absorption properties, conferring virtually complete full-band ultraviolet shielding ability to the blend film. Additionally, FA endowed the blended film with significant antioxidant activity. The effectiveness of the chitosan complex/PVA blended film in preserving peanut butter from oxidative spoilage was demonstrated, showcasing its robustness in food preservation. Our research underscores the significance of creating advanced packaging materials from sustainable sources.

Antibiotic resistance genes associated with size-segregated bioaerosols from wastewater treatment plants: A review.

The antibiotic-resistant pollution in size-segregated bioaerosols from wastewater treatment plants (WWTPs) is of increasing concern due to its public health risks, but an elaborate review is still lacking. This work overviewed the profile, mobility, pathogenic hosts, source, and risks of antibiotic resistance genes (ARGs) in size-segregated bioaerosols from WWTPs. The dominant ARG type in size-segregated bioaerosols from WWTPs was multidrug resistance genes. Treatment units that equipped with mechanical facilities and aeration devices, such as grilles, grit chambers, biochemical reaction tanks, and sludge treatment units, were the primary sources of bioaerosol antibiotic resistome in WWTPs. Higher enrichment of antibiotic resistome in particulate matter with an aerodynamic diameter of <2.5 µm, was found along the upwind-downwind-WWTPs gradient. Only a small portion of ARGs in inhalable bioaerosols from WWTPs were flanked by mobile genetic elements. The pathogens with multiple drug resistance had been found in size-segregated bioaerosols from WWTPs. Different ARGs or antibiotic resistant bacteria have different aerosolization potential associated with bioaerosols from various treatment processes. The validation of pathogenic antibiotic resistance bacteria, deeper investigation of ARG mobility, emission mechanism of antibiotic resistome, and development of treatment technologies, should be systematically considered in future.

Inverse design of chiral functional films by a robotic AI-guided system.

Artificial chiral materials and nanostructures with strong and tuneable chiroptical activities, including sign, magnitude, and wavelength distribution, are useful owing to their potential applications in chiral sensing, enantioselective catalysis, and chiroptical devices. Thus, the inverse design and customized manufacturing of these materials is highly desirable. Here, we use an artificial intelligence (AI) guided robotic chemist to accurately predict chiroptical activities from the experimental absorption spectra and structure/process parameters, and generate chiral films with targeted chiroptical activities across the full visible spectrum. The robotic AI-chemist carries out the entire process, including chiral film construction, characterization, and testing. A machine learned reverse design model using spectrum embedded descriptors is developed to predict optimal structure/process parameters for any targeted chiroptical property. A series of chiral films with a dissymmetry factor as high as 1.9 (gabs ~ 1.9) are identified out of more than 100 million possible structures, and their feasible application in circular polarization-selective color filters for multiplex laser display and switchable circularly polarized (CP) luminescence is demonstrated. Our findings not only provide chiral films with the highest reported chiroptical activity, but also have great fundamental value for the inverse design of chiroptical materials.

Construction of metallo-helicoids with high antimicrobial activity via intermolecular coordination.

Metallo-helicoids are constructed by intermolecular coordination interactions between covalent linear polymer and tritopic/hexatopic molecular templates. These metallo-polymers with helicoidal conformation exhibit high antimicrobial activities against both Gram-positive and Gram-negative pathogens.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells.

γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.

The F1Fo-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism.

Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1ß, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.

Bridging the gap between fundamental research and product development of long acting injectable PLGA microspheres.

INTRODUCTION: Long-acting Injectable PLGA microspheres have gained more and more interest and attention in the field of life cycle management of pharmaceutical products due to their biocompatibility and biodegradability. So far, a multitude of trial-and-error experiments at lab scale have been used for establishing the correlation relationship between critical process parameters, critical material attributes and critical quality attributes. However, few published studies have elaborated on the development of PLGA microspheres from an industrial perspective. AREAS COVERED: In this review, the scale-up feasibility of translational technologies of PLGA microspheres manufacturing has been evaluated. Additionally, state-of-the-art of technologies and facilities in PLGA development have been summarized. Meanwhile, the industrial knowledge matrix of PLGA microspheres development and research is establishing which provides comprehensive insight for understanding properties of PLGA microspheres as controlled/sustained release vehicle. EXPERT OPINION: There is still big gap between fundamental research in academic institute and product development in pharmaceuticals. Therefore, the difference and connection between them should be identified gradually for better understanding of PLGA microspheres development.

The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans.

Fungal infections, especially candidiasis and aspergillosis, claim a high fatality rate. Fungal cell growth and function requires ATP, which is synthesized mainly through oxidative phosphorylation, with the key enzyme being F1Fo-ATP synthase. Here, we show that deletion of the Candida albicans gene encoding the δ subunit of the F1Fo-ATP synthase (ATP16) abrogates lethal infection in a mouse model of systemic candidiasis. The deletion does not substantially affect in vitro fungal growth or intracellular ATP concentrations, because the decrease in oxidative phosphorylation-derived ATP synthesis is compensated by enhanced glycolysis. However, the ATP16-deleted mutant displays decreased phosphofructokinase activity, leading to low fructose 1,6-bisphosphate levels, reduced activity of Ras1-dependent and -independent cAMP-PKA pathways, downregulation of virulence factors, and reduced pathogenicity. A structure-based virtual screening of small molecules leads to identification of a compound potentially targeting the δ subunit of fungal F1Fo-ATP synthases. The compound induces in vitro phenotypes similar to those observed in the ATP16-deleted mutant, and protects mice from succumbing to invasive candidiasis. Our findings indicate that F1Fo-ATP synthase δ subunit is required for C. albicans lethal infection and represents a potential therapeutic target.

Comprehensive Thermal Analysis of Diamond in a High-Power Raman Cavity Based on FVM-FEM Coupled Method.

Despite their extremely high thermal conductivity and low thermal expansion coefficients, thermal effects in diamond are still observed in high-power diamond Raman lasers, which proposes a challenge to their power scaling. Here, the dynamics of temperature gradient and stress distribution in the diamond are numerically simulated under different pump conditions. With a pump radius of 100 µm and an absorption power of up to 200 W (corresponding to the output power in kilowatt level), the establishment period of thermal steady-state in a millimeter diamond is only 50 µs, with the overall thermal-induced deformation of the diamond being less than 2.5 µm. The relationship between the deformation of diamond and the stability of the Raman cavity is also studied. These results provide a method to better optimize the diamond Raman laser performance at output powers up to kilowatt-level.

Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance.

Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of Candida albicans invasive infection. Here, we found that deletion of ATP2 (atp2Δ/Δ) in C. albicans resulted in a dramatic decrease from 69.2% (WT) to 1.2% in the escape rate in vitro. The effect of ATP2 on macrophage clearance stands out among the genes currently known to affect clearance. In the normal mice, the atp2Δ/Δ cells were undetectable in major organs 72 h after systemic infection, while WT cells persisted in vivo. However, in the macrophage-depleted mice, atp2Δ/Δ could persist for 72 h at an amount comparable to that at 24 h. Regarding the mechanism, WT cells sustained growth and switched to hyphal form, which was more conducive to escape from macrophages, in media that mimic the glucose-deficient environment in macrophages. In contrast, atp2Δ/Δ cells can remained viable but were unable to complete morphogenesis in these media, resulting in them being trapped within macrophages in the yeast form. Meanwhile, atp2Δ/Δ cells were killed by oxidative stress in alternative carbon sources by 2- to 3-fold more than WT cells. Taken together, ATP2 deletion prevents C. albicans from escaping macrophage clearance, and therefore ATP2 has a functional basis as a drug target that interferes with macrophage clearance.

Profiles of neonicotinoid insecticides and characteristic metabolites in paired urine and blood samples: Partitioning between urine and blood and implications for human exposure.

Neonicotinoid insecticides (NEOs) are widely used for pest control worldwide. However, only a few studies have analyzed NEOs and their metabolites in blood samples, and no study has measured the concentrations of NEOs and their metabolites in paired urine and blood samples. In this study, six NEOs and three characteristic metabolites were detected in 196 paired urine and blood samples collected from young adults from China. The NEOs and their metabolites were widely detected in paired urine (67%-91%) and blood (64%-97%) samples, and the median levels ranged within 0.01-1.15 ng/mL in urine and 0.08-0.80 ng/mL in blood. Olefin-imidacloprid (Of-IMI) and 1-methyl-3-(tetrahydro-3-furylmethyl) urea (UF) were the most abundant target compounds in the urine (32.4%) and blood (26.4%) samples, respectively. Gender-related differences were observed in the concentrations of most NEOs and their metabolites in the urine and blood samples. The partitioning of target analytes between blood and urine (NEOs-B/NEOs-U ratios) was also calculated in this study. The B/U ratios of most NEOs and their metabolites were below 1, and positive correlations were observed between urine and blood in most levels of NEOs and their metabolites. This finding indicates that urinary levels are good predictors of human exposure to NEOs and their metabolites. The estimated daily intake (EDI) and the imidacloprid-equivalent (IMIeq) levels of NEOs and their metabolites in 196 young adults were also determined. The median EDI values (ng/kg bw/day) of ΣNEOs (sum of NEOs and their metabolites) and IMIeq in females (194.9 and 458.2) were slightly higher than (p > 0.05) those in males (157.1 and 439.7). This finding shows young adults are extensively exposed to NEOs and their metabolites. To our knowledge, this study is the first to report about NEOs and their metabolites in paired samples of urine and blood in China.

The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation.

Invasive fungal infections are a major cause of human mortality due in part to a very limited antifungal drug arsenal. The identification of fungal-specific pathogenic mechanisms is considered a crucial step to current antifungal drug development and represents a significant goal to increase the efficacy and reduce host toxicity. Although the overall architecture of F1FO-ATP synthase is largely conserved in both fungi and mammals, the subunit i/j (Su i/j, Atp18) and subunit k (Su k, Atp19) are proteins not found in mammals and specific to fungi. Here, the role of Su i/j and Su k in Candida albicans was characterized by an in vivo assessment of the virulence and in vitro growth and mitochondrial function. Strikingly, the atp18Δ/Δ mutant showed significantly reduced pathogenicity in systemic murine model. However, this substantial defect in infectivity exists without associated defects in mitochondrial oxidative phosphorylation or proliferation in vitro. Analysis of virulence-related traits reveals normal in both mutants, but shows cell wall defects in composition and architecture in the case of atp18Δ/Δ. We also find that the atp18Δ/Δ mutant is more susceptible to attack by macrophages than wild type, which may correlate well with the abnormal cell wall function and increased sensitivity to oxidative stress. In contrast, no significant changes were observed in any of these studies for the atp19Δ/Δ. These results demonstrate that the fungal-specific Su i/j, but not Su k of F1FO-ATP synthase may play a critical role in C. albicans infectivity and represent another opportunity for new therapeutic target investigation. LAY ABSTRACT: This study aims to investigate biological functions of fungal-specific subunit i/j and subunit k of ATP synthase in C. albicans oxidative phosphorylation and virulence potential. Our results revealed that subunit i/j, and not subunit k, is critical for C. albicans pathogenicity.

Occurrence of neonicotinoid insecticides and their metabolites in tooth samples collected from south China: Associations with periodontitis.

Neonicotinoid insecticides (NEOs) are widely used in agricultural production processes in China and worldwide. NEOs have been an increasing concern because of their potential toxicity to nontarget organisms. However, studies that focused on human exposure to NEOs in China are limited. In this study, levels of six parent NEOs (p-NEOs), namely imidacloprid (IMI), acetamiprid (ACE), clothianidin (CLO), dinotefuran (DIN), thiamethoxam (THIX), and thiacloprid (THI), and three metabolites (m-NEOs), such as 5-hydroxy-imidacloprid (5-OH-IMI), 1-methyl-3-(tetrahydro-3-furyl methyl) urea (UF), and N-desmethyl-acetamiprid (N-dm-ACE) were measured in 127 tooth samples collected from South China. P-NEOs and m-NEOs are frequently detected (76%-93%) in tooth samples, with median levels of 0.03-1.20 ng/g. UF is the most abundant NEOs in tooth samples (36%). Females have higher NEO levels than males, and gender-related differences in NEO levels are found. Associations among most p-NEOs are also found (p < 0.05), indicating the source of human exposure to p-NEOs is related. However, no significant relationships (p > 0.05) between levels of m-NEOs and their corresponding p-NEOs are found, suggesting that exogenous m-NEOs contribute to exposure. We have also examined the associations between human NEOs exposure and periodontitis, and associations between NEO exposure and periodontitis are observed (OR = 2.63-7.33; 95% CI = 1.01-21.1, p-trend < 0.05). Our results suggest that NEO levels are associated with increased odds of prevalent periodontitis. This study is the first to report about p-NEOs and m-NEOs in tooth samples collected from South China.

Nanofibrous spongy microspheres to deliver rabbit mesenchymal stem cells and anti-miR-199a to regenerate nucleus pulposus and prevent calcification.

Lower back pain is mainly caused by intervertebral disc degeneration, in which calcification is frequently involved. Here novel nanofibrous spongy microspheres (NF-SMS) are used to carry rabbit bone marrow mesenchymal stromal cells (MSCs) to regenerate nucleus pulposus tissues. NF-SMS are shown to significantly enhance the MSC seeding, proliferation and differentiation over control microcarriers. Furthermore, a hyperbranched polymer (HP) with negligible cytotoxicity and high microRNA (miRNAs) binding affinity is synthesized. The HP can complex with anti-miR-199a and self-assemble into "double shell" polyplexes which are able to achieve high transfection efficiency into MSCs. A double-emulsion technique is used to encapsulate these polyplexes in biodegradable nanospheres (NS) to enable sustained anti-miR-199 delivery. Our results demonstrate that MSC/HP-anti-miR-199a/NS/NF-SMS constructs can promote the nucleus pulposus (NP) phenotype and resist calcification in vitro and in a subcutaneous environment. Furthermore, injection of MSC/HP-anti-miR-199a/NS/NF-SMS can stay in place, produce functional extracellular matrix, maintain disc height and prevent intervertebral disc (IVD) calcification in a rabbit lumbar degeneration model.

Three-Dimensional Electrodeposition of Calcium Phosphates on Porous Nanofibrous Scaffolds and Their Controlled Release of Calcium for Bone Regeneration.

To mimic the bone matrix of mineralized collagen and to impart microporous structure to facilitate cell migration and bone regeneration, we developed a nanofibrous (NF) polymer scaffold with highly interconnected pores and three-dimensional calcium phosphate coating utilizing an electrodeposition technique. The mineral content, morphology, crystal structure, and chemical composition could be tailored by adjusting the deposition temperature, voltage, and duration. A higher voltage and a higher temperature led to a greater rate of mineralization. Furthermore, nearly linear calcium releasing kinetics was achieved from the mineralized 3D scaffolds. The releasing rate was controlled by varying the initial electrodeposition conditions. A higher deposition voltage and temperature led to slower calcium release, which was associated with the highly crystalline and stoichiometric hydroxyapatite content. This premineralized NF scaffold enhanced bone regeneration over the control scaffold in a subcutaneous implantation model, which was associated with released calcium ions in facilitating osteogenic cell proliferation.

Prussian blue coated with reduced graphene oxide as high-performance cathode for lithium-Sulfur batteries.

Lithium-sulfur (Li-S) batteries with their outstanding theoretical energy density are strongly considered to take over the post-lithium ion battery era; however, they are limited by sluggish reaction kinetics and the severe shuttling of soluble lithium polysulfides. Prussian blue analogues (PBs) have demonstrated their efficiency in hindering the shuttle effects as host materials of sulfur; unfortunately, they show an inferior electronic conductivity, exhibiting considerable lifespan but poor rate performance. Herein, we rationally designed a PB@reduced graphene oxide as the host material for sulfur (S@PB@rGO) hybrids via a facile liquid diffusion and physical absorption method, in which the sulfur was integrated into Na2Co[Fe(CN)6] and rGO framework. When employed as a cathode, the as-prepared hybrid exhibited excellent rate ability (719 mA h g-1 at 1C) and cycle stability (918 mA h g-1 at 0.5C after 100 cycles). The improved electrochemical performance was attributed to the synergetic effect of PB and conductive rGO, which not only enhanced the physisorption of polysulfides but also provided a conductive skeleton to ensure rapid charge transfer kinetics, achieving high energy/power outputs and considerable lifespan simultaneously. This study may offer a new method manufacturing high performance Li-S batteries.

Pore size directs bone marrow stromal cell fate and tissue regeneration in nanofibrous macroporous scaffolds by mediating vascularization.

In the U.S., 30% of adults suffer joint pain, most commonly in the knee, which severely limits mobility and is often attributed to injury of cartilage and underlying bone in the joint. Current treatment methods such as microfracture result in less resilient fibrocartilage with eventual failure; autografting can cause donor site morbidity and poor integration. To overcome drawbacks in treatment, tissue engineers can design cell-instructive biomimetic scaffolds using biocompatible materials as alternate therapies for osteochondral defects. Nanofibrous poly (l-lactic acid) (PLLA) scaffolds of uniform, spherical, interconnected and well-defined pore sizes that are fabricated using a thermally-induced phase separation and sugar porogen template method create an extracellular matrix-like environment which facilitates cell adhesion and proliferation. Herein we report that chondrogenesis and endochondral ossification of rabbit and human bone marrow stromal cells (BMSCs) can be controlled by scaffold pore architecture, particularly pore size. Small-pore scaffolds support enhanced chondrogenic differentiation in vitro and cartilage formation in vivo compared to large-pore scaffolds. Endochondral ossification is prevented in scaffolds with very small pore sizes; pore interconnectivity is critical to promote capillary ingrowth for mature bone formation. These results provide a novel strategy to control tissue regenerative processes by tunable architecture of macroporous nanofibrous scaffolds. STATEMENT OF SIGNIFICANCE: Progress in understanding the relationship between cell fate and architectural features of tissue engineering scaffolds is critical for engineering physiologically functional tissues. Sugar porogen template scaffolds have uniform, spherical, highly interconnected macropores. Tunable pore-size guides the fate of bone marrow stromal cells (BMSCs) towards chondrogenesis and endochondral ossification, and is a critical design parameter to mediate neotissue vascularization. Preventing vascularization favors a chondrogenic cell fate while allowing vascularization results in endochondral ossification and mineralized bone formation. These results provide a novel strategy to control tissue regenerative processes by tunable architecture of macroporous nanofibrous scaffolds.