Structural Maturation Research Articles

Development and intra-renal delivery of renal progenitor organoids for effective integration in vivo.

Renal progenitor organoids have been proposed as a source of tissue for kidney regeneration; however, their clinical translatability has not been demonstrated due to an inability to mass-produce comprehensive renal progenitor organoids and the lack of an effective intra-renal delivery platform that facilitates rapid integration into functionally meaningful sites. This study addresses these shortcomings. Human-induced pluripotent stem cells were differentiated into renal progenitor cells using an established protocol and aggregated using a novel assembly method to produce high yields of organoids. Organoids were encapsulated in collagen-based scaffolds for in vitro study and in vivo implantation into mouse renal cortex. In vitro, the organoids demonstrated sustained cell viability and renal structure maturation over time. In vivo delivered organoids showed rapid integration into host renal parenchyma while showing tubular and glomerular-like structure development and maturity markers. This proof-of-concept study presents many promising results, providing a system of renal organoid formation and delivery that may support the development of clinically translatable therapies and the advancement of in vitro renal organoid studies.

Reduced intestinal-to-diffuse conversion and immunosuppressive responses underlie superiority of neoadjuvant immunochemotherapy in gastric adenocarcinoma.

Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment-naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25%vs. 4%, p<0.05). Interestingly, pretreatment intestinal subtype of Lauren's classification was predictive of pathologic regression following NAIC, but not NAC. A substantial portion of cancers underwent intestinal-to-diffuse transition, which occurred less following NAIC and correlated with treatment failure. Moreover, NAIC prevented reprogramming to an immunosuppressive TIME with less active fibroblasts and exhausted CD8+ T cells, and increased numbers of mature tertiary lymphoid structures. Mechanistically, activation of the tumor necrosis factor alpha (TNFα)/nuclear factor-kappa B (NF-κB) signaling pathway was associated with response to NAIC. Together, NAIC is superior to NAC for locally advanced GAC, likely due to reduced intestinal-to-diffuse conversion and reprogramming to an immuno-active TIME. Modulation of the histological conversion and immunosuppressive TIME could be translatable approaches to improve neoadjuvant therapeutic efficacy.

Structural Covariance Networks in the Fetal Brain Reveal Altered Neurodevelopment for Specific Subtypes of Congenital Heart Disease.

Altered structural brain development has been identified in fetuses with congenital heart disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. We extracted structural covariance networks from the log Jacobian determinants of 435 in utero T2 weighted image magnetic resonance imaging scans, (n=67 controls, 368 with CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery, and CHD diagnosis were significant predictors of structural covariance. We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of structural covariance networks, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra-axial cerebrospinal fluid, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. Structural covariance networks offer a sensitive, data-driven approach to explore whole-brain structural changes without anatomical priors. We used them to stratify a heterogenous patient cohort with CHD, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.

Maturity and density of tertiary lymphoid structures associate with tumor metastasis and chemotherapy response.

Tertiary Lymphoid Structures (TLSs) are abnormal clusters of immune cells that form in tissues not normally associated with the immune system, usually in cases of long-lasting inflammation, like cancer. TLSs have been suggested as a potential prognostic indicator in various cancer types. We retrospectively enrolled 223 gastric cancer (GC) patients who had surgical resections in this study. We utilized hematoxylin and eosin (HE) staining to detect the presence, abundance, and maturity of TLSs. In serial sections, we used immunohistochemistry to examine the cellular composition of TLSs. The pathological review identified TLSs in 95.1% of the tumors, lymphoid aggregates in 79.8%, primary follicles in 45.7%, and lymphoid aggregates in 95.1% of the cases. Based on Kaplan-Meier curves, the maturation and abundance of TLSs contributed to longer disease-free survival (DFS) and overall survival (OS). In addition, the density of TLSs was strongly associated with the occurrence of tumor metastases and the response to adjuvant chemotherapy. We validated the prognostic value of TLSs in GC patients in both independent cohorts, and the maturity and density of TLS correlated with tumor metastasis. In addition, TLS may reflect sustained antitumor potency, which has important implications for adjuvant chemotherapy.

Optimization of culture conditions to generate vascularized multi-lineage liver organoids with structural complexity and functionality

Hepatic organoids (HOs), primarily composed of hepatobiliary cells, do not represent the pathogenesis of liver diseases due to the lack of non-parenchymal cells. Multi-lineage liver organoids (mLOs) containing various cell types found in the liver offer a promising in vitro disease model. However, their structural complexity remains challenging to achieve due to the difficulty in optimizing culture conditions that meet the growth need of all component cell types. Here, we demonstrate that cystic HOs generated from hPSCs can be expanded long-term and serve as a continuous source for generating complex mLOs. Assembling cystic HOs with hPSC-derived endothelial and hepatic stellate cell-like cells under conventional HO culture conditions failed to support the development of multiple cell types within mLOs, resulting in biased differentiation towards specific cell types. In contrast, modulating the cAMP/Wnt/Hippo signaling pathways with small molecules during assembly and differentiation phases efficiently generate mLOs containing both hepatic parenchymal and non-parenchymal cells. These mLOs exhibited structural complexity and functional maturity, including vascular network formation between parenchymal lobular structures, cell polarity for bile secretion, and the capacity to respond to fibrotic stimuli. Our study underscores the importance of modulating signaling pathways to enhance mLO structural complexity for applications in modeling liver pathologies.

Segregation of the regional radiomics similarity network exhibited an increase from late childhood to early adolescence: A developmental investigation

Brain development is characterized by an increase in structural and functional segregation, which supports the specialization of cognitive processes within the context of network neuroscience. In this study, we investigated age-related changes in morphological segregation using individual Regional Radiomics Similarity Networks (R2SNs) constructed with a longitudinal dataset of 494 T1-weighted MR scans from 309 typically developing children aged 6.2 to 13 years at baseline. Segertation indices were defined as the relative difference in connectivity strengths within and between modules and cacluated at the global, system and local levels. Linear mixed-effect models revealed longitudinal increases in both global and system segregation indices, particularly within the limbic and dorsal attention network, and decreases within the ventral attention network. Superior performance in working memory and inhibitory control was associated with higher system-level segregation indices in default, frontoparietal, ventral attention, somatomotor and subcortical systems, and lower local segregation indices in visual network regions, regardless of age. Furthermore, gene enrichment analysis revealed correlations between age-related changes in local segregation indices and regional expression levels of genes related to developmental processes. These findings provide novel insights into typical brain developmental changes using R2SN-derived segregation indices, offering a valuable tool for understanding human brain structural and cognitive maturation.

Bank loan maturity and corporate investment

This study analyzes bank loan maturity and corporate investment linkage by using novel firm-level data covering the universe of all incorporated firms in Türkiye over the last decade. The results of the panel regression model with multi-dimensional fixed effects reveal that loan maturity has a significant positive association with investment, indicating that longer debt maturity fosters corporate investment. The results reveal that the positive linkage between longer debt maturity and investment is more pronounced for small and medium-sized enterprises (SMEs). This is also the case for young firms and firms with high growth opportunities. Considering the evidence provided in the literature that bank lending conditions, including maturity structure, are highly cyclical and vulnerable to financial conditions and economic policy uncertainties, our findings highlight the importance of reducing the policy uncertainties as well as the importance of policies that make equity financing more attractive and deepen the capital markets.

Isotope Encoded chemical Imaging Identifies Amyloid Plaque Age Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

It is of critical importance to our understanding of Alzheimer's disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (Aβ) plaques is the major pathological hallmark of AD and Aβ has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how Aβ plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood. The primary aim of our research is to elucidate the biochemical processes underlying early Aβ plaque formation in brain tissue. We recently introduced a chemical imaging paradigm based on mass spectrometry imaging (MSI) and metabolic isotope labelling to follow stable isotope labelling kinetics (iSILK) in vivo to track the in vivo build-up and deposition of Aβ. Herein, knock-in Aβ mouse models (App NL-F ) that develop Aβ pathology gradually are metabolically labeled with stable isotopes. This chemical imaging approach timestamps amyloid plaques during the period of initial deposition allowing the fate of aggregating Aβ species from before and during the earliest events of plaque pathology through plaque maturation to be tracked. To identify the molecular and cellular response to plaque maturation, we integrated iSILK with single plaque transcriptomics performed on adjacent tissue sections. This enabled changes in gene expression to be tracked as a function of plaque age (as encoded in the Aβ peptide isotopologue pattern) distinct from changes due to the chronological age or pathological severity. This approach identified that plaque age correlates negatively with gene expression patterns associated with synaptic function as early as in 10-month-old animals but persists into 18 months. Finally, we integrated hyperspectral confocal microscopy into our multiomic approach to image amyloid structural isomers, revealing a positive correlation between plaque age and amyloid structural maturity. This analysis identified three categories of plaques, each with a distinct impact on the surrounding microenvironment. Here, we identified that older, more compact plaques were associated with the most significant synapse loss and toxicity. These data show how isotope-encoded MS imaging can be used to delineate Aβ toxicity dynamics in vivo. Moreover, we show for the first time a functional integration of dynamic MSI, structural plaque imaging and whole genome-wide spatial transcriptomics at the single plaque level. This multiomic approach offers an unprecedented combination of temporal and spatial resolution enabling a description of the earliest events of precipitating amyloid pathology and how Aβ modulates synaptotoxic mechanisms.

Exploring associations between psychotic experiences and structural brain age: a population-based study in late adolescence.

Neuroimaging studies show advanced structural "brain age" in schizophrenia and related psychotic disorders, potentially reflecting aberrant brain ageing or maturation. The extent to which altered brain age is associated with subthreshold psychotic experiences (PE) in youth remains unclear. We investigated the association between PE and brain-predicted age difference (brain-PAD) in late adolescence using a population-based sample of 117 participants with PE and 115 without PE (aged 19-21 years) from the Avon Longitudinal Study of Parents and Children. Brain-PAD was estimated using a publicly available machine learning model previously trained on a combination of region-wise T1-weighted grey-matter measures. We found little evidence for an association between PEs and brain-PAD after adjusting for age and sex (Cohen's d = -0.21 [95% CI -0.47, 0.05], p = 0.11). While there was some evidence for lower brain-PAD in those with PEs relative to those without PEs after additionally adjusting for parental social class (Cohen's d = -0.31 [95% CI -0.58, -0.03], p = 0.031) or birth weight (Cohen's d = -0.29 [95% CI -0.55, -0.03], p = 0.038), adjusting for maternal education or childhood IQ did not alter the primary results. These findings do not support the notion of advanced brain age in older adolescents with PEs. However, they weakly suggest there might be a younger-looking brain in those individuals, indicative of subtle delays in structural brain maturation. Future studies with larger samples covering a wider age range and multimodal measures could further investigate brain age as a marker of psychotic experiences in youth.

B cell mechanosensing regulates ER remodeling at the immune synapse.

Engagement of the B-cell receptor with immobilized antigens triggers the formation of an immune synapse (IS), a complex cellular platform where B-cells recruit signaling molecules and reposition lysosomes to promote antigen uptake and processing. Calcium efflux from the endoplasmic reticulum (ER) released upon BCR stimulation is necessary to promote B-cell survival and differentiation. Whether the spatial organization of the ER within the B-cell synapse can tune IS function and B-cell activation remains unaddressed. Here, we characterized ER structure and interaction with the microtubule network during BCR activation and evaluated how mechanical cues arising from antigen presenting surfaces affect this process. B-cells were cultured on surfaces of varying stiffness coated with BCR ligands, fixed, and stained for the ER and microtubule network. Imaging analysis was used to assess the distribution of the ER and microtubules at the IS. Upon BCR activation, the ER is redistributed towards the IS independently of peripheral microtubules and accumulates around the microtubule-organization center. Furthermore, this remodeling is also dependent on substrate stiffness, where greater stiffness triggers enhanced redistribution of the ER. Our results highlight how spatial reorganization of the ER is coupled to the context of antigen recognition and could tune B-cell responses. Additionally, we provide novel evidence that the structural maturation of the ER in plasma cells is initiated during early activation of B-cells.

Three-dimensional structures of Vibrio cholerae typing podophage VP1 in two states

Lytic podophages (VP1-VP5) play crucial roles in subtyping Vibrio cholerae O1 biotype El Tor. However, until now no structures of these phages have been available, which hindered our understanding of the molecular mechanisms of infection and DNA release. Here, we determined the cryoelectron microscopy (cryo-EM) structures of mature and DNA-ejected VP1 structures at near-atomic and subnanometer resolutions, respectively. The VP1 head is composed of 415 copies of the major capsid protein gp7 and 11 turret-shaped spikes. The VP1 tail consists of an adapter, a nozzle, a slender ring, and a tail needle, and is flanked by three extended fibers I and six trimeric fibers II. Conformational changes of fiber II in DNA-ejected VP1 may cause the release of the tail needle and core proteins, forming an elongated tail channel. Our structures provide insights into the molecular mechanisms of infection and DNA release for podophages with a tail needle.

Deformation and microregion fracture mechanisms in type 316L welded joint under isothermal and thermo-mechanical fatigue loadings

Isothermal (IF) and thermo-mechanical fatigue (TMF) tests were conducted on 316L welded joints to investigate the effects of phase angle (in-phase (IP), clockwise-diamond (CD), and out-of-phase (OP)) and mechanical strain amplitude (±0.4 %, ±0.5 %, ±0.6 %) on deformation and microregion fracture mechanisms. Results reveal that increasing strain amplitude induces a higher softening rate, reduced fatigue life, and more pronounced dynamic strain aging (DSA). Nevertheless, there is a complicated discrepancy in the cyclic deformation between various phase angles. At high strain amplitudes, local embrittlement along the austenite/δ-ferrite interface induces cracking in the weld metal (WM) under both IF and TMF loadings, with TMF life increasing with phase angle. At a lower strain amplitude of 0.4 %, however, fracture location migration and different TMF life were observed. Microstructural analysis reveals that during TMF a lower strain amplitude of 0.4 %, the microstructure in both base metal (BM) and WM evolves from simple planar structures to low-energy substructures, characterized by an increase in kernel average misorientation, geometrically necessary dislocations, and low-angle grain boundaries, together with a reduction in high-angle grain boundaries and twin boundaries. In the WM, increasing phase angle tends to reduce dislocation density and reproduces planar dislocation structures due to enhanced DSA, thereby lowering cellular structure maturity. Conversely, in the BM, dislocation proliferation and interaction intensify, enhancing cellular structure maturity and de-twinning effect, which reduces BM fracture resistance and causes fracture migration from the WM to the BM. Moreover, active DSA under CD loading improves deformation resistance in both microregions, prolonging fatigue life and contributing to the observed different TMF life.

Morphological Characteristics of the Ulna Fracture Zone in Rats Undergoing Therapy With Modified Mesenchymal Stem Cells in Experimental Osteoporosis

Osteoporosis is a progressive systemic disease characterized by a decrease in bone density. This leads to increased bone fragility and a higher likelihood of fractures. New approaches to cellular therapy have been developed for the effective treatment of this pathology, based on the use of modified osteophilic polymers with mesenchymal stem cells (MSCs) for local action on damaged bone areas. The aim of the study was to morphologically assess the effectiveness of modified osteophilic polymer MSCs on reparative osteogenesis processes during the post-traumatic period in animals with a fracture of the ulna and underlying osteoporosis. Material and methods. The experiment involved Wistar rats (females, n=40; 200–300 g, 3 months old). Osteoporosis was simulated by bilateral ovariectomy, and the fracture was simulated through diaphysis osteotomy of the ulna. All rats were randomly distributed into four groups: Group I (control, n=10; buffered solution); Group II (n=10; osteophilic polymer, 1 mg/ml); Group III (n=10; MSC suspension, 1×106); Group IV (n=10; modified osteophilic polymer MSCs, 1×106). The experiment results were evaluated in 1 and 6 months after the fracture. Results. MSCs were applied after exposure to the osteophilic polymer to restore the pool of osteoblast precursors in the fracture area of the ulna in experimental osteoporosis. In all animals, regeneration foci with varying degrees of structural and functional maturation of cellular and intercellular substrates were formed in the fracture area. The most pronounced processes of bone tissue restoration were observed with the use of modified osteophilic polymer MSCs. This is likely associated with the high concentration of modified osteophilic polymer MSCs and their retention in zones of damaged bone regeneration, subsequently stimulating osteogenesis. The paradigm of provisionality, as a universal model manifestating histogenesis and organogenesis, was utilized to gain a more comprehensive biological understanding and interpretation of the observed changes. Conclusion. MSCs applied after exposure to an osteophilic polymer significantly enhance the process of reparative osteogenesis in fractures of long bones in patients with estrogen-induced osteoporosis, thus making this technology promising for combined therapy.

Does firm culture influence corporate financing decisions? Evidence from debt maturity choice

This study establishes a relation between corporate culture and debt maturity choice. Specifically, superior corporate culture is associated with the choice of shorter-term debt, supporting the notion that superior culture reduces managerial agency problems resulting in managers being more receptive to external monitoring through the choice of shorter-term debt. The culture subcomponents of integrity, teamwork, and innovation are found to have a meaningful influence on the debt maturity structure choice. The relation between culture and debt maturity is more pronounced in firms with higher managerial stock ownership and those that are financially constrained, but is weakened in firms with a greater CEO sensitivity to stock prices. Additionally, firms with superior culture are shown to have higher long-term credit ratings. These findings contribute at the confluence of corporate culture and debt financing literatures. A battery of robustness tests, including addressing endogeneity concerns, validate the findings.

Altered development and network connectivity in a human neuronal model of 15q11.2 deletion-related neurodevelopmental disorders.

The chromosome 15q11.2 locus is deleted in 1.5% of patients with genetic epilepsy and confers a risk for intellectual disability and schizophrenia. Individuals with this deletion demonstrate increased cortical thickness, decreased cortical surface area and white matter abnormalities. Human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPC) from 15q11.2 deletion individuals exhibit early adhesion junction and migration abnormalities, but later neuronal development and function have not been fully assessed. Imaging studies indicating altered structure and network connectivity in the anterior brain regions and the cingulum suggest that in addition to alterations in progenitor dynamics, there may also be structural and functional changes within discrete networks of mature neurons. To explore this, we generated human forebrain cortical neurons from iPSCs derived from individuals with or without 15q11.2 deletion and used longitudinal imaging and multielectrode array analysis to evaluate neuronal development over time. 15q11.2 deleted neurons exhibited fewer connections and an increase in inhibitory neurons. Individual neurons had decreased neurite complexity and overall decreased neurite length. These structural changes were associated with a reduction in multiunit action potential generation, bursting and synchronization. The 15q11.2 deleted neurons also demonstrated specific functional deficits in glutamate and GABA mediated network activity and synchronization with a delay in the maturation of the inhibitory response to GABA. These data indicate that deletion of the 15q11.2 region is sufficient to impair the structural and functional maturation of cortical neuron networks which likely underlies the pathologic changes in humans with the 15q11.2 deletion.

Mechanical force promotes tissue and molecular changes in adipose tissue regeneration post-transplantation.

Fat grafting often yields inconsistent and suboptimal results, necessitating improved fat processing techniques. A stromal vascular fraction (SVF) gel created using mechanical emulsification demonstrates superior retention rates to conventional Coleman fat grafts. This study investigated the mechanisms at play by transplanting fat aspirates from liposuction patients-either processed as Coleman fat grafts or further refined into an SVF gel via mechanical shear force-onto the backs of nude mice. The retention rate of the SVF gel after transplantation surpassed that observed for Coleman fat. Hematoxylin and eosin (HE) staining and immunofluorescence results demonstrated that the SVF gel group could form new adipose tissue characterized by well-organized mature fat structures. Mechanical shear force application induced increased mesenchymal stem cell abundance. Rather than merely surviving regeneration, fat was regenerated after transplantation, and the regenerated cells were mainly from mice, which was supported by microarray analysis. RNA-seq highlighted 601 genes expressed between SVF gel and Coleman fat groups, with 164 genes upregulated (cell cycle processes), and 437 genes downregulated (lipid metabolism). The application of mechanical shear force reduces the risk of complications and fosters cell proliferation and division, thereby enhancing the retention and regeneration of transplanted fat.

Financial resilience, growth and risk sharing in the EU

We build a financial resilience index capturing the structure and stability features of financial systems and benchmark EU financial systems against their ability to enhance stable growth and international risk sharing. The index comprises financial openness, market orientation, equity deepening, maturity structure, and institutional soundness. Our results show that: (i) EU financial systems are highly heterogeneous and converge to a clustered pattern; (ii) the index is highly significant in growth regressions, suggesting that financial structure and institutional soundness are key to enduring growth; (iii) the heterogeneity of EU financial systems has implications for the vulnerability to domestic output shocks: the risk-sharing mechanism is more effective in the market-based and institutionally sound economies that group in the top financial clusters, whereas unsmoothed consumption is higher in economies belonging to the low-resilience clusters, especially in the aftermath of the global financial crisis, when the credit channel is significantly downsized.

The Neurogenic Effects of Pasak bumi (Eurycoma longifolia Jack) and Seluang Fish (Rasbora spp.) in Malnutrition-Induced Rat

Highlights:1. This study analyzed the effects of using locally sourced pasak bumi extract and seluang fish on the parameters of neurogenesis in malnourished rat models.2. It promotes further exploration into modified treatments for malnutrition, emphasizing nutritional strategies that harness locally available natural resources. Abstract Early developmental malnutrition exerts adverse effects on the structural, neurochemical, and neurophysiological maturation of cerebral cells by disrupting the process of neurogenesis. Pasak bumi (Eurycoma longifolia Jack) and seluang fish (Rasbora spp.), two indigenous natural resources of South Kalimantan, Indonesia, are believed to harbor nutritional components capable of mitigating these deleterious effects. We aimed to assess the impact of administering pasak bumi, seluang fish, and pure docosahexaenoic acid (DHA) on the neurogenesis process in malnourished rat models. The Rattus norvegicus specimens were partitioned into seven distinct cohorts, each consisting of five rats: healthy rats in the negative control group (KN), while malnourished rats in the positive control (KP) and treatment groups (P1, P2, P3, P4, and P5). Both the KP and KN groups received a placebo and a standard feed. The treatment groups received different interventions for five weeks: standard feed alongside pasak bumi extract for the P1 group, standard feed and DHA for the P2 group, standard feed in combination with pasak bumi extract and DHA for the P3 group, seluang fish for the P4 group, and pasak bumi extract and seluang fish for the P5 group. The doses determined for the pasak bumi extract and DHA were 15 and 1 mg/kg bw, respectively. The parameters evaluated consisted of the levels of brain-derived neurotrophic factor (BDNF), neural progenitor cell β-tubulin 3 (Tuj-1) expression, and peroxisome proliferator-activated receptor gamma (PPARγ). The data were subjected to analysis through the Kruskal-Wallis test and analysis of variance (ANOVA) at a 95% confidence level. A value of p&lt;0.05 was considered significant. Statistically significant differences were observed in the BDNF levels (p=0.00) and Tuj-1 expressions (p=0.01) across all groups. In conclusion, the combined administration of pasak bumi and seluang fish demonstrates the capacity of enhancing neurogenesis in malnourished rats, as evidenced by elevated BDNF levels and Tuj-1 expressions.

Chemotherapy drives tertiary lymphoid structures that correlate with ICI-responsive TCF1+CD8+ T cells in metastatic ovarian cancer.

Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICIs) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. We harnessed a variety of transcriptomic, spatial and functional assays to characterize the differential impact of neo-adjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to NACT-naïve HGSOC samples from 5 independent patient cohorts. We found neo-adjuvant chemotherapy (NACT)-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD-1+ CD8+ T cells over their ICI-insensitive TIM-3+PD-1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD-1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.

Pore structure of the mixed sedimentary reservoir of Permian Fengcheng Formation in the Hashan area, Junggar Basin

The Permian Fengcheng Formation (P1f.) in the Hashan area, situated on the southwestern margin of the Junggar Basin, has witnessed a remarkable breakthrough in shale oil exploration in recent years with nearly 789 million tons of shale oil resources. As a unique set of mixed sedimentary shales, the Fengcheng Formation in the Hashan area is characterized by mixed sedimentation of terrigenous siliciclastic sediments, authigenic minerals, and tuffaceous materials. However, the understanding of pore characteristics in the mixed sedimentary reservoir still remains limited, prohibiting accurate estimation of the oil content and insights into oil mobility. Scanning electron microscopy (SEM), X-ray diffraction (XRD), mercury injection capillary pressure (MICP), nuclear magnetic resonance (NMR), X-Ray Computer Tomography (X-CT), and geochemical analysis were performed to investigate the pore size distribution and main controlling factors of the mixed sedimentary reservoir. Results showed that the main pore types in the mixed sedimentary reservoir are intergranular pores and dissolution pores. The pores of the P1f. mixed shales in the Hashan area were classified into II-micropores (< 25 nm), I-micropores (25–100 nm), mesopores (100–1000 nm) and macropores (> 1000 nm). In general, the mixed sedimentary rocks of P1f. formation feature few macropores but a large number of micropores and mesopores. The CS exhibits the most favourable physical properties among all lithofacies. It is concluded that the abundance and maturity of organic matter, mineral composition, sedimentary structure, and diagenesis of reservoir together impact the pore structure in the mixed sedimentary reservoirs. The maturity of organic matter and the content of tuffaceous minerals are the most significant in influencing the pore structure of P1f. shales. Overall, the pore structure of complex lithologic reservoir formed by mixed deposition and its influence on physical properties are studied, and the characteristics of the microscopic pore-throat system of the dominant lithofacies in the Hashan area are clarified, which is of great significance as a guide for the exploration and development of mixed sedimentary reservoirs in continental shale oil in China.