Mature State Research Articles

On the relation of injury to pain—an infant perspective*

Abstract Forty-five years ago, Patrick Wall published his John J Bonica lecture “On the relation of injury to pain.” 90 In this lecture, he argued that pain is better classified as an awareness of a need-state than as a sensation. This need state, he argued, serves more to promote healing than to avoid injury. Here I reframe Wall's prescient proposal to pain in early life and propose a set of different need states that are triggered when injury occurs in infancy. This paper, and my own accompanying Bonica lecture, is dedicated to his memory and to his unique contribution to the neuroscience of pain. The IASP definition of pain includes a key statement, “through their life experiences, individuals learn the concept of pain.” 69 But the relation between injury and pain is not fixed from birth. In early life, the links between nociception (the sense) and pain (the need state) are very different from those of adults, although no less important. I propose that injury evokes three pain need states in infancy, all of which depend on the state of maturity of the central nervous system: (1) the need to attract maternal help; (2) the need to learn the concept of pain; and (3) the need to maintain healthy activity dependent brain development.

Structural roles of Ump1 and β-subunit propeptides in proteasome biogenesis.

The yeast pre1-1(β4-S142F) mutant accumulates late 20S proteasome core particle precursor complexes (late-PCs). We report a 2.1 Å cryo-EM structure of this intermediate with full-length Ump1 trapped inside, and Pba1-Pba2 attached to the α-ring surfaces. The structure discloses intimate interactions of Ump1 with β2- and β5-propeptides, which together fill most of the antechambers between the α- and β-rings. The β5-propeptide is unprocessed and separates Ump1 from β6 and β7. The β2-propeptide is disconnected from the subunit by autocatalytic processing and localizes between Ump1 and β3. A comparison of different proteasome maturation states reveals that maturation goes along with global conformational changes in the rings, initiated by structuring of the proteolytic sites and their autocatalytic activation. In the pre1-1 strain, β2 is activated first enabling processing of β1-, β6-, and β7-propeptides. Subsequent maturation of β5 and β1 precedes degradation of Ump1, tightening of the complex, and finally release of Pba1-Pba2.

The myocardium of human dilated nonischemic cardiomyopathy harbors unique tissue-resident lymphocyte subsets

Abstract Purpose The etiology of dilated nonischemic cardiomyopathy (NICM) is often unclear, but thought to be multifactorial, involving an interplay between genetic factors and direct myocardial damage caused by infection, autoimmunity, or toxins. Tissue-resident lymphocytes are non-circulating immune cells which are retained within various tissues and play integral roles in maintaining homeostasis, responding to infection, regulating inflammation, and mediating tissue repair. Despite their likely involvement in various cardiac pathologies, the presence of tissue-resident lymphocytes in the human heart has not yet been well-characterized, neither in health nor in disease. Methods Human left ventricular tissue and paired peripheral blood samples were obtained from six adult organ donors with normal heart function who died of noncardiac causes and from the explants of six adult patients with end-stage nonischemic cardiomyopathy. Heart tissue was processed using mechanical and enzymatic digestion. Mononuclear cells were isolated from both heart and paired blood by density centrifugation. Isolated mononuclear cells were surface stained with an antibody cocktail and interrogated using multidimensional flow cytometry. Results The adult human heart contains a diverse immune cell population (Fig 1A). Both healthy and NICM cardiac lymphocytes express distinct phenotypic profiles which resemble those of resident lymphocytes found across various tissues, distinct from those isolated from paired blood. Frequencies of effector memory T (Tem) cells (CD45RA- CCR7-) were higher in heart than in blood among both CD4+ and CD8+ T-cells. In heart compared to blood, significantly more Tem expressed CD69, a canonical marker of tissue-resident memory T (Trm) cells (Fig 1B). Cardiac Trm, especially CD8+ Trm, expressed classical Trm signature markers including integrins CD103 (epithelial binding) and CD49a (collagen binding). NICM Trm expressed more CD49a than healthy heart Trm (Fig 1C). NK-cells also demonstrated higher CD69 expression (trNK) in heart than in blood, with associated expression of CD103, CD49a, and CXCR6 (Fig 1D). Compared to healthy hearts, NICM trNK were predominantly CD56bright/CD16- (Fig 1E and 1F) and expressed less CD57 (Fig 1D), overall indicating a less mature state with lower cytotoxic potential. Confocal imaging of cardiac tissue revealed CD69-expressing tissue-resident lymphocytes within the cardiac interstitium. Conclusions The adult human heart contains diverse populations of lymphocytes which express canonical markers of tissue residency, similar to lymphocytes resident in other tissues. Compared to healthy hearts, NICM hearts have more CD49a+ Trm, perhaps related to greater fibrosis, and also harbor a distinct subset of immature tissue-resident NK cells which may shed light on pathophysiology. Future work is focused on better exploring the functional phenotypes of these resident cells and better localizing them within the myocardium.FA - Figure 1

Naturally acquired microchimerism: clinical, scientific and ethical issues

Microchimerism (MC) is understood as the presence in the body of cells genetically different from the population of the individual, capable of existence and persistence, that is, reproduction and differentiation. This process is associated with the exchange of cellular material between mother and fetus. The consequences of the intrauterine acquisition of maternal MC (MMC) by the fetus are essentially different from the acquisition by the mother of fetal CM (FMC) in the mature state of the organism. Microchimerism has been implicated in the development of autoimmune diseases, but it also helps the body limit a particular disease. Since all these processes take place during the early development of the fetal immune system, the initial response of the immune system is the development of specific tolerance to maternal antigens. MMС can modify immune functions and reactivity through the nongenetic acquisition of cellular and subcellular material. Both FMС and MMС are quite common phenomena, which affects the body of the child and mother, the differentiation and functionality of the host cells. All this allows us to consider foreign cells as a potential target for drugs in the fight against autoimmune diseases or, conversely, stimulation of regeneration processes of damaged tissues. Issues of evolution and prospects for the prevention of various pathological conditions are considered from the standpoint of taking into account maternal and fetal chimerism syndrome.

Institutional Logic of Fragile States: Afghanistan and South Sudan in Comparative Perspective

ABSTRACT In the violence trap framework, ruling elites use rents to control contending elites who pose a violent threat. Political development results in transitions from a fragile state, wherein rents are tentative and personalized, to a basic natural state, and then a mature natural state, through standardization of elite privileges, consolidated state control of the political-military apparatus, and the enactment of a credible contracts regime. Accordingly, the institutional logic of fragile states is rooted in the incentives that undergird elite bounded rationality, transacting under highly personalized, tentative patronage networks. The paper addresses the question of why fragile states fail to develop into basic natural states. In doing so, it applies the violence trap analytical framework to illustrate the logic of the fragile state through a most different systems (MDS) comparison of Afghanistan and South Sudan. The main finding is that the institutional logic of the fragile state in the two cases is rooted in a lack of three necessary conditions: institutional incentives for broadening elite consensus, credible patronage agreements among different elite groups, and a consolidated state with specialized political and military functions.

The interaction of relative age with maturation and body size in female handball talent selection.

The relative age effects (RAEs) and biological maturation are two distinct factors that have been identified to affect talent identification and selection. Previous research has suggested that talent selection should include sport-specific technical tasks instead of body size and/or physical test measurements, assuming that the technical tasks are less influenced by variations in maturation. Our purpose was to examine the prevalence of RAEs and to assess biological maturity, body size, and body composition within a single talent selection program for female handball players. Team coaches' recommendations, handball-specific drills, and in-game performance were the selection criteria. Birth distribution of all U14 female handball players were analysed (N = 3198) grouped in two-year age cohort. Measurements of body size, body composition (InBody 720), and bone age were performed in all players who were selected to participate in the selection program (n = 264) (mean±sd age: 13.1±0.6 years) and in a sample of not-selected players (n = 266) (mean±sd age: 13.2±0.6 years). Players were grouped in quarter-year intervals based on their date of birth. Chi-square was used to examine quartile distributions, differences between quartiles were tested with one-way analysis of variance, whereas differences between the selected and not-selected groups were examined with independent sample t-test (Cohen d effect size). Binary logistic regression was used to determine the effects of the predictors on the selection. In terms of all registered players, there was no difference in birth distribution. RAEs appeared at the first selection stage and were evident at all following stages. Quartiles differed only between the first and the last quartiles in body size and muscle mass. Only bone age differed between consecutive quartile or semi-year groups. Body size, body composition, and maturity had a significant, but of moderate power, effect on the selection. Larger body height increased the likelihood of selection by about 12%, larger muscle mass by 12% to 25%, larger bone age by 350-400%, while larger percent body fat decreased selection chances by 7%. The sport-specific criteria could not eliminate the prevalence of the RAEs. Relative age was connected to bone age, but not convincingly to body size and muscle mass. Although bone age had the largest effect on the selection, this was not associated with larger body size or muscle mass. Early maturation increased selection chances mainly during the coaches' subjective evaluation, but not convincingly when sport-specific tasks were applied. Given that differences were mostly evident between players of more than 1.5-year variation in their chronological age, one-year age cohorts within talent selection or the rotation of the cut-off dates of the bi-annual age grouping could be a promising strategy while also including maturation status and relative age in performance evaluations.

Unraveling the developmental heterogeneity within the human retina to reconstruct the continuity of retinal ganglion cell maturation and stage-specific intrinsic and extrinsic factors.

Tissue development is a complex spatiotemporal process with multiple interdependent components. Anatomical, histological, sequencing, and evolutional strategies can be used to profile and explain tissue development from different perspectives. The introduction of scRNAseq methods and the computational tools allows to deconvolute developmental heterogeneity and draw a decomposed uniform map. In this manuscript, we decomposed the development of a human retina with a focus on the retinal ganglion cells (RGC). To increase the temporal resolution of retinal cell classes maturation state we assumed the working hypothesis that that maturation of retinal ganglion cells is a continuous, non-discrete process. We have assembled the scRNAseq atlas of human fetal retina from fetal week 8 to week 27 and applied the computational methods to unravel maturation heterogeneity into a uniform maturation track. We align RGC transcriptomes in pseudotime to map RGC developmental fate trajectories against the broader timeline of retinal development. Through this analysis, we identified the continuous maturation track of RGC and described the cell-intrinsic (DEGs, maturation gene profiles, regulons, transcriptional motifs) and -extrinsic profiles (neurotrophic receptors across maturation, cell-cell interactions) of different RGC maturation states. We described the genes involved in the retina and RGC maturation, including de novo RGC maturation drivers. We demonstrate the application of the human fetal retina atlas as a reference tool, allowing automated annotation and universal embedding of scRNAseq data. Altogether, our findings deepen the current knowledge of the retina and RGC maturation by bringing in the maturation dimension for the cell class vs. state analysis. We show how the pseudotime application contributes to developmental-oriented analyses, allowing to order the cells by their maturation state. This approach not only improves the downstream computational analysis but also provides a true maturation track transcriptomics profile.

External nutrients fattening promotes hepatopancreases development, metabolism, nutrient deposition and flavor yield during the maturation stage in female Chinese mitten crab (Eriocheir sinensis)

The nutritive value and maturity status of hepatopancreases dominates the quality of Chinese mitten crab, Eriocheir sinensis. However, the underlying function and regulatory mechanism, as well as the external nutrient factors on the development of hepatopancreases in different growth stages of E. sinensis remains unclear. In this study, we first revealed the function of hepatopancreases feeding with iced trash fish (ITF) during the whole culture period; and further investigated the underlying mechanism on nutrient deposition and flavor yield feeding with formulated feed (FEED) in replacement of ITF in female E. sinensis. From the results, growth performance and metabolism indicate E. sinensis was robustly developed, and ITF promotes growth and hepatopancreases development during the maturation period. Meanwhile, activation of fatty acid and amino acid metabolism in hepatopancreases resulted in depletion of monounsaturated fatty acids (MUFAs) but promoted protein deposition during the maturation stage. Integrated analysis of transcriptome and metabolome reveal metabolism, biosynthesis, and flavor presentation were intensively active during maturation, evidenced by the expression of key genes of ALDH, TBXAs, HADHA, UPB1, CYP2, GST, and γ-GT-X1; as well as the key metabolites of GMP and IMP. Additionally, substitution of ITF with FEED further confirm full price artificial feed could meet the nutrient requirements during the maturation period, evidenced by the growth performance, fatty acid and amino acid derived nutrient and flavor yield in hepatopancreases. In conclusion, nutrient and flavor deposition was associated with the fast development of hepatopancreases, and fatten with full price compound feed contributes to the nutrient requirement and flavor yield during the maturation stage.

Multiplexed single-cell imaging reveals diverging subpopulations with distinct senescence phenotypes during long-term senescence induction.

Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16 INK4a . The aggregated population of cells responded to etoposide with an accumulation of stress response factors over the first 11 days, followed by a plateau in most proteins. At the single-cell level, however, we identified two distinct senescence cell populations, one defined primarily by larger nuclear area and the second by higher protein concentrations. Trajectory inference suggested that cells took one of two discrete molecular paths from unperturbed healthy cells, through a common transitional subpopulation, and ending at the discrete terminal senescence phenotypes. Our results underscore the importance of using single-cell proteomics to identify the mechanistic pathways governing the transition from senescence induction to a mature state of senescence characterized by the SASP.

A novel approach for rapidly determining the reproductive status of walleye pollock (Gadus chalcogrammus) using Raman spectroscopy

Knowledge of the reproductive biology of fishes is essential for effective fisheries management. Information derived from an understanding of fish reproduction, such as size and age at maturity, is used in models to assess fish stocks and can affect estimates of important ecological processes such as recruitment, abundance, and trophic interactions. Common practices for determining the reproductive status of teleost fishes include macroscopic evaluation of gonads as well as histological analysis. However, macroscopic evaluation can be biased and histological analysis is time-consuming, resulting in limitations to spatial and temporal data availability. Here, we explore Raman spectroscopy of ovaries as a novel approach to rapidly determine the reproductive status of walleye pollock (Gadus chalcogrammus), a commercially and ecologically important species in the North Pacific. We used a two-stage partial least-squares (PLS) regression analysis followed by a linear discriminant analysis (LDA) to classify walleye pollock ovary samples as physiologically mature or immature and to subsequently predict their histologically-determined reproductive stage based on the Raman spectra. Biologically mature samples with visible yolk differentiated from mature and immature samples (non-yolked; 99% accuracy). Non-yolked ovaries that were physiologically mature (either mature non-developing or previously spawned) were further differentiated from physiologically immature ovaries (93% accuracy). In addition, detailed, histologically-determined reproductive stages of yolked samples also differentiated via Raman spectroscopy, but with reduced accuracy (79% - 86% accuracy). Our results indicate that accurate identification of maturity status and the reproductive staging of oocytes of walleye pollock based on spectral data from ovaries is possible. This can provide a fast and efficient way to increase the availability of a key component of reproductive data to inform fisheries research and management.

Environmental Cues Facilitate Maturation and Patterning of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Advances in induced pluripotent stem cell (iPSC) technology allow for reprogramming of adult somatic cells into stem cells from which patient- and disease-specific cardiomyocytes (CMs) can be derived. Yet, the potential of iPSC technology to revolutionize cardiovascular research is limited, in part, by the embryonic nature of these cells. Here, we test the hypothesis that decellularized porcine left ventricular extracellular cardiac matrix (ECM) provides environmental cues that promote transcriptional maturation and patterning of iPSC-CMs in culture. Cardiac progenitor cells were plated on ECM or standard tissue plates (2D monolayer) for 30 days, after which CM orientation and single cell transcriptomics were evaluated using confocal imaging and singe cell RNA-sequencing, respectively. Cardiac progenitors differentiated on left ventricular ECM formed longitudinal fibers that differed quantitatively from progenitors differentiated in standard 2D conditions. Unsupervised clustering of single cell transcriptomics identified a CM cluster expressing a higher level of genes related to CM maturation. CMs differentiated on ECM were overrepresented in this cluster, indicating a bias toward CM maturation, compared to cells differentiated in standard 2D monolayer conditions. Our data suggest that environmental cues related to the left ventricular ECM may promote differentiation to a more mature CM state compared to cells differentiated on a standard 2D monolayer, while facilitating organization into longitudinal micro-fibers. Our study highlights the utility of ECM as a differentiation substrate to promote CM maturation and fiber orientation in vitro .

Correlation between preoperative cephalic vein pathological types and autogenous arteriovenous fistula (AVF) maturation in patients with stage 5 chronic kidney disease.

To explore the correlation between preoperative cephalic vein pathological types and the maturation of autogenous arteriovenous fistula (AVF) in patients with chronic kidney disease (CKD), providing new ideas and methods for clinical prediction of fistula maturation. A retrospective analysis was performed in 80 patients who underwent AVF creation surgery from June 2021 to June 2023 at our hospital. Patients were followed up for 6 months. Patients were classified into the mature group (n = 57) and the power loss group (n = 23) based on the AVF maturation status. Preoperative excised venous tissues were examined using Masson's trichrome staining to compare the intimal area (Ia), medial area (Ma), lumen diameter (Ld), average intimal thickness (Avg It), and average medial thickness (Avg Mt), along with the calculations and comparisons of Ia/Ma, Avg It/Avg Mt ratios. Factors influencing AVF power loss were identified using the multifactorial logistic regression analysis. Ia, Ia/Ma, and Ld were lower in the power loss group compared to the mature group (P < 0.01). No significant difference was found in Avg Mt and Avg It/Avg Mt levels between the two groups (P > 0.05). The level of Avg It was higher in the power loss group (P < 0.05). Avg It was a risk factor (P < 0.001), while Ld was a protective factor for AVF power loss (P < 0.05). The levels of Avg It and Ld in preoperative cephalic vein tissue before AVF formation were correlated with AVF power loss. Early monitoring may improve therapeutic outcomes and prognosis of patients with stage 5 CKD.

No Impact of Anthropometric and Fitness Factors on Speed-Agility in Young Soccer Players: Is It a Cognitive Influence?

Agility in young soccer players has long been associated with physical attributes like strength, speed, and power. The aims of this study were toinvestigate the relationship between cognitive factors and agility performance in this unique population. 39 young soccer players age 13.56 (SD 0.58)years were assessed for leg-muscle function (jump tests) and maturation status (peak height velocity). TheY-Agility Test, which included decision making in players, was used to measure performance. Cognitive factors such as perceptual skillsand decision making were evaluated with theY-Agility Test. The linear regression showed an absence of significance between theY-Agility Test and drop-jump contact (P = .283), Y-Agility Testand drop-jump flight (P = .185), Y-Agility Test and squat jump (P = .868), and Y-Agility Test and countermovement jump (P = .310). The linear mixed-model analyses suggested a difference between early-average maturers (P = .009) and early-late maturers (P = .005) but did not show a difference between average-late subjects (P = 1.000). Drop-jump flight did not show a difference in maturation (early-average P = 1.000; early-late P = 1.000; average P = 1.000). Squat-jump performance did not demonstrate any significance (early-average P = .618; early-late P = 1.000; P = 1.000). Countermovement-jump performance did not show any significance (early-average P = 1.000; early-late P = 1.000; average-late P = .492). Finally, agility performance does not show any significance between maturation levels(early-average maturer P = .450; early-late P = 1.000; average-late P = .830). Agility in young soccer players appears to follow a nonlinear trajectory, with cognitive factors possibly playing a more significant role than previously thought.

E-taxing maturity in developing economies: evidence from corporate tax payers in Ghana

Purpose The adoption of e-taxing plays an important role in modernizing tax administration. Ghana, like many other developing countries, has adopted e-taxing to modernize its revenue collection processes and improve its tax-to-GDP ratio. This study aims to examine the current state of e-taxing maturity in Ghana, focusing on the advancements made and what can be done to achieve a mature e-taxing system. Design/methodology/approach Through qualitative design, interviews were conducted with Ghana Revenue Authority, National Information Technology Agency and Businesses to provide an in-depth understanding of the strengths, weaknesses and opportunities for improving e-taxing maturity. Findings The study reveals mixed e-taxing maturity. While the digital service aspect of e-taxing has seen progress, digital infrastructure, digital analytics, digital integration and digital culture hinder the full actualization of mature e-taxing. Research limitations/implications The findings suggest the need for a comprehensive plan that addresses regulatory, cultural, technical and organizational aspects to drive digital transformation in e-taxing tax implementation. Social implications The lack of resilient infrastructure, especially in rural areas, can worsen societal inequalities. Owing to the lack of telecommunication infrastructure and poor internet connectivity in rural areas, businesses in these areas may lack the needed information for business growth and expansion. This can result in unfair treatment of rural businesses widening the inequality gap between businesses in urban areas and rural areas. Therefore, the study is important from the standpoint that implementing the recommendations will help to bridge the gap between businesses in urban areas and rural areas. Originality/value To the best of the author’s knowledge, this study is among the first to conduct an empirical study on e-taxing maturity in Ghana.

Lymphocyte Function in Tertiary Lymphoid Structures Predicts Hepatocellular Carcinoma Outcome

An increasing number of studies have revealed a correlation between tertiary lymphoid structures (TLSs) and the outcome of hepatocellular carcinoma (HCC). Nevertheless, the associations between the heterogeneity of cellular composition and the overall survival (OS) in HCC remain unexplored. Here, we evaluated the cancer tissues from 150 HCC individuals treated at the Tumor Hospital Affiliated with Nantong University using multiplex immunofluorescence to determine the presence and characteristics of TLS and to investigate the relationship between intra-TLS immunologic activity, TLS maturation, and intratumoral immune cell infiltration. Prognostic factors influencing the outcome were identified through both univariate and multivariate analyses. Additionally, the levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1, programmed death-ligand 1, and lymphocyte activation gene-3 were determined, as well as their relationship with TLS features were determined. TLS was detected in 71 (47.3%) of the 150 HCC cases and was related to higher intratumoral infiltration levels of lymphocytes. Additionally, intra-TLS lymphocyte proliferation correlated with that of intratumoral lymphocytes, and the presence of TLS and a high proportion of mature TLS demonstrated a significant correlation with better prognosis (P = .013 and P = .03, respectively). Among TLS-positive tumors, a high proportion of B cells expressing activation-induced cytidine deaminase and a high proportion of CD8+ T cells expressing CD45RO were significantly related to improved OS (P = .01 and P < .001, respectively). Comparatively, a high proportion of CD21+CD20+ B cells demonstrated a significant correlation with poorer OS (P < .002). A markedly reduced number of CTLA-4+ cells in the stromal regions in TLS-negative tumors was observed compared with TLS-positive tumors (P = .01). These findings reveal a correlation between TLS presence and improved OS in HCC patients. However, TLS exhibited significant variation in maturation state, T- and B-cell proliferation, and expression of markers related to B- and T-cell function. Notably, these characteristics were also found to possess prognostic significance, indicating that certain TLS might hinder tumor immunity by inhibiting immune cells, whereas others may foster antigen-driven immune responses, likely influenced by the composition and functional status of intra-TLS lymphocytes.

Is it me or is it you? Physiological effects of the honey bee microbiota may instead be due to host maturation.

Microbiota-mediated impacts on host physiology and behavior have been widely reported in honey bees (Apis mellifera). However, most of these studies are conducted in artificial lab settings and fail to take into account, or make incorrect assumptions about, the complex physical and social structures inherent to natural hive conditions. A new study by Liberti et al. (J. Liberti, E. T. Frank, T. Kay, L. Kesner, et al., mBio 15:e01034-24, 2024, https://doi.org/10.1128/mbio.01034-24) identifies one such overlooked aspect-the behavioral maturation from nurses to foragers-that can be a serious confounding factor in bee microbiota experiments. Using cuticular hydrocarbon profiling to discern between the two maturation states, they find that multiple physiological and behavioral differences between age-matched lab bees could potentially be explained by their maturation state instead of the intended treatment conditions, such as microbial inoculation. This study serves as a stark wake-up call on the necessity of careful replication and cross-disciplinary knowledge transfer (e.g., between animal specialists and microbiologists) in order to truly understand complex host-microbe systems.

Assessing neurocognitive maturation in early adolescence based on baby and adult functional brain landscapes.

Adolescence is a period of growth in cognitive performance and functioning. Recently, data-driven measures of brain-age gap, which can index cognitive decline in older populations, have been utilized in adolescent data with mixed findings. Instead of using a data-driven approach, here we assess the maturation status of the brain functional landscape in early adolescence by directly comparing an individual's resting-state functional connectivity (rsFC) to the canonical early-life and adulthood communities. Specifically, we hypothesized that the degree to which a youth's connectome is better captured by adult networks compared to infant/toddler networks is predictive of their cognitive development. To test this hypothesis across individuals and longitudinally, we utilized the Adolescent Brain Cognitive Development (ABCD) Study at baseline (9-10 years; n = 6,489) and 2-year-follow-up (Y2: 11-12 years; n = 5,089). Adjusted for demographic factors, our anchored rsFC score (AFC) was associated with better task performance both across and within participants. AFC was related to age and aging across youth, and change in AFC statistically mediated the age-related change in task performance. In conclusion, we showed that a model-fitting-free index of the brain at rest that is anchored to both adult and baby connectivity landscapes predicts cognitive performance and development in youth.

Differentiating leukemia subtypes based on metabolic signatures using hyperpolarized 13C NMR.

Leukemia is a group of blood cancers that are classified in four major classes. Within these four classes, many different subtypes exists with similar origin, genetic mutations, and level of maturity, which can make them difficult to distinguish. Despite their similarities, they might respond differently to treatment, and therefore distinguishing between them is of crucial importance. A deranged metabolic phenotype (Warburg effect) is often seen in cancer cells, leukemia cells included, and is increasingly a target for improved diagnosis and treatment. In this study, hyperpolarized 13C NMR spectroscopy was used to characterize the metabolic signatures of the six leukemia cell lines ML-1, CCRF-CEM, THP-1, MOLT-4, HL-60, and K562. This was done using [1-13C]pyruvate and [1-13C]alanine as bioprobes for downstream metabolite quantification and kinetic analysis on cultured cells with and without 2-deoxy-D-glucose treatment. The metabolic signatures of similar leukemia subtypes could be readily distinguished. This includes ML-1 and THP-1, which are of the similar M4 and M5 AML subtypes, CCRF-CEM and MOLT-4, which are of the similar T-ALL lineage at different maturation states, and HL-60 and K562, which are of the closely related M1 and M2 AML subtypes. The data presented here demonstrate the potential of hyperpolarized 13C NMR spectroscopy as a method to differentiate between leukemia subtypes of similar origin. Combining this method with bioreactor setups could potentially allow for better leukemia disease management as metabolic signatures could be acquired from a single biopsy through repeated experimentation and intervention.

Exploring the impact of tertiary lymphoid structures maturity in NSCLC: insights from TLS scoring.

Tertiary Lymphoid Structures (TLS) are lymphoid structures commonly associated with improved survival of cancer patients and response to immunotherapies. However, conflicting reports underscore the need to consider TLS heterogeneity and multiple features such as TLS size, composition, and maturation status, when assessing their functional impact. With the aim of gaining insights into TLS biology and evaluating the prognostic impact of TLS maturity in Non-Small Cell Lung Carcinoma (NSCLC), we developed a multiplex immunofluorescent (mIF) panel including T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (FDC) (CD21, CD23) and mature dendritic cell (DC-LAMP) markers. We deployed this panel across a cohort of primary tumor resections from NSCLC patients (N=406) and established a mIF image analysis workstream to specifically detect TLS structures and evaluate the density of each cell phenotype. We assessed the prognostic significance of TLS size, number, and composition, to develop a TLS scoring system representative of TLS biology within a tumor. TLS relative area, (total TLS area divided by the total tumor area), was the most prognostic TLS feature (C-index: 0.54, p = 0.04). CD21 positivity was a marker driving the favorable prognostic impact, where CD21+ CD23- B cells (C-index: 0.57, p = 0.04) and CD21+ CD23- FDC (C-index: 0.58, p = 0.01) were the only prognostic cell phenotypes in TLS. Combining the three most robust prognostic TLS features: TLS relative area, the density of B cells, and FDC CD21+ CD23- we generated a TLS scoring system that demonstrated strong prognostic value in NSCLC when considering the effect of age, sex, histology, and smoking status. This TLS Score also demonstrated significant association with Immunoscore, EGFR mutational status and gene expression-based B-cell and TLS signature scores. It was not correlated with PD-L1 status in tumor cells or immune cells. In conclusion, we generated a prognostic TLS Score representative of the TLS heterogeneity and maturity undergoing within NSCLC tissues. This score could be used as a tool to explore how TLS presence and maturity impact the organization of the tumor microenvironment and support the discovery of spatial biomarker surrogates of TLS maturity, that could be used in the clinic.

Impact of fruit reserve conditions from harvest to processing on the chemical composition and quality of coffee

Changes in the different stages of fruit processing are becoming a differentiating factor in coffee quality. Currently, generating delays in the processing of the fruit, that is, reserve, is a practice that can modify the sensory profile of the beverage. In this study, the fruit was reserved in three stages of maturity, two temperatures (15° and 20°C) and at two timepoints (24 and 48 h), establishing its chemical composition and sensory characteristics using analytical techniques such as liquid and gas chromatography. The state of maturity 1 showed an effect on malic and quinic acids due to the interaction of temperature and reserve time, while stage of maturity 3 showed an effect on glucose and fructose. The state of maturity 2 showed an effect of the reserve time on the same compounds of states 1 and 3, in addition to the content of defective beans and sucrose. The sensory quality expressed as the total SCA (Specialty Coffee Association) score and the attributes did not show treatments effect, the reserve of the fruit under the evaluated conditions presents an effect on the descriptors of the flavor. Extending the fruit reserve time from 24 to 48 h showed an increase in the groups of flavor descriptors associated with fruit and red fruits from 33.33 to 66.66% and from 34.04 to 65.95%. This implies that the constituent parts of the fruit such as the exocarp and mesocarp interact with the bean, leading to changes in the chemical composition and the improvement of the qualitative complexity of the sensory quality. This is a consequence of the increase in the frequency of the flavor descriptors of the fruit and red fruit category.