Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.

Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.

An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.

Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure.

Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Author Correction: Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A large-scale microelectromechanical-systems-based silicon photonics LiDAR.

Three-dimensional (3D) imaging sensors allow machines to perceive, map and interact with the surrounding world1. The size of light detection and ranging (LiDAR) devices is often limited by mechanical scanners. Focal plane array-based 3D sensors are promising candidates for solid-state LiDARs because they allow electronic scanning without mechanical moving parts. However, their resolutions have been limited to 512 pixels or smaller2. In this paper, we report on a 16,384-pixel LiDAR with a wide field of view (FoV, 70° × 70°), a fine addressing resolution (0.6° × 0.6°), a narrow beam divergence (0.050° × 0.049°) and a random-access beam addressing with sub-MHz operation speed. The 128 × 128-element focal plane switch array (FPSA) of grating antennas and microelectromechanical systems (MEMS)-actuated optical switches are monolithically integrated on a 10 × 11-mm2 silicon photonic chip, where a 128 × 96 subarray is wire bonded and tested in experiments. 3D imaging with a distance resolution of 1.7 cm is achieved with frequency-modulated continuous-wave (FMCW) ranging in monostatic configuration. The FPSA can be mass-produced in complementary metal-oxide-semiconductor (CMOS) foundries, which will allow ubiquitous 3D sensors for use in autonomous cars, drones, robots and smartphones.

Precision probiotics supplement strategy in aging population based on gut microbiome composition.

With the increasing prevalence of age-related chronic diseases burdening healthcare systems, there is a pressing need for innovative management strategies. Our study focuses on the gut microbiota, essential for metabolic, nutritional, and immune functions, which undergoes significant changes with aging. These changes can impair intestinal function, leading to altered microbial diversity and composition that potentially influence health outcomes and disease progression. Using advanced metagenomic sequencing, we explore the potential of personalized probiotic supplements in 297 older adults by analyzing their gut microbiota. We identified distinctive Lactobacillus and Bifidobacterium signatures in the gut microbiota of older adults, revealing probiotic patterns associated with various population characteristics, microbial compositions, cognitive functions, and neuroimaging results. These insights suggest that tailored probiotic supplements, designed to match individual probiotic profile, could offer an innovative method for addressing age-related diseases and functional declines. Our findings enhance the existing evidence base for probiotic use among older adults, highlighting the opportunity to create more targeted and effective probiotic strategies. However, additional research is required to validate our results and further assess the impact of precision probiotics on aging populations. Future studies should employ longitudinal designs and larger cohorts to conclusively demonstrate the benefits of tailored probiotic treatments.

Results of Two Cases of Pig-to-Human Kidney Xenotransplantation.

BACKGROUND: Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS: We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS: The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS: Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).

Global Prevalence of Helicobacter pylori Infection and Incidence of Gastric Cancer Between 1980 and 2022.

BACKGROUND & AIMS: We aimed to assess the secular trend of the global prevalence of Helicobacter pylori (H pylori) infection in adults and children/adolescents and to show its relation to that of gastric cancer incidence. METHODS: We performed a systematic review and meta-analysis to calculate overall prevalence, adjusted by multivariate meta-regression analysis. The incidence rates of gastric cancer were derived from the Global Burden of Disease Study and Cancer Incidence in Five Continents. RESULTS: Of the 16,976 articles screened, 1748 articles from 111 countries were eligible for analysis. The crude global prevalence of H pylori has reduced from 52.6% (95% confidence interval [CI], 49.6%-55.6%) before 1990 to 43.9% (95% CI, 42.3%-45.5%) in adults during 2015 through 2022, but was as still as high as 35.1% (95% CI, 30.5%-40.1%) in children and adolescents during 2015 through 2022. Secular trend and multivariate regression analyses showed that the global prevalence of H pylori has declined by 15.9% (95% CI, -20.5% to -11.3%) over the last 3 decades in adults, but not in children and adolescents. Significant reduction of H pylori prevalence was observed in adults in the Western Pacific, Southeast Asian, and African regions. However, H pylori prevalence was not significantly reduced in children and adolescents in any World Health Organization regions. The incidence of gastric cancer has decreased globally and in various countries where the prevalence of H pylori infection has declined. CONCLUSIONS: The global prevalence of H pylori infection has declined during the last 3 decades in adults, but not in children and adolescents. The results raised the hypothesis that the public health drive to reduce the prevalence of H pylori as a strategy to reduce the incidence of gastric cancer in the population should be confirmed in large-scale clinical trials.

The microRNA399d-PHOSPHATE2 module alters rice sensitivity to rice ragged stunt virus by manipulating phosphate uptake.

Rice (Oryza sativa L.) production frequently faces threats from biotic and abiotic stressors, with rice ragged stunt virus (RRSV) as a substantial biotic factor. The relationship between inorganic phosphorus (Pi) content and susceptibility to RRSV is crucial yet poorly understood. This study investigates how phosphorus metabolism influences rice resistance to RRSV, focusing on genetic manipulations that modulate this relationship. The RRSV infection increased phosphate (Pi) content in the aerial parts of rice plants by enhancing Pi uptake and transport. Furthermore, the upregulation of microRNA399d (miR399d) and the suppression of its target gene OsPHOSPHATE2 (OsPHO2) enhanced Pi accumulation, increasing rice susceptibility to RRSV infection. Additionally, elevated Pi levels, which are associated with altered ROS dynamics, reduced ROS activity and potentially dampened the plant's innate immune response to viral infection. The miR399d-PHO2 module was identified as pivotal in mediating phosphate uptake and influencing susceptibility to RRSV through modulations in the phosphorus and ROS pathways. This study shed light on the regulatory mechanisms of phosphorus nutrition in rice, revealing a critical interaction between phosphorus metabolism, ROS dynamics, and viral defense. The findings suggest potential strategies for manipulating Pi levels to enhance plant resistance against viruses, opening avenues for agricultural improvements and disease management in rice.

Cell surface- and rho GTPase-based auxin signaling controls cellular interdigitation in Arabidopsis.

Auxin is a multifunctional hormone essential for plant development and pattern formation. A nuclear auxin-signaling system controlling auxin-induced gene expression is well established, but cytoplasmic auxin signaling, as in its coordination of cell polarization, is unexplored. We found a cytoplasmic auxin-signaling mechanism that modulates the interdigitated growth of Arabidopsis leaf epidermal pavement cells (PCs), which develop interdigitated lobes and indentations to form a puzzle-piece shape in a two-dimensional plane. PC interdigitation is compromised in leaves deficient in either auxin biosynthesis or its export mediated by PINFORMED 1 localized at the lobe tip. Auxin coordinately activates two Rho GTPases, ROP2 and ROP6, which promote the formation of complementary lobes and indentations, respectively. Activation of these ROPs by auxin occurs within 30 s and depends on AUXIN-BINDING PROTEIN 1. These findings reveal Rho GTPase-based auxin-signaling mechanisms, which modulate the spatial coordination of cell expansion across a field of cells.

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.

Enhanced phasic calf muscle activation with swing resistance enhances propulsion of the paretic leg in people post-stroke.

Reduced propulsion of the paretic leg contributes to impaired walking in people post-stroke. The goal of this study was to determine whether phasic electrical stimulation to the paretic gastrocnemius muscle combined with resistance applied to the non-paretic leg during swing phase while walking would enhance muscle activation of the paretic gastrocnemius and propulsive force of the paretic leg. Fifteen individuals who had a stroke visited the lab once to complete two experimental sessions (i.e., cross-over design; session order randomized). Each session consisted of 1) treadmill walking with either "motor stimulation and swing resistance" or "swing resistance only" (10-min walking: 1-min baseline, 7-min adaptation to intervention, & 2-min post-adaptation) and 2) instrumented treadmill walking before and after treadmill walking. Results: Participants showed enhanced muscle activation of the paretic gastrocnemius (P=0.03) and improved anteroposterior ground reaction force of the paretic leg (P=0.01) immediately after the treadmill walking with "motor stimulation and swing resistance", whereas no improvements after the walking with "swing resistance only". Those enhanced gastrocnemius muscle activation (P=0.02) and improved ground reaction force (P=0.03) were retained until the late post-adaptation period and 10 min after treadmill walking, respectively. Conclusion: Walking with "motor stimulation and swing resistance" may enhance forced use of the paretic leg and improve propulsive force of the paretic leg. Applying phasic electrical stimulation to the paretic gastrocnemius muscle and swing resistance to the non-paretic leg during walking can be used as a novel intervention strategy to improve motor control of the paretic leg and walking in people post-stroke.

Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Motor interference on lateral pelvis shifting towards the paretic leg during walking and its cortical mechanisms in persons with stroke.

Motor interference, where new skill acquisition disrupts the performance of a previously learned skill, is a critical yet underexplored factor in gait rehabilitation post-stroke. This study investigates the interference effects of two different practice schedules, applying interleaved (ABA condition) and intermittent (A-A condition) pulling force to the pelvis during treadmill walking, on lateral pelvis shifting towards the paretic leg in individuals with stroke. Task A involved applying resistive pelvis force (pulling towards the non-paretic side), and Task B applied assistive force (pulling towards the paretic side) at the stance phase of the paretic leg during walking. Sixteen individuals with chronic stroke were tested for gait pattern changes, including lateral pelvis shifting and spatiotemporal gait parameters, and neurophysiological changes, including muscle activity in the paretic leg and beta band absolute power in the lesioned cortical areas. A-A condition demonstrated increased lateral pelvis shifting towards the paretic side, extended paretic stance time and longer non-paretic step length after force release while ABA condition did not show any changes. These changes in gait pattern after A-A condition were accompanied by increased muscle activities of the ankle plantarflexors, and hip adductors/abductors. A-A condition demonstrated greater changes in beta band power in the sensorimotor regions compared to ABA condition. These findings suggest that while walking practice with external force to the pelvis can improve lateral pelvis shifting towards the paretic leg post-stroke, practicing a new pelvis shifting task in close succession may hinder the performance of a previously obtained lateral pelvis shifting pattern during walking.

OsCSN2 orchestrates Oryza sativa L. growth and development through modulation of the GA and BR pathways.

The COP9 signalosome (CSN) is a conserved protein complex found in higher eukaryotes, consisting of eight subunits, and it plays a crucial role in regulating various processes of plant growth and development. Among these subunits, CSN2 is one of the most conserved components within the COP9 signalosome complex. Despite its prior identification in other species, its specific function in Oryza sativa L. (Rice) has remained poorly understood. In this study, we investigated the role of CSN2 in rice using gene editing CRISPR/Cas9 technology and overexpression techniques. We created two types of mutants: the oscsn2 mutant and the OsCSN2-OE mutant, both in the background of rice, and also generated point mutants of OsCSN2 (OsCSN2K64E, OsCSN2K67E, OsCSN2K71E and OsCSN2K104E) to further explore the regulatory function of OsCSN2. Phenotypic observation and gene expression analysis were conducted on plants from the generated mutants, tracking their growth from the seedling to the heading stages. The results showed that the loss and modification of OsCSN2 had limited effects on plant growth and development during the early stages of both the wild-type and mutant plants. However, as the plants grew to 60 days, significant differences emerged. The OsCSN2 point mutants exhibited increased tillering compared to the OsCSN2-OE mutant plants, which were already at the tillering stage. On the other hand, the OsCSN2 point mutant had already progressed to the heading and flowering stages, with the shorter plants. These results, along with functional predictions of the OsCSN2 protein, indicated that changes in the 64th, 67th, 71st, and 104th amino acids of OsCSN2 affected its ubiquitination site, influencing the ubiquitination function of CSN and consequently impacting the degradation of the DELLA protein SLR1. Taken together, it can be speculated that OsCSN2 plays a key role in GA and BR pathways by influencing the functional regulation of the transcription factor SLR1 in CSN, thereby affecting the growth and development of rice and the number of tillers.

Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.

BACKGROUND: Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach. METHODS: We did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls. FINDINGS: The data collected from xenografts suggested early signs of antibody-mediated rejection, characterised by microvascular inflammation with immune deposits, endothelial cell activation, and positive xenoreactive crossmatches. Capillary inflammation was mainly composed of intravascular CD68+ and CD15+ innate immune cells, as well as NKp46+ cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was not observed in control pig kidney autografts or in ischaemia-reperfusion models. INTERPRETATION: Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. FUNDING: OrganX and MSD Avenir.

Impact of time period and birth cohort on the trend of advanced neoplasm prevalence in the 40-49 average-risk screening population.

BACKGROUND AND AIMS: Early-onset colorectal cancer (CRC) is increasing globally. While the United States have lowered the age of initiation of screening to 45, other countries still start screening at age 50. In Taiwan, the incidence of CRC has declined in 55-74 year-olds after the initiation of screening, but still increased in those 50-54, potentially due to rising precancerous lesion incidence in 40-49 year-olds. This study aimed to explore the chronological trend of the prevalence of colorectal advanced neoplasms (AN) in the screening population aged 40-54. METHODS: We retrospectively analyzed a screening colonoscopy cohort for prevalence of AN in average-risk subjects aged 40-54 from 2003 to 2019. Logistic regression was used to distinguish cohort effect from time-period effect on the prevalence of AN. RESULTS: In total, 27,805 subjects (52.1% male) men were enrolled. There were notable increases in prevalence of AN in all three age groups during the 17-year span, but these were more rapid in age 40-44 (0.99% to 3.22%) and 45-49 (2.50% to 4.19%). Age 50-54 had higher risk of AN [aOR=1.62(1.19-2.19)] in 2003-2008 but not in later periods [2009-2014: aOR=1.08(0.83-1.41)] and [2015-2019: aOR=0.76(0.56-1.03)] when compared with age 45-49. CONCLUSION: The prevalence of AN in age 40-54 increased in the Taiwanese population, with a later birth cohort having a higher prevalence of AN. However, the prevalence of AN in age 45-49 increased more remarkably and approximated that in age 50-54, which may justify earlier initiation of CRC screening at age 45.

Fabricating Ultrathin Imprinting Layer for Fast Capture of Valsartan via a Metal Affinity-Oriented Surface Imprinting Method.

Rapid separation and enrichment of targets in biological matrixes are of significant interest in multiple life sciences disciplines. Molecularly imprinted polymers (MIPs) have vital applications in extraction and sample cleanup owing to their excellent specificity and selectivity. However, the low mass transfer rate, caused by the heterogeneity of imprinted cavities in polymer networks and strong driving forces, significantly limits its application in high-throughput analysis. Herein, one novel metal affinity-oriented surface imprinting method was proposed to fabricate an MIP with an ultrathin imprinting layer. MIPs were prepared by immobilized template molecules on magnetic nanoparticles (NPs) with metal ions as bridges via coordination, and then polymerization was done. Under the optimized conditions, the thickness of the imprinting layer was merely 1 nm, and the adsorption toward VAL well matched the Langmuir model. Moreover, it took just 5 min to achieve adsorption equilibrium significantly faster than other reported MIPs toward VAL. Adsorption capacity still can reach 25.3 mg/g ascribed to the high imprinting efficiency of the method (the imprinting factor was as high as 5). All evidence proved that recognition sites were all external cavities and were evenly distributed on the surface of the NPs. The obtained MIP NPs exhibited excellent selectivity and specificity toward VAL, with good dispersibility and stability. Coupled with high-performance liquid chromatography, it was successfully used as a dispersed solid phase extraction material to determine VAL in serum. Average recoveries are over 90.0% with relative standard deviations less than 2.14% at three spiked levels (n = 3). All evidence testified that the MIPs fabricated with the proposed method showed a fast trans mass rate and a large rebinding capacity. The method can potentially use high-throughput separation and enrichment of target molecules in batch samples to meet practical applications.