Analysis of the relationship between shorter sleep duration and wrist fractures: based on NHANES.

BACKGROUND: Wrist fracture is one of the common limb fractures. Its incidence rate increases with age and osteoporosis. Nowadays, Sleep health is increasingly valued, but the relationship between wrist fractures and sleep time is not yet clear. METHODS: Data in this study were collected and screened from the NHANES from 2005 to 2010 and 2013 to 2014. The variables were extracted from interviews and compared between the wrist fractures and the sleep duration. The data was analyzed by weighted multivariate logistic regression. RESULTS: After excluding individuals who were not eligible and had invalid data, we finally identified 1835 participants for inclusion in this study. We found a negative association between the sleep duration and the fractured of the wrist (OR = 1.027,95% CI (1.027, 1.028), P < 0.00001). CONCLUSION: This study demons that the association between the sleep duration and the fractures of the wrist is significant. Our findings provide a better understanding of the relationship between sleep duration and wrist fractures. This study may help us reducing the incidence of wrist fractures in the population based on healthy sleep management in the future, and improve the quality of life of middle-aged and elderly patients. Provide evidence for clinical patients to manage healthy sleep.

Second harmonic generation of visible vortex laser based on a waveguide-grating emitter in LBO.

In this work, we propose a practical solution to visible vortex laser emission at 532 nm based on second harmonic generation (SHG) in a well-designed waveguide-grating structure. Such an integrated structure is fabricated by femtosecond laser direct writing (FsLDW) in an LBO crystal. Confocal micro-Raman spectroscopy is employed for detailed analysis of FsLDW-induced localized crystalline damage. By optical excitation at 1064 nm, the guiding properties, SHG performance, as well as vortex laser generation of the waveguide-grating hybrid structure are systematically studied. Our results indicate that FsLDW waveguide-grating emitter is a reliable design holding great promise for nonlinear vortex beam generation in integrated optics.

Tm,Ho:YLF waveguide lasers at 2.05†µm.

In this work, we report on the first, to our knowledge, 2.05-µm laser based on femtosecond-laser direct written (FsLDW) Tm,Ho:YLF cladding waveguides. A channel waveguide with a 90-µm diameter "fiber-like" low-index cladding is fabricated in a 6 at. % Tm3+, 0.4 at. % Ho3+:LiYF4 crystal by FsLDW. Pumped by Ti:sapphire laser at 795.1 nm, the fabricated waveguide supports efficient lasing oscillation at 2050 nm with a maximum output power of 47.5 mW, a minimum lasing threshold of 181 mW, and a slope efficiency of 20.1%. The impacts of cavity conditions and polarizations of the pump light on the obtained lasing performance are well studied. The experimental results obtained in this study demonstrate the great potential of utilizing Tm,Ho:YLF and FsLDW for the development of durable mid-infrared lasers featuring compact designs.

p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer.

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which was exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition. In vivo experiments using a novel, orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression.

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

Clinical features and management of germline CEBPA-mutated carriers.

Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.

Use of the Serum Level of Cholinesterase as a Prognostic Marker of Nonfatal Clinical Outcomes in Patients Hospitalized with Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Introduction: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) contributes to a poor prognosis. Reliable biomarkers to predict adverse outcomes during hospitalization are important. Aim: To investigate the relationship between the serum cholinesterase (ChE) level and adverse clinical outcomes, including hypoxemia severity, hypercapnia, duration of hospital stay (DoHS), and noninvasive ventilation (NIV) requirement, in patients with AECOPD. Methods: Patients hospitalized with AECOPD in the Wuhu Hospital of Traditional Chinese Medicine between January 2017 and December 2021 were included. Results: A total of 429 patients were enrolled. The serum ChE level was significantly lower in patients with hypercapnia, who required NIV during hospitalization and who had a DoHS of >10 days, with an oxygenation index < 300. The ChE level was correlated negatively with the C-reactive protein level and neutrophil-to-lymphocyte ratio and correlated positively with the serum albumin level. Multivariate logistic regression analysis indicated that a serum ChE level of ≤4116 U/L (OR = 2.857, 95% CI = 1.46-5.58, p = 0.002) was associated significantly with NIV requirement. Conclusions: The serum ChE level was correlated significantly with complicating severe hypoxemia, hypercapnia, prolonged DoHS, and the need for NIV in patients hospitalized with AECOPD. The serum ChE level is a clinically important risk-stratification biomarker in patients hospitalized with AECOPD.

Recent Progress of Solid-Liquid Interface-Mediated Contact-Electro-Catalysis.

Contact electrification (CE) is a common physical process by which triboelectric charges are generated through the mutual contact between two objects. Despite the ongoing debates on CE's mechanism, recent advancements in technology have elucidated the primary role of electron transfer in most CE processes. This discovery leads to the spawning of an emerging field, known as contact-electro-catalysis (CEC), which utilizes the electron transfer phenomenon during CE to initiate CEC. In this work, we provide the first comprehensive review of the recent progress of the solid-liquid interface-mediated CEC process, including its working principles, relationship with surface science, recent breakthroughs in applications, and future challenges. We aim to provide fundamental guidance for researchers to understand the reaction mechanism of the CEC process and to propose potential pathways to enhance CEC efficiency from a surface and interfacial science perspective. Later, recent application scenarios using the novel CEC techniques are summarized, including wastewater treatment, efficient generation of hydrogen peroxide (H2O2), lithium-ion battery recycling, and CO2 reduction. In general, CEC technology has opened a new avenue for catalysis, effectively expanding the range of catalyst options and holding promise as a solution to a variety of complex catalytic challenges in the future.

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer.

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.

Online mindfulness-based stress reduction improves anxiety and depression status and quality of life in caregivers of patients with severe mental disorders. / ç½‘ç»œæ­£å¿µå‡åŽ‹ç–—æ³•å¯æ”¹å–„ä¸¥é‡ç²¾ç¥žéšœç¢æ‚£è€ ç §æ–™è€ ç„¦è™‘æŠ‘éƒçŠ¶æ€åŠå ¶ç”Ÿæ´»è´¨é‡.

OBJECTIVES: To explore the effects of online mindfulness-based stress reduction (MBSR) on the anxiety and depression status, and quality of life in the caregivers of patients with severe mental disorders. METHODS: Ninety-three caregivers for patients with schizophrenia or bipolar disorder, who were hospitalized in Yunnan Provincial Mental Hospital in March 2021, were enrolled and randomly divided into control group (n=47) and MBSR intervention group (n=46). Both groups received basic health education and rehabilitation skill training, while the intervention group received additional online MBSR for 8 weeks. The anxiety and depression status, and the quality of life of the caregivers were evaluated by Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS) and the 36-item Short Form Health Survey (SF-36) before and 8 weeks after intervention, respectively. RESULTS: Thirteen caregivers dropped out of the study, and 80 subjects (40 in each group) were included in the final analysis. At the baseline, there were no significant differences in SAS, SDS and SF-36 scores between two groups (all P>0.05). Compared with the baseline, SAS and SDS scores in the intervention group significantly decreased after 8 weeks of intervention (both P<0.01) and were significantly lower than those in the control group (both P<0.01). There were no significant changes in the control group (all P>0.05). Except the physiological function dimension, the total score and the scores of each dimension of SF-36 in the intervention group were significantly increased after 8-week intervention (all P<0.05), and were significantly higher than those in the control group (all P<0.01). There were no significant changes in the control group before and after intervention (all P>0.05). CONCLUSIONS: Online MBSR can reduce the anxiety and depression levels, improve the quality of life in the caregivers of patients with severe mental disorders.

Effects of ozone on activated sludge: performance of anaerobic digestion and structure of the microbial community.

The treatment and disposal of activated sludge are currently challenging tasks in the world. As a common biological engineering technology, biological fermentation exists with disadvantages such as low efficiency and complex process. Ozone pretreatments are commonly applied to improve this problem due to their high efficiency and low cost. In this study, the significant function of ozone in anaerobic fermentation gas production was verified with excess sludge. Compared with other untreated sludge, ozone pretreatment can effectively degrade activated sludge. After ozone treatment and mixing with primary sludge, the methane production of excess sludge increased by 49.30 and 50.78%, and the methanogenic activity increased by 69.99 and 73.83%, respectively. The results indicated that the mixing of primary sludge with excess sludge possessed synergistic effects, which contributed to the anaerobic fermentation of excess sludge. The results of microbial community structure exhibited that methanogenic processes mainly involve hydrogenogens, acidogens and methanogens. The relative abundance of both bacteria and microorganisms changed significantly in the early stage of hydraulic retention time, which coincided exactly with the gas production stage. This study provided a feasible pretreatment strategy to improve sludge biodegradability and revealed the role of microorganisms during anaerobic digestion.

Nd:YSAG waveguide-grating vortex laser: design and implementation.

In this work, we fabricate a hybrid waveguide-grating vortex laser in Nd:YSAG by using femtosecond laser direct writing (FsLDW). The detailed parameters of the hybrid structure are fixed by optical simulation. In experiments, an efficient vortex beam is produced in the passive operation at 1064 nm. Under optical pumping at 808 nm, a dual-wavelength waveguide laser at 1060/1062 nm as well as a waveguide-grating vortex laser at 1060 nm are obtained. The laser performance and diffraction properties of the generated vortex laser are detailed, studied, and discussed, providing meaningful reference results toward the practical applications of FsLDW and waveguide-grating structures in integrated photonics.

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

Recombinant GM-CSF enhances the bactericidal ability of PMNs by increasing intracellular IL-1ß and improves the prognosis of secondary Pseudomonas aeruginosa pneumonia in sepsis.

This study tested the hypothesis that recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances polymorphonuclear neutrophils (PMNs) via interleukin (IL)-1ß to improve the prognosis of secondary infection in sepsis. The latter stage of sepsis is prone to induce immunosuppression, resulting in secondary fatal infections. Recombinant GM-CSF has become a way for sepsis-induced immunosuppression due to its immunomodulatory effect. However, the functional impact of GM-CSF on PMNs in sepsis remains obscure. This study aimed to study the role of recombinant GM-CSF on the bactericidal ability of PMNs in septic mice, assessing its effect on the prognosis of secondary pneumonia, and explore the mechanism of recombinant GM-CSF by intervening PMNs in patients with sepsis. The C57BL/6J sepsis mouse model was induced by cecal ligation and puncture. Recombinant murine GM-CSF (rmGM-CSF) was used in vivo when mice developed immunosuppression, which was characterized by abnormal bactericidal function of PMNs in peripheral blood. rmGM-CSF improved the prognosis of secondary pneumonia and reversed the function of PMNs. PMNs isolated by Percoll from septic patients were treated by recombinant human GM-CSF (rhGM-CSF) in vitro. The expression of CD11b, reactive oxygen species, phagocytosis, and neutrophil extracellular trap release in PMNs were enhanced by rhGM-CSF treatments. Whole-transcriptomic sequencing of mouse PMNs indicated that recombinant GM-CSF increased the expression of Il1b gene in PMNs. Blocking and inhibiting IL-1ß release effectively counteracted the enhancing effect of GM-CSF on the bactericidal function of PMNs. rmGM-CSF enhances the bactericidal function of PMNs in vivo and improves the prognosis of secondary pneumonia in septic mice, and recombinant GM-CSF increases IL-1ß precursor reserves, which, if stimulated, can rapidly enhance the bactericidal capacity of PMNs.

Analysis of the Influence of the Motion State of Ultra-Thin Sapphire Based on Layer-Stacked Clamping (LSC).

Ultra-thin sapphire wafer processing is receiving increasing attention in the LED substrate industry. In the cascade clamping method, the motion state of the wafer determines the uniformity of material removal, while the motion state of the wafer is related to its friction coefficient in the biplane processing system, but there is little relevant literature discussing the relationship between the motion state of wafer and friction coefficient. In this study, an analytical model of the motion state of sapphire wafers in the layer-stacked clamping process based on the frictional moment is established, the effect of each friction coefficient on its motion is discussed, the base plate of different materials and different roughness are experimentally studied, the layer-stacked clamping fixture is prepared in this way, and finally the failure form of the limiting tab is analyzed experimentally. The theoretical analysis shows that the sapphire wafer is mainly driven by the polishing plate, while the base plate is mainly driven by the holder, and the rotation speed of the two is not the same; the material of the base plate of the layer-stacked clamping fixture is stainless steel, the material of the limiter is glass fiber plate, and the main form of failure of the limiter is to be cut by the edge of the sapphire wafer and damage the material structure.

Dimethyloxalylglycine Attenuates Steroid-Associated Endothelial Progenitor Cell Impairment and Osteonecrosis of the Femoral Head by Regulating the HIF-1α Signaling Pathway.

Endothelial impairment and dysfunction are closely related to the pathogenesis of steroid-associated osteonecrosis of the femoral head (SONFH). Recent studies have showed that hypoxia inducible factor-1α (HIF-1α) plays a crucial role in endothelial homeostasis maintenance. Dimethyloxalylglycine (DMOG) could suppress HIF-1 degradation and result in nucleus stabilization by repressing prolyl hydroxylase domain (PHD) enzymatic activity. Our results showed that methylprednisolone (MPS) remarkably undermined biological function of endothelial progenitor cells (EPC) by inhibiting colony formation, migration, angiogenesis, and stimulating senescence of EPCs, while DMOG treatment alleviated these effects by promoting HIF-1α signaling pathway, as evidenced by senescence-associated ß-galactosidase (SA-ß-Gal) staining, colony-forming unit, matrigel tube formation, and transwell assays. The levels of proteins related to angiogenesis were determined by ELISA and Western blotting. In addition, active HIF-1α bolstered the targeting and homing of endogenous EPCs to the injured endothelium in the femoral head. Histopathologically, our in vivo study showed that DMOG not only alleviated glucocorticoid-induced osteonecrosis but also promoted angiogenesis and osteogenesis in the femoral head as detected by microcomputed tomography (Micro-CT) analysis and histological staining of OCN, TRAP, and Factor Ⅷ. However, all of these effects were impaired by an HIF-1α inhibitor. These findings demonstrate that targeting HIF-1α in EPCs may constitute a novel therapeutic approach for the treatment of SONFH.

Efficacy of Antibiotic Cement in Preserving Endoplants After Infection With Plate Exposure.

Background: To study the feasibility and efficacy of antibiotic cement in preserving endoplants after infection in patients with early tibial plateau fracture on plate exposure. Patients and Methods: A retrospective analysis of 23 patients treated for post-operative infection with plate exposure after tibial plateau fracture between 2017 and 2021. They were divided into the observation group (10 patients) and the control group (13 patients). Total operation time, length of hospitalization, hospitalization cost, the number of surgeries, white blood cell (WBC) count, neutrophil (NEUT) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), the post-operative evaluation index, and complications were observed during the follow-up period. Results: All patients were followed up for 6 to 12 months; wound healing was observed in both groups. The total operation time for patients in the control group was longer compared with the observation group. However, the length of hospitalization, hospitalization cost, and number of surgeries in the observation group were less compared with the control group. No difference in WBC, NEUT, ESR, and CRP levels was observed one day after surgery. Furthermore, WBC, NEUT, ESR, and CRP levels were higher in patients in the control group compared with the observation group 72 hours after surgery. There were no differences in the post-operative evaluation index and complications in both groups. Conclusions: The antibiotic cement coating used for treating early post-operative infection in patients with tibial plateau fracture could effectively control infection while retaining endoplant, thereby promoting wound healing. It could also reduce pain and the medical burden on patients.

RTFusion: A Multimodal Fusion Network with Significant Information Enhancement.

Multimodal medical fusion images are important for clinical diagnosis because they can better reflect the location of disease and provide anatomically detailed information. Existing medical image fusion methods can cause significant information loss in fusion images to varying degrees. Therefore, we designed a residual transformer fusion network (RTFusion): a multimodal fusion network with significant information enhancement. We use the residual transformer to make the image information interact remotely to ensure the global information of the image and use the residual structure to enhance the feature information to prevent information loss. Then the channel attention and spatial attention module (CASAM) is added to the fusion process to enhance the significant information of the fusion image, and the feature interaction module is used to promote the interaction of specific information of the source image. Finally, the loss function of the block calculation is designed to drive the fusion network to retain rich texture details, structural information, and color information, to optimize the subjective visual effect of the image. Extensive experiments show that our method can better recover the significant information of the source image and outperform other advanced methods in subjective visual description and objective metric evaluation. In particular, the color information and texture information are balanced to enhance the visual effect of the fused image.

Cellulose-based slippery covalently attached liquid surfaces for synergistic rain and solar energy harvesting.

For solar cell-triboelectric nanogenerator (TENG) integration, the design of the solid substrate for the TENG device becomes one of the challenges. The TENG needs to have superior contact electrification properties and be transparent so as to ensure light transmittance. Here, by spontaneous polymerization of dichlorodimethylsilane in the absence of any toxic solvent, we have fabricated a controllable liquid-like polydimethylsiloxane brush, featuring hydrophobicity, long-term stability, robustness, and UV resistance. A drop of liquid slides off at tilt angles below 5° and there is dynamic contact angle hysteresis of no more than 10° that can provide strong self-cleaning ability to the solid substrate. This recipe is also applicable to surfaces composed of hydroxyl group-rich cellulose-based surfaces, such as flexible cellulose acetate film (CAF). Importantly, PDMS@CAF, a flexible, transparent, and self-cleaning TENG device with a light transmission rate of 99% or more, was prepared using a conductive polymer film of PH 1000. The hybrid energy harvesting system formed by the combination of this transparent TENG equipped with solar cells is promising for harvesting energy from the environment in different weather conditions.

Transcriptional Regulatory Network of Plant Cadmium Stress Response.

Cadmium (Cd) is a non-essential heavy metal with high toxicity to plants. Plants have acquired specialized mechanisms to sense, transport, and detoxify Cd. Recent studies have identified many transporters involved in Cd uptake, transport, and detoxification. However, the complex transcriptional regulatory networks involved in Cd response remain to be elucidated. Here, we provide an overview of current knowledge regarding transcriptional regulatory networks and post-translational regulation of the transcription factors involved in Cd response. An increasing number of reports indicate that epigenetic regulation and long non-coding and small RNAs are important in Cd-induced transcriptional responses. Several kinases play important roles in Cd signaling that activate transcriptional cascades. We also discuss the perspectives to reduce grain Cd content and improve crop tolerance to Cd stress, which provides a theoretical reference for food safety and the future research of plant varieties with low Cd accumulation.