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Background: Calcium signaling is implicated in multiple processes including immune response that important in tumor progression. Kidney renal clear cell carcinoma (KIRC) is the most frequent histological type of renal cell carcinoma with up to a third of cases develop metastases. As a result of a lack of in-depth understanding of the mechanisms underlying KIRC, treatment options have been limited. Here, we aim to comprehensively investigate the landscape of Ca2+ channels, pumps and exchangers in KIRC patients.Methods: The mRNA expression profiles and gene variations of 58 calcium-related genes (CRGs) in KIRC patients and normal control cases were downloaded from TCGA database. CRGs-related risk score was constructed to quantify calcium patterns by using least absolute shrinkage and selection operator (LASSO) regression. The prognostic value, biological functions, immune landscape and therapeutic sensitivities based on CRGs-related risk score were then evaluated using multiple methods. Finally, key gene of CRGs was identified by weighted gene co-expression network analysis (WGCNA). TCGA-CPTAC, GSE53757 datasets, as well as human tissues were used for validation.Results: KIRC patients had significant differences in CRG expression, prognosis, and biological functions between two CRG clusters. CRGs-related risk score was then determined. The prognosis, tumor mutation burden, immune cell infiltration, immune checkpoints, and the response of targeted inhibitors were remarkably different between high and low CRGs-related risk subtypes. CRGs-related high-risk subtype was characterized by immunosuppressive microenvironment with poor prognosis. Meanwhile, several targeted drugs showed distinct sensitivity between CRGs-related risk subtypes. Finally, TRPM3 was identified as a key CRG based on risk score in KIRC patients. TRPM3 mRNA and protein expression were significantly lower in KIRC tumors than in normal controls. Low TRPM3 expression was associated with poor prognosis in KIRC patients.Conclusion: Our study highlighted the promising prognostic value of CRGs in KIRC tumors. The evaluation of CRGs-related risk score will contribute to predicting prognosis and clinical therapy in KIRC patients.

Tunnel boring machine (TBM) tunneling data have been extensively collected to utilize TBM information technology by analyzing and mining the data for achieving a safe and efficient TBM tunneling. Feature extraction of big data could reduce the complexity for problems, but conventional indexes based on feature extraction, such as field penetration index (FPI), specific penetration (SP), and boreability index (BI), have some disadvantages. Thus, we present novel boring indexes derived from tunneling data in the Yinchao TBM project. Linear thrust-penetration and torque-penetration relationships in filtered ascending sections (p ≥ 2 mm/r) are proposed using statistical features and through physical mechanism analysis of parameters in the TBM cyclic tunneling process. Boring indexes, such as normal boring difficulty index, initial rock mass fragmentation difficulty index, and tangential boring difficulty index, are defined using the coefficients of the linear thrust-penetration and torque-penetration relationships. Subsequently, the defined boring indexes are verified using performance prediction of 291 cyclic tunneling processes. Finally, a preliminary application of support measure suggestions is conducted using the statistical features of boring indexes, where certain criteria are proposed and verified. The results showed that the criterion of boring indexes for support measure suggestions could achieve a reasonable confirmation, potentially providing quantitative quotas for support measure suggestions in the subsequent construction process.

The cranial anatomy of the flat-skulled hadrosaurine Edmontosaurus regalis (Ornithischia: Hadrosauridae) is extensively described here, based on the holotype and paratype collected from the middle part of the Horseshoe Canyon Formation in southern Alberta. Focus is given to previously undocumented features of ontogenetic and phylogenetic importance. This description facilitates overall osteological comparisons between E. regalis and other hadrosaurids (especially E. annectens), and revises the diagnosis of E. regalis, to which a new autapomorphy (the dorsal half of the jugal anterior process bearing a sharp posterolateral projection into the orbit) is added. We consider the recently named Ugrunaaluk kuukpikensis from the upper Campanian/lower Maastrichtian of Alaska a nomen dubium, and conservatively regard the Alaskan material as belonging to Edmontosaurus sp.. A phylogenetic analysis of Hadrosauroidea using maximum parsimony further corroborates the sister-taxon relationship between E. regalis and E. annectens. In the strict consensus tree, Hadrosaurus foulkii occurs firmly within the clade comprising all non-lambeosaurine hadrosaurids, supporting the taxonomic scheme that divides Hadrosauridae into Hadrosaurinae and Lambeosaurinae. Within Edmontosaurini, Kerberosaurus is posited as the sister taxon to the clade of Shantungosaurus + Edmontosaurus. The biogeographic reconstruction of Hadrosaurinae in light of the time-calibrated cladogram and probability calculation of ancestral areas for all internal nodes reveals a significantly high probability for the North American origin of the clade. However, the Laramidia-Appalachia dispersals around the Santonian-Campanian boundary, inferred from the biogeographic scenario for the North American origin of Hadrosaurinae, are in conflict with currently accepted paleogeographic models. By contrast, the Asian origin of Hadrosaurinae with its relatively low probability resulting from the biogeographic analysis is worth seriously considering, despite the lack of fossil material from the Santonian and lower Campanian of Asia. Extra fossil collecting in appropriate geographic locations and stratigraphic intervals of Asia and Europe will help to clarify the biogeographic dynamics of hadrosaurine dinosaurs in the near future.

Abstract Background Good gastric preparation is indispensable for Magnetic-controlled Capsule Endoscopy (MCE) examination, but there is no consensus yet. We aim to explore the clinical application value of positioning exercises in improving the quality of MCE examination. Methods Clinical data of 326 patients who underwent MCE examination from January 2020 to December 2023 were collected. The included patients were divided into two groups: the conventional medication preparation group (CMP group, accepted mucosal cleansing medication only) and the positioning exercises group (PE group, accepted mucosal cleansing medication plus positioning exercises). A comparison was made between the two groups in terms of gastric cavity cleanliness score, visibility score, and detection rate of positive lesions. Results The examination time was (21.29 ± 5.82) minutes in the PE group and (30.54 ± 6.37) minutes in the CMP group, showing a significant difference between the two groups (P 0.05). Conclusion Positioning exercises before MCE examination can improve the quality of gastric mucosal images and reduce the duration of the examination for patients.

ObjectiveTo describe the current state of research and future research hotspots through a metrological analysis of the literature in the field of forensic anthropological remains identification research.MethodsThe data retrieved and extracted from the Web of Science Core Collection （WoSCC）， the core database of the Web of Science information service platform （hereinafter referred to as “WoS”）， was used to analyze the trends and topic changes in research on forensic identification of human remains from 1991 to 2022. Network visualisation of publication trends, countries （regions）, institutions, authors and topics related to the identification of remains in forensic anthropology was analysed using python 3.9.2 and Gephi 0.10.ResultsA total of 873 papers written in English in the field of forensic anthropological remains identification research were obtained. The journal with the largest number of publications was Forensic Science International （164 articles）. The country （region） with the largest number of published papers was China （90 articles）. Katholieke Univ Leuven （Netherlands， 21 articles） was the institution with the largest number of publications. Topic analysis revealed that the focus of forensic anthropological remains identification research was sex estimation and age estimation, and the most commonly studied remains were teeth.ConclusionThe volume of publications in the field of forensic anthropological remains identification research has a distinct phasing. However, the scope of both international and domestic collaborations remains limited. Traditionally, human remains identification has primarily relied on key areas such as the pelvis, skull, and teeth. Looking ahead, future research will likely focus on the more accurate and efficient identification of multiple skeletal remains through the use of machine learning and deep learning techniques.

BackgroundSouthwestern Henan Province in central China contains many down-faulted basins, including the Xixia Basin where the Upper Cretaceous continental sediments are well exposed. The Majiacun Formation is a major dinosaur-bearing stratigraphic unit that occurs in this basin.Methodology/principal findingsA new basal hadrosauroid dinosaur, Zhanghenglong yangchengensis gen. et sp. nov., is named based on newly collected specimens from the middle Santonian Majiacun Formation of Zhoujiagou Village, Xixia Basin. Two transitional features between basal hadrosauroids and hadrosaurids are attached to the diagnosis of the new taxon, namely five maxillary foramina consisting of four small scattered ones anteroposteriorly arranged in a row and a large one adjacent to the articular facet for the jugal, and dentary tooth crowns bearing both median and distally offset primary ridges. Zhanghenglong also displays a unique combination of plesiomorphic and derived features of hadrosauroids, and is clearly morphologically transitional between basal hadrosauroids and hadrosaurids. Furthermore, some measurement attributes in osteology are applied to the quantitative analysis of Zhanghenglong. For these attributes, the partition of the dataset on most hadrosauroid species resulting from model-based cluster analysis almost matches taxonomic separation between basal hadrosauroids and hadrosaurids. Data of Zhanghenglong on selected measurement attributes straddle the two combinations of intervals of partitioned datasets respectively related to basal hadrosauroids and hadrosaurids. This condition is similar to mosaic evolution of morphological characters present in the specimens of the taxon. The phylogenetic analysis of Hadrosauroidea recovers a clade composed of Zhanghenglong, Nanyangosaurus, and Hadrosauridae with an unresolved polytomy.Conclusions/significanceZhanghenglong is probably a relatively derived non-hadrosaurid hadrosauroid, based on the inferences made from the morphological comparisons, quantitative evaluation of measurements, and cladistic analysis. In combination with information on the stratigraphy, phylogeny and biogeography, the material of Zhanghenglong provides direct evidence for the hypothesis that hadrosaurids might have originated in Asia.

Abstract Background Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. Methods This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. Discussion APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. Trial registration Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Abstract Background Spontaneous bacterial peritonitis (SBP) is a common complication in patients with cirrhosis. The diagnosis of SBP is still mostly based on ascites cultures and absolute ascites polymorphonuclear (PMN) cell count, which restricts the widely application in clinical settings. This study aimed to identify reliable and easy-to-use biomarkers for both diagnosis and prognosis of cirrhotic patients with SBP. Methods We conducted a retrospective study including 413 cirrhotic patients from March 2013 to July 2022 in the First Affiliated Hospital of Guangxi Medical University. Patients’ clinical characteristics and laboratory indices were collected and analyzed. Two machine learning methods (Xgboost and LASSO algorithms) and a logistic regression analysis were adopted to screen and validate the indices associated with the risk of SBP. A predictive model was constructed and validated using the estimated area under curve (AUC). The indices related to the survival of cirrhotic patients were also analyzed. Results A total of 413 cirrhotic patients were enrolled in the study, of whom 329 were decompensated and 84 were compensated. 52 patients complicated and patients with SBP had a poorer Child–Pugh score (P

Abstract Objective The purpose of this study was to evaluate the CT and MRI findings, clinicopathologic features, and differential diagnosis of Sclerosing angiomatoid nodular transformation (SANT). Methods and materials Seven men and seven women with pathological diagnoses of SANT were included in this retrospect study. Patients underwent at least one radiological examination before surgery. The number, shape, margin, size, attenuation, signal intensity, homogeneity, and enhancing pattern of the lesion were evaluated by two abdominal radiologists independently. Immunohistochemistry reports were available for 11 patients. The immunoreactivity to the vascular markers CD8, CD31, and CD34 was assessed. Results The 14 SANT patients (7 men, 7 women; mean age, 43.5 years; age range, 24–56 years) presented with a single lesion and showed no specific clinical symptoms. Among 14 patients, 12 patients underwent MR scan, 5 patients underwent CT scan and 3 patients underwent PET-CT. On CT, all 5 lesions showed hypodensity on non-contrast images and spoke-wheel enhancing pattern after contrast administration, and calcification was observed. On T2WI, 10 cases(83.3%)showed hypointensity and 2 cases (16.7%) showed hyperintensity with central hypointensity. On T1WI, 10 cases (83.3%) were isointense and 2 cases (16.7%) were slightly hypointense. 10 cases (83.3%) showed hypointensity on DWI and 2 cases (16.7%) showed slightly hyperintensity on DWI. After contrast administration, all 12 lesions showed progressive enhancement. 18 F-fluorodeoxyglucose (FDG) uptake in the tumor was seen in all three cases that underwent PET-CT. The maximum standardized uptake value (SUVmax) was 4.5, 5.1, and 3.8 respectively. Results Apart from the progressive spoke-wheel enhancing pattern, DWI and ADC findings will add value to the diagnosis of SANT.

Abstract Background The detection rate of methylated Septin9 (mSEPT9) in colorectal cancer (CRC) is varied greatly across the studies. This study aimed to evaluate the diagnostic ability of mSEPT9 in CRC, and compare the diagnostic efficacy with fecal immunochemical test (FIT). Methods 326 subjects from four centers were prospectively recruited, including 179 CRC and 147 non-CRC subjects. The plasma was collected for mSEPT9 and CEA, AFP, CA125, CA153 and CA199 test, and fecal samples for FIT tests. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic curve were calculated to evaluate the diagnostic value of each biomarker. Results The positive rate in mSEPT9 and FIT, and the level of CEA, CA125 and CA199 were significantly higher in CRC compared with non-CRC subjects. The mSEPT9 positive rate was not associated with TNM stage and tumor stage. The sensitivity, specificity and AUC of mSEPT9 in diagnostic CRC were 0.77, 0.88 and 0.82, respectively, while the value in FIT was 0.88, 0.80 and 0.83, respectively. mSEPT9 and FIT have higher AUC value than that of CEA, CA125 and CA199. Combination of both mSEPT9 and FIT positive increased sensitivity and AUC to 0.98 and 0.83, respectively, but the specificity was declined. mSEPT9 has a slightly low sensitivity in diagnosis of colon cancer (0.87) compared with rectal cancer (0.93). Conclusion mSEPT9 demonstrated moderate diagnostic value in CRC detection, which was similar to the FIT but superior to the CEA, CA125 and CA199. Combination of mSEPT9 and FIT further improved diagnostic sensitivity in CRC. Trial registration: ChiCTR2000038319.

Ultrathin zirconium‐based metal−organic framework (MOF) nanosheets, embedded with photochromic units, are expected to be highly efficient heterogeneous photocatalysts, thanks to their rich catalytic sites, short diffusion paths, and effective separation of photogenerated charge carriers. Herein, we reported the synthesis of novel Zr‐MOF nanosheets (Zr‐BTDB) through a solvothermal synthesis that integrates benzothiadiazole (BTz) as a photochromic moiety within the framework of MOF. The Zr‐BTDB nanosheets processes a [Zr12(μ3‐O)8(μ3‐OH)8(μ2‐OH)6] cluster with hcp topology. Importantly, Zr‐BTDB nanosheets exhibit excellent photocatalytic activity for the photooxidation of sulfides and amines at room temperature under blue light irradiation. Notably, these nanosheets maintain their photocatalytic activity and selectivity for up to five cycles without significant loss of activity and crystallinity. Systematical catalytic reactions revealed that the Zr‐BTDB nanosheets enable the generation of singlet oxygen (1O2) and superoxide radical (O2⋅−) under visible light irradiation, which is critical reactive oxygen species for the photooxidation of sulfides and benzylamines. Our work represents a straightforward route for the preparation of ultrathin, water stable, and visible‐light‐activated Zr‐MOF nanosheets, offering new potentials for the selective photooxidation of sulfides and amines in an eco‐friendly way. [ABSTRACT FROM AUTHOR]

ObjectiveTo explore the research hotspots and development trends of the field of forensic drowning from 1991 to 2020 by bibliometrics methods.MethodsBased on Web of Science， CNKI database， Wanfang Data knowledge service platform， python 3.9.2， CiteSpace 5.8.R3, Gephi 0.9.2, etc. were used to analyze the publishing trends， countries/regions， institutions， authors and topics of the study on drowning.ResultsA total of 631 English literature were obtained， including 59 articles from Chinese authors， and 386 Chinese literature were obtained. The Chinese and English journals with the largest number of related literatures were Chinese Journal of Forensic Science （80 articles） and Forensic Science International （106 articles）， respectively. Japan published the most articles in English， and China ranked third. Osaka City Univ （Japan，28 articles） published the most English articles，and Guangzhou Forens Sci Inst （China，22 articles） ranked second. Among Chinese literature， Guangzhou Forens Sci Inst （32 articles） published the most. The topic analysis of Chinese and English literature showed that diatom examination， virtual autopsy， postmortem biochemical examination， the nature of death， and postmortem submersion interval were the hot spots of current research， but English literature had more studies on new technologies and methods， while Chinese literature was more inclined to practice， application and experience summary.ConclusionThe number of literature in forensic medicine on drowning is relatively stable. The scope of international and domestic collaborations in this field is still limited. The automated examination of diatoms， the establishment of diatom DNA barcodes and virtual autopsy will be the most important research hotspots in the coming period and are expected to achieve breakthroughs in drowning diagnosis， drowning location inference， postmortem submersion interval estimation， etc.

BackgroundA novel protocol for accurate stellate ganglion block under ultrasound guidance was designed in rats. This technique raises the success rate of stellate ganglion block and reduces the incidence of brachial plexus and vagus nerve block.MethodsFifty-six Sprague-Dawley were randomly divided into an ultrasound-guided group (n = 28) and a blind technique group (n = 28). The rats in the blind technique group were injected with 1.5% lidocaine mixed with methylene blue after signs of brachial plexus stimulation were elicited. The lateral side of the cephalic brachial vein was located under the first rib, where lidocaine was injected into the rats in the ultrasound-guided group. The up-and-down sequential method of Dixon was used to determine the minimum effective volume for stellate ganglion block in rats. Furthermore, we calculated the required operative duration of the two methods and observed the difference in the lidocaine diffusion range between the two groups.ResultsThe minimum effective volume for stellate ganglion block in the ultrasound-guided group was 0.040 ml, and the 95% CI was 0.026–0.052 ml. In the blind technique group, the minimum effective volume was 0.639 ml, and the 95% CI was 0.490–0.733 ml. Within the 95% CI of the lowest effective volume, the incidence of brachial plexus block as a complication of stellate ganglion block under ultrasound guidance was 10.00%.ConclusionStellate ganglion block under ultrasound guidance is more accurate than blind detection, which the incidence of complications of stellate ganglion block under ultrasound guidance was significantly lower than under blind detection; the rate of methylene blue staining in the vagus nerve was significantly lower under ultrasound guidance.

High-level wheel polygon wear is common in high-speed EMUs. Wheel polygon wear causes high-frequency vibration of vehicles and track systems, which seriously affects the safe operation of vehicles. Some key influencing factors are of great significance for restraining wheel polygon wear. In this paper, a long-term wear iterative model is established by combining the coupled vehicle/track dynamic model with the Archard wear model, which is used to simulate the whole development process of high-speed train wheel polygon. The development process of wheel polygon is simulated when the vehicle runs at 300 km/h. The simulating results are consistent with the actual situation. It is found that changing the speed of the vehicle can prevent the rapid development of the wheel polygon of a fixed order, so as to slow down the development of the wheel polygon. As the wheel hardness increases, the roughness level gradually decreases. If there is corrugation in the rail, it will greatly accelerate the development of wheel polygon, especially when the wavelength of rail corrugation can divide the wheel circumference. In addition, with the increase of rail corrugation amplitude, the promoting effect will gradually increase.

BackgroundAtopic dermatitis (AD) is a common inflammatory skin disease, with the incidence peaks in infancy. A meta-analysis was performed to assess the levels of T helper type 22 (Th22) cells, T helper type 17 (Th17) cells, interleukin (IL)-17, and Tregs in peripheral blood of patients with AD.MethodsA comprehensive literature search was performed in PubMed, Embase, China National Knowledge Internet, and Wan-fang Data from the day of inception of this study to July 2021. Two authors independently extracted the data, which were pooled and calculated using Stata software version 15.ResultsA total of eight studies met the inclusion criteria. Compared with control group, patients with AD had an increased proportion of Th22 cells [weighted mean difference (WMD) = 2.07, 95% CI (1.33, 2.81), p < 0.001], Th17 cells [WMD = 1.04, 95% CI [0.66, 1.43], p < 0.001], IL-17 [WMD = 17.56, 95% CI (11.1, 24.03), p < 0.001], and a decreased proportion of Tregs [WMD = −2.49, 95% CI (−2.93, −2.05), p < 0.001] in peripheral blood. The subgroup analysis showed that patients with higher disease severity had higher levels of Th22 [mild: WMD = 1.33, 95% CI (1.24, 1.41), p < 0.001; moderate: WMD = 1.41, 95% CI (1.36, 1.54), p < 0.001; severe: WMD = 3.46, 95% CI (3.34, 2.81), p < 0.001] and lower levels of Tregs [mild: WMD = −1.43, 95% CI (−1.75, −1.11), p < 0.001; moderate: WMD = −2.16, 95% CI (−2.46, −1.86), p < 0.001; severe: WMD = −2.96, 95% CI (−3.25, −2.67), p < 0.001] in peripheral blood compared to healthy controls.ConclusionThe random effect model of the meta-analysis showed patients with AD had an increased proportion of Th22 cells, Th17 cells, and IL-17, whereas a decreased proportion of Tregs was found in peripheral blood. The results demonstrated that Th22 cells, Th17 cells, IL-17, and Tregs may be involved in the pathogenic mechanisms of AD.

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.