A New Species of the Blind Cave Loach Genus Protocobitis (Cypriniformes: Cobitidae), Protocobitis longicostatus sp. nov., from Guangxi, China.

Protocobitis species are typical cave-dwelling fish, exhibiting distinctive morphological adaptations such as colorless body, lack of eyes, and reduced scales and ribs in response to their extreme cave habitats. Distinct from the recorded species, P. anteroventris, P. polylepis, and P. typhlops, a new species, Protocobitis longicostatus sp. nov., is described from Guangxi Zhuang Autonomous Region, China. Protocobitis longicostatus sp. nov. can easily be distinguished from all known congeners by the following characteristics: whole body covered by scales except head, 12 branched caudal fin rays, and long ribs. These species face threats from habitat degradation, hydrological changes, and environmental pollution. Thus, the conservation of cavefish in China has become an urgent issue.

Effect of Paricalcitol Combined with Cinacalcet on Calcium and Phosphorus Metabolism in Patients Receiving Maintenance Hemodialysis.

This study was designed to compare the beneficial effects of paricalcitol combined with or without cinacalcet on calcium and phosphorus metabolism in patients undergoing maintenance hemodialysis (MHD). A total of 140 patients who received MHD in our hospital from March 2021 to March 2022 were randomly divided into a control group (intravenous paricalcitol, n = 70) and a test group (intravenous paricalcitol combined with oral cinacalcet, n = 70). Clinical baseline data and relevant laboratory parameters before treatment were compared. Additionally, calcium, phosphorus, intact parathyroid hormone in serum were measured and compared between the 2 groups before treatment and 1, 2, 3, 4, 5, 6, 9, 10, and 12 months after treatment. As a result, comparison before treatment demonstrated no significant difference in baseline data such as age, sex, and most laboratory parameters between the 2 groups (P > .05), but there was a significant difference in mean corpuscular volume (P < .001). The serum phosphorus level decreased and calcium level increased significantly in the 2 groups after treatment, while the intact parathyroid hormone level showed no significant change within 12 months of treatment (P > .05). In addition, the combined treatment for 6-12 months caused a much lower phosphorus level (P < .05) and higher calcium level (P < .05) than the treatment with paricalcitol alone, and the difference increased with the extension of treatment time. Collectively, paricalcitol combined with cinacalcet, which is more effective than paricalcitol alone, has a positive effect on calcium and phosphorus metabolism in patients receiving MHD.

Balitoraanlongensis, the first cavefish species of the genus Balitora (Teleostei, Balitoridae) from Guizhou Province, southwest China.

This work describes a new species, Balitoraanlongensissp. nov., collected from a cave at Xinglong Town, Anlong County, Guzihou, China. Phylogenetic trees reconstructed based on two mitochondrial and three nuclear genes show that the new species represents an independent evolutionary lineage with large genetic differences, 7.1%-12.0% in mitochondrial gene cytochrome b and 9.2%-12.1% in cytochrome oxidase subunit 1, from congeners. Morphologically, the new species can be distinguished from the 18 species currently assigned to the genus Balitora by a combination of characters, most clearly by having two pairs of maxillary barbels; 8½ branched dorsal-fin rays; 5½ branched anal-fin rays; pectoral fin not reaching pelvic fin origin; dorsal-fin origin in front of pelvic fin origin; eye small (eye diameter approximately equal to outer maxillary barbel length); and fins lacking pigment in live fish. The new species represents the first record of Balitora inhabiting caves in China and increases the number of species in the genus Balitora in its present concept from 18 to 19. The study suggests that more evidence is needed to further clarify the taxonomic composition of the genus Balitora.

Four new hypogean species of the genus Triplophysa (Osteichthyes, Cypriniformes, Nemacheilidae) from Guizhou Province, Southwest China, based on molecular and morphological data.

Recently described cave species of the genus Triplophysa have been discovered in southwestern China, suggesting that the diversity of the genus is severely underestimated and that there may be many undescribed species. In this work, four new species of the genus Triplophysa are described from southwestern Guizhou Province, China, namely Triplophysacehengensis Luo, Mao, Zhao, Xiao & Zhou, sp. nov. and Triplophysarongduensis Mao, Zhao, Yu, Xiao & Zhou, sp. nov. from Rongdu Town, Ceheng County, Guizhou, Triplophysapanzhouensis Yu, Luo, Lan, Xiao & Zhou, sp. nov. from Hongguo Town, Panzhou City, Guizhou, and Triplophysaanlongensis Song, Luo, Lan, Zhao, Xiao & Zhou, sp. nov. from Xinglong Town, Anlong County, Guizhou. These four new species can be distinguished from all recognized congeners by a combination of morphological characteristics and significant genetic divergences. The discovery of these species increases the number of known cave species within the genus Triplophysa to 39, making the genus the second most diverse group of cave fishes in China after the golden-line fish genus Sinocyclocheilus. Based on the non-monophyletic relationships of the different watershed systems in the phylogenetic tree, this study also discusses the use of cave species of the genus Triplophysa to determine the possible historical connectivity of river systems.

Formosaniaimmaculata, a new species of hillstream loach (Teleostei, Cypriniformes, Gastromyzontidae) from the Ou-Jiang River, Southeast China.

Formosaniaimmaculata, a new species, is described from the Ou-Jiang basin in Zhejiang Province, Southeast China. It is distinguished from other species of the genus by having a combination of the following characteristics: body without obvious mottling; snout length longer than postorbital length; abdominal scaleless area extending to middle of pectoral-fin base; shorter rostral barbels, the outermost pair length 112.9%-140.0% of eye diameter; and shorter lower lip papillae, length 19.9%-24.4% of eye diameter. Its validity is also affirmed by its distinct Cytb gene sequence divergence from all congeners and its monophyly recovered in a Cytb gene-based phylogenetic analysis.

Oreonectesdamingshanensis (Cypriniformes, Nemacheilidae), a new species of stream fish from Guangxi, Southwest China.

In this work, a new species of the genus Oreonectes is described, named Oreonectesdamingshanensis Yu, Luo, Lan, Xiao & Zhou, sp. nov., collected from the Damingshan Mountains of the Guangxi Zhuang Autonomous Region, China. Phylogenetic trees constructed based on the mitochondrial Cyt b showed that the new species represents an independent evolutionary lineage, with uncorrected genetic distances (p-distance) from congeners ranging from 6.1% to 8.9%. Morphologically, the new species can be distinguished from five other species of the genus by a combination of characters. The discovery of this new species raises the number of known species of Oreonectes from five to six. Our study suggests that O.platycephalus may be a complex containing multiple species and that previously recorded areas need to be further delimited and reevaluated.

Sinocyclocheiluslongicornus (Cypriniformes, Cyprinidae), a new species of microphthalmic hypogean fish from Guizhou, Southwest China.

Sinocyclocheiluslongicornussp. nov. is described from the Pearl River basin in Hongguo Town, Panzhou City, Guizhou Province, Southwest China. Based on the presence of the long horn-like structure on the back of the head, Sinocyclocheiluslongicornussp. nov. is assigned to the Sinocyclocheilusangularis species group. Sinocyclocheiluslongicornussp. nov. is distinguished from its congeners by a combination of morphological characters: (1) presence of a single, relatively long horn-like structure on the back of the head; (2) pigmentation absent; (3) reduced eyes; (4) dorsal-fin rays, ii, 7; (5) pectoral-fin rays, i, 13; (6) anal-fin rays, iii, 5; (7) pelvic-fin rays, i, 7; (8) lateral line pores 38-49; (9) gill rakers well developed, nine on first gill arch; and (10) tip of adpressed pelvic fin not reaching anus.

Phylogenetic analysis of combined mitochondrial genome and 32 nuclear genes provides key insights into molecular systematics and historical biogeography of Asian warty newts of the genus Paramesotriton (Caudata: Salamandridae).

The Paramesotriton Chang, 1935 genus of Asian warty newts is the second most diverse genus in the family Salamandridae, currently containing 14 recognized species from northern Vietnam to southwest-central and southern China. Although species of this genus have been included in previous phylogenetic studies, the origin and interspecific relationships of the genus are still not fully resolved, especially at key nodes in the phylogeny. In this study, we sequenced mitochondrial genomes and 32 nuclear genes from 27 samples belonging to 14 species to reconstruct the interspecific phylogenetic relationships within Paramesotriton and explore its historical biogeography in southern China. Both Bayesian inference and maximum-likelihood analyses highly supported the monophyly of Paramesotriton and its two recognized species groups ( P. caudopunctatus and P. chinensis groups) and further identified five hypothetical phylogenetic cryptic species. Biogeographic analyses indicated that Paramesotriton originated in southwestern China (Yunnan-Guizhou Plateau/South China) during the late Oligocene. The time of origin of Paramesotriton corresponded to the second uplift of the Himalayan/Qinghai-Xizang (Tibetan) Plateau (QTP), rapid lateral extrusion of Indochina, and formation of karst landscapes in southwestern China. Principal component analysis (PCA), independent sample t-tests, and niche differentiation using bioclimatic variables based on locations of occurrence suggested that Paramesotriton habitat conditions in the three current regions (West, South, and East) differ significantly, with different levels of climatic niche differentiation. Species distribution model (SDM) predictions indicated that the most suitable distribution areas for the P. caudopunctatus and P. chinensis species groups are western and southern/eastern areas of southern China. This study increases our knowledge of the taxonomy, biodiversity, origin, and suitable distribution areas of the genus Paramesotriton based on phylogenetic, biogeographic, and species distribution models.

Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) has replaced viral hepatitis as the main driver of the rising morbidity and mortality associated with cirrhosis and liver cancer worldwide, while no FDA-approved therapies are currently known. Kinsenoside (KD), naturally isolated from Anoectochilus roxburghii, possesses multiple biological activities, including lipolysis, anti-inflammation, and hepatoprotection. However, the effects of KD on NASH remain unclear. PURPOSE: This study aimed to explore the roles of KD in NASH and its engaged mechanisms. METHODS: Two typical animal models of NASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese NASH) and mice fed a high-fat and -fructose diet (HFFD) (representing obese NASH), were used to investigate the effect of KD on NASH in vivo. Transcriptome sequencing was performed to elucidate the underlying mechanisms of KD. Lipopolysaccharide (LPS)-stimulated THP-1 cells and transforming growth factor ß1 (TGF-ß1)-activated LX-2 cells were applied to further explore the effects and mechanisms of KD in vitro. RESULTS: The intragastric administration of KD remarkably alleviated MCD/HFFD-induced murine NASH almost in a dose-dependent manner. Specifically, KD reduced lipid accumulation, inflammation, and fibrosis in the liver of NASH mice. KD ameliorated alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), and malondialdehyde (MDA) abnormalities. In addition, it decreased the level of serum proinflammatory factors (IL-12p70, IL-6, TNF-α, MCP-1, IFN-γ) and the hepatic expression of typical fibrosis-related molecules (α-SMA, Col-I, TIMP-1). Mechanically, KD attenuated the MCD/HFFD-induced NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Consistently, KD reduced inflammation stimulated by LPS in THP-1 cells via suppressing the NF-κB/NLRP3 pathway. Furthermore, it prevented the activation of LX-2 cells directly, by inhibiting the proliferation stimulated by TGF-ß1, and indirectly, by inactivating the NLRP3 inflammasome in macrophages. CONCLUSION: For the first time, the practical improvement of NASH by KD was revealed. Our study found that KD exerted its alleviative effects on NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Given its hepatoprotective and nontoxic properties, KD has the potential to be a novel and effective drug to treat NASH.

Hub-collision avoidance and leaf-node options algorithm for fractal dimension and renormalization of complex networks.

The box-covering method plays a fundamental role in the fractal property recognition and renormalization analysis of complex networks. This study proposes the hub-collision avoidance and leaf-node options (HALO) algorithm. In the box sampling process, a forward sampling rule (for avoiding hub collisions) and a reverse sampling rule (for preferentially selecting leaf nodes) are determined for bidirectional network traversal to reduce the randomness of sampling. In the box selection process, the larger necessary boxes are preferentially selected to join the solution by continuously removing small boxes. The compact-box-burning (CBB) algorithm, the maximum-excluded-mass-burning (MEMB) algorithm, the overlapping-box-covering (OBCA) algorithm, and the algorithm for combining small-box-removal strategy and maximum box sampling with a sampling density of 30 (SM30) are compared with HALO in experiments. Results on nine real networks show that HALO achieves the highest performance score and obtains 11.40%, 7.67%, 2.18%, and 8.19% fewer boxes than the compared algorithms, respectively. The algorithm determinism is significantly improved. The fractal dimensions estimated by covering four standard networks are more accurate. Moreover, different from MEMB or OBCA, HALO is not affected by the tightness of the hubs and exhibits a stable performance in different networks. Finally, the time complexities of HALO and the compared algorithms are all O(N2), which is reasonable and acceptable.

The complete mitochondrial genome of Formosania galericula (Cypriniformes: Gastromyzontidae).

This study determined the complete mitochondrial genome of Formosania galericula (Cypriniformes: Gastromyzontidae) from Zhejiang, China, for the first time. The complete mitochondrial genome of F. galericula was sequenced to be 16,555 bp in length. The genome contained 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs, two central non-coding regions (the control region and the origin of light strand replication), identical to most other vertebrates. Phylogenetic analysis highly supported that F. galericula was close to Crossostoma lacustre and the genus Vanmanenia fish. However, F. galericula was not firstly clustered with Formosania chenyiyui but after the genus Vanmanenia fish. These data would explain the evolutionary mechanisms and biogeography of the family Gastromyzontidae and is helpful for the conservation of genetics and stock evaluation for F. galericula.

Effectiveness of montelukast for uremic pruritus in hemodialysis patients: A protocol for systematic review and meta-analysis.

BACKGROUND: Uremic pruritus (UP) is a common and tormenting symptom in end-stage renal disease patients undergoing maintenance hemodialysis. An increasing number of studies have been published in recent years to support the effectiveness of montelukast for UP. We will conduct a comprehensive systematic review and meta-analysis to evaluate effectiveness of montelukast for UP in hemodialysis patients. METHODS: The following electronic databases were searched: Pubmed, Embase, Web of Science, Cochrane Library, the China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database. The range of publication time was from the inception of the database to December 2020. Two reviewers will independently conduct article selection, data collection, and assessment of risk of bias. Any disagreement will be resolved by discussion with the third reviewer. Meta-analysis will be performed by Review Manager 5.3. The Cochrane Collaboration tool will be used to assess the risk of bias. RESULTS: This study will provide a systematic synthesis of current published data to explore the effectiveness of montelukast for UP in hemodialysis patients. CONCLUSIONS: This systematic review and meta-analysis will provide clinical evidence for the effectiveness of montelukast for UP in hemodialysis patients and inform our understanding of the value of montelukast in improving pruritus symptoms. This study will help clinicians, patients, and policy makers to make better decisions regarding the appropriate role of montelukast as a part of patient management routines. STUDY REGISTRATION NUMBER: INPLASY2020100043.

Didymocarpus lobulatus (Gesneriaceae), a new species from Zhejiang Province, East China.

Didymocarpus lobulatus, a new species endemic to Zhejiang province, eastern China, is described and illustrated with photographs. The new species is morphologically similar to D. heucherifolius, D. cortusifolius and D. salviiflorus in leaf morphology, but can be easily distinguished by a combination of characters, including the shape of bracts, calyx and calyx lobes.

Newly identified viral genomes in pangolins with fatal disease.

Epizootic pathogens pose a major threat to many wildlife species, particularly in the context of rapidly changing environments. Pangolins (order Pholidota) are highly threatened mammals, in large part due to the trade in illegal wildlife. During July to August 2018 four sick wild pangolins (three Manis javanica and one Manis pentadactyla) exhibiting a variety of clinical symptoms were rescued by the Jinhua Wildlife Protection Station in Zhejiang province, China. Although three of these animals died, fortunately one recovered after 2 weeks of symptomatic treatment. Using meta-transcriptomics combined with reverse transcription polymerase chain reaction (RT-PCR), we identified two novel RNA viruses in two of the dead pangolins. Genomic analysis revealed that these viruses were most closely related to pestiviruses and coltiviruses, although still highly genetically distinct, with more than 48 and 25 per cent sequence divergence at the amino acid level, respectively. We named these Dongyang pangolin virus (DYPV) and Lishui pangolin virus (LSPV) based on the sampling site and hosts. Although coltiviruses (LSPV) are known to be transmitted by ticks, we found no evidence of LSPV in ticks sampled close to where the pangolins were collected. In addition, although DYPV was present in nymph ticks (Amblyomma javanense) collected from a diseased pangolin, they were not found in the local tick population. Epidemiological investigation revealed that both novel viruses might have been imported following the illegal international trade of pangolins. Hence, these data indicate that illegal wildlife trafficking not only threatens the status of pangolin populations, but may also spread epizootic pathogens.

Refreshing Piezoelectrics: Distinctive Role of Manganese in Lead-Free Perovskites.

Driven by an ever-growing demand for environmentally compatible materials, the past two decades have witnessed the booming development in the field of piezoelectrics. To maximally explore the potential of lead-free piezoelectrics, chemical doping could be an effective approach, referenced from tactics adopted in lead-based piezoelectrics. Herein, we reveal the distinct role of manganese in a promising lead-free perovskite (K, Na)NbO3 (denoted by KNN) in comparison to that in market-dominating lead-based counterparts [Pb(Zr, Ti)O3, PZT]. In contrast to the scenario in PZT, manganese doping in KNN results in tremendously improved piezoelectric coefficient d33 by nearly 200%, whereas the same doping species in PZT deteriorates the d33 down to less than 30% of its original value. The result is rationalized from macroscopic and local electrical characterizations down to atomic-scale visualization. This study demonstrates that there is enormous space to further enhance piezoelectricity in lead-free systems because the chemical doping effect may completely differ in lead-containing and lead-free perovskites.

Predictive role of CHADS2 and CHA2DS2-VASc scores on stroke and thromboembolism in patients without atrial fibrillation: a meta-analysis.

OBJECTIVE: CHA2DS2-VASc is the extension of the CHADS2 score developed by Birmingham 2009. This risk stratification schema is often used in clinical setting when considering additional risk factors for developing stroke in AF patients. However, its role in the non-AF population is unknown. This study was designed to evaluate the accuracy of the CHADS2 and the CHA2DS2-VASc scoring systems. METHODS: Studies designed for CHADS2 and CHA2DS2-VASc score in stratifying the risks for stroke development in non-AF patients were included. RESULTS: Among the 114 studies identified, six trials were chosen finally and included for meta-analysis. The pooled diagnostic odds ratio (DOR) for CHADS2 and CHA2DS2-VASc was 2.86 (95% CI =1.83-4.28) and 2.80 (95% CI =1.83-4.28), respectively. CHA2DS2-VASc score was of better sensitivity than CHADS2 score (0.920 vs. 0.768). However, both scores were showed to have inherent heterogeneity and poor specificity. CONCLUSIONS: Though having good diagnostic accuracy, the clinical application of the CHADS2 and CHA2DS2-VASc scores in predicting risk of stroke development in non-AF patients still needs further validation. Key message The overall diagnostic accuracy of CHADS2 and CHA2DS2-VASc in stroke-risk stratification was good in patients with non-atrial fibrillation.

Pulse pressure as an independent predictor of stroke: a systematic review and a meta-analysis.

BACKGROUND: Recent evidence suggests that pulse pressure (PP) is a strong cardiovascular diseases' risk factor. We systematically evaluated all relevant studies to determine whether PP can be used as an independent predictor of stroke and mortality. METHODS AND RESULTS: A meta-analysis was performed by searching the published literature using MEDLINE, Cochrane and Google Scholar databases up to December 15, 2015. We measured the effect size expressed by hazard ratio (HR) and 95 % confidence interval (95 % CI). Eleven publications were included in the analysis. Pooled results demonstrated that 10 mmHg increase in PP was associated with increased risk of stroke occurrence (pooled HR 1.046, 95 % CI 1.025-1.068, P < 0.001). Additionally, systolic blood pressure (SBP) (pooled HR 1.053, 95 % CI 1.033-1.073, P < 0.001) and diastolic blood pressure (DPB) (pooled HR 1.056, 95 % CI 1.038-1.074, P < 0.001) were found to be significant predictors for stroke. We did not find a significant association between PP and all-cause mortality (pooled HR 1.022, 95 % CI 0.983-1.063, P = 0.270). We found SBP (pooled HR 1.008, 95 % CI 1.002-1.014, P = 0.012), but not DBP (pooled HR 1.023, 95 % CI 0.964-1.085, P = 0.451) to be significantly associated with all-cause mortality. CONCLUSIONS: Current data confirms that PP is an independent risk factor for stroke but is not a predictor of mortality.

[Effect of Chuanhuang No. 1 recipe on renal function and micro-inflammation in phase 3 chronic kidney disease patients].

OBJECTIVE: To observe the effect of Chuanhuang No.1 Recipe (CHR) on renal function and micro-inflammation in phase 3 chronic kidney disease (CKD) patients. METHODS: Totally 60 phase 3 CKD patients were randomly assigned to the treatment group (treated by CHR) and the control group (treated by Losartan Potassium), 30 in each group. All patients received basic treatment. Patients in the treatment group took CHR decoction, 400 mL each time, one dose per day, while those in the control group took Losartan Potassium, 50-100 mg per day. All medication lasted for 24 weeks. Changes of serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), serum uric acid (UA), 24 h urinary protein excretion (24 h U-pro), urinary microalbumin (U-Alb), high-sensitivity C-reactive protein (hs-CRP), serum tumor necrosis factor (TNF)-alpha, and serum IL-6 were detected and compared before and after treatment. Efficacy was also compared. RESULTS: Compared with before treatment, SCr and BUN significantly decreased in the treatment group (P<0.05, P<0.01); eGFR in- creased (P<0.05). Only UA obviously decreased in the control group (P<0.05), but with no obvious change in SCr, BUN, or eGFR. Compared with before treatment, 24 h U-pro decreased after treatment in the treatment group (P<0.05), but with less decreased level when compared with the control group. U- Alb was also significantly decreased in the control group (P<0.01). There was statistical difference in 24 h U-pro and U-Alb between the two groups after treatment (P<0.05). Compared with before treatment, hs-CRP obviously decreased after treatment in the two groups, but serum levels of TNF-alpha and IL-6 obviously decreased only in the treatment group (P<0.05). The total effective rate was obviously higher in the treatment group than in the control group (70.00% vs. 43.33%, P<0.01). CONCLUSION: CHR could efficiently improve the renal function of phase 3 CKD patients and alleviate the micro-inflammation.

Dialysis method alters the expression of microRNA-33a and its target genes ABCA1, ABCG1 in THP-1 macrophages.

Atherosclerosis and accompanying cardiovascular disease are the first causes of mortality in patients undergoing maintenance hemodialysis. Anti-atherosclerotic effects of hemodiafiltration (HDF) have been reported. Our study aimed to investigate the effect of serum derived from a healthy group (n = 23), before and after hemodialysis (HD) therapy (n = 23), and before and after HDF therapy (n = 17) on the expression of microRNA-33a and its target genes adenosine triphosphate-binding cassette transporter A1,G1 (ABCA1, ABCG1) in THP-1 macrophages. Meanwhile, blood lipids and high-sensitivity C-reactive protein (hs-CRP) were measured in these groups. Our data showed that the expression of miRNA-33a was lower (P < 0.05) and ABCA1 and ABCG1 were higher (P < 0.05) in the healthy group than pre-HD and pre-HDF. miR-33a was significantly decreased (P < 0.05) but ABCA1, ABCG1 was significantly increased (P < 0.05) in post-HDF compared with pre-HDF, while these parameters in pre- and post- HD groups did not show any significant change (P > 0.05). High density lipoprotein cholesterol (HDL-C) was higher and hs-CRP was lower in the healthy group than pre-HD and pre-HDF groups. Moreover, a significant increase of HDL-C (P < 0.05) and decrease (P < 0.05) of hs-CRP was shown in post-HDF compared with pre-HDF, but HD appeared to have no significant change in these subjects. HDF therapy can downregulate miR-33a expression, and then result in ABCA1, ABCG1 upregulation and an increase in circulating HDL-C, leading to a possible anti-atherosclerosis effect to some extent.