Occult and Overt HBV Co-Infections Independently Predict Postoperative Prognosis in HCV-Associated Hepatocellular Carcinoma

Objective and Background

The roles of chronic hepatitis B virus (HBV) co-infection (CI) in carcinogenesis of hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) remained controversial. To gain new insights into this issue, we investigated the postoperative prognostic value of HBVCI in HCV-associated HCC.

Methods

A study cohort of 115 liver tissues obtained from the noncancerous parts of surgically removed HCV-associated HCCs were subjected to virological analysis in a tertiary care setting. Assayed factors included clinicopathological variables, tissue amounts of viral genomes, genotypic characterization of viruses, as well as the presence of overt (serum HBsAg positive) or occult (serum HBsAg negative but tissue HBV-DNA positive) HBVCI. Cox proportional hazard model was used to estimate postoperative survivals.

Results

Of the 115 patients, overt and occult HBVCIs were detected in 35 and 16 patients, respectively. Multivariate analysis revealed that tumor size >3 cm (adjusted hazard ratio (AHR), 2.079 [95% confidence interval, 1.149∼3.761]), alpha-fetoprotein >8 ng/mL (AHR, 5.976 [2.007∼17.794]) albumin <4 g/dL(AHR, 2.539 [1.399∼4.606]), ALT >50 U/L (AHR,1.086 [1.006∼1.172]), presence of occult HBVCI (AHR, 2.708 [1.317∼5.566]), and absence of overt HBVCI (AHR, 2.216 [1.15∼4.269]) were independently associated with unfavorable disease-free survival. Patients with occult HBVCI had a shorter disease-free (P = 0.002), a shorter overall survival (P = 0.026), a higher bilirubin level (P = 0.003) and a higher prevalence of precore G1896A mutation (P = 0.006) compared with those with overt HBVCI.

Conclusion

Occult and overt HBVCI served as independent predictors for postoperative survival in HCV-associated HCC.     

无偿献血者中隐匿性乙型肝炎病毒感染及表面抗原突变分析

采用多种免疫学检测和核酸检测相结合的方法调查了我国南方某城市无偿献血者中隐匿性乙型肝炎病毒(HBV)感染的存在情况。结果在9023例乙肝表面抗原(HBsAg)阴性的无偿献血者中,共发现17例HBV DNA阳性,隐匿性HBV感染者的发生率为0.19%(95%CI:0.11～0.30%)。序列分析显示其中6例在HBsAg"a"表位(aa124～aa147)存在不同程度氨基酸突变,突变发生率为42.9%(6/14,有3例未扩增出"a"表位片段序列),G145R突变是该地区隐匿性HBV携带者中发生频率最高的突变(4/6,66.7%)。隐匿性HBV感染者中基因型C的比例(10/17)显著高于HBsAg阳性的HBV感染者(0/15,P<0.01)。     

Leukocyte Lactate Dehydrogenase Changes as an Indicator of Infection Prior to Overt Symptoms

Lactic acid dehydrogenase (LDH) concentration of rabbit serum and leukocytes was followed during the course of an acute infection with Diplococcus pneumoniae. Control values were obtained prior to infection, and again 4, 24, and 48 hr later. LDH isozymes were characterized by acrylamide gel electrophoresis and quantitated by densitometry. An increase in serum LDH was observed as early as 4 hr after infection. These levels returned to normal in 24 hr and rose again 48 hr after infection. The LDH level of leukocytes, from 10 of 12 infected rabbits, rose rapidly during the 24-hr period after exposure. The levels were two to three times the original preinoculation level for that animal. In six of these rabbits, this LDH elevation occurred 4 hr after inoculation and preceded the onset of fever. Change in the type of leukocyte did not account for the increase in cellular LDH. All infected rabbits showed approximately the same increase in polymorphonuclear leukocytes, but not all developed comparable increases in LDH. The isozyme patterns obtained, when defined amounts of enzyme were applied to the gel for electrophoresis, were characterized for the most part by a three-enzyme pattern. Increasing amounts of enzyme occasionally revealed a fourth, more cathodal, enzyme. The more cathodic enzymes appear to be the most responsive when sudden shifts in enzyme concentration occur within the cell.     

The Intracellular HBV DNAs as Novel and Sensitive Biomarkers for the Clinical Diagnosis of Occult HBV Infection in HBeAg Negative Hepatocellular Carcinoma in China

This study aimed to investigate the virological status in liver (both tumor and adjacent non-tumor tissue), the clinical features and the contribution of occult HBV infection (OBI) to postoperative prognosis in HBeAg-negative(−) hepatocellular carcinoma (HCC) patients in China. Using quantitative TaqMan fluorescent real-time PCR assays, HBV covalently closed circular DNA (cccDNA) and total DNA (tDNA) were both quantified in 11 (HBsAg(−)) and 57 (HBsAg-positive(+)) pairs of tumor tissue (TT) and adjacent non-tumor tissue (ANTT) obtained from HBeAg(−) HCC patients who received no antiviral treatment and were negative for anti-HCV before surgical treatment. Of 11 HBsAg(−) patients, 36% were with HBsAb(+) HBeAb(+) HBcAb(+). However, only 9% of the HBsAg(−) patients were HBsAb(−) HBeAb(+) HBcAb(+), which accounted for the majority (93%) in the HBsAg(+) group. TT and ANTT HBV tDNAs in 11 HCC patients with HBsAg (−) and HBeAg (−) were all detectable. HBV cccDNA and tDNA were all lower in the HBsAg(−) group than those in the HBsAg(+) group. By Kaplan-Meier analysis, patients with OBI were associated with a lower risk of cirrhosis and better overall survival (OS). The intracellular HBV DNAs, such as HBV cccDNA and tDNA are valuable biological markers for the diagnosis of occult HBV infection in HCC patients. This would assist the clinical implementation of a more personalized therapy for viral re-activation control and improve the survival rate of OBI patients.     

青海地区献血者HBV感染隐匿风险与基因型分析

目的:探讨青海地区献血者乙型肝炎病毒(hepatitis b virus,HBV)感染隐匿风险与基因型的相关性。方法:采用回顾性研究方法,选择2014年2月-2018年1月在我院进行无偿献血的青海地区人群750例,采用聚合酶链式反应-限制性内切酶片段法(PCR-RFLP)检测HBV DNA基因的多态性,并进行HBV感染隐匿风险分析。结果:在750例人群中,检出HBV隐匿性感染8例,检出率为1.1%,其中窗口期感染3例,一过性感染5例;基因C型6例,基因B型2例,基因B型患者的都为窗口期感染,核酸定量都≤20 IU/m L,与基因C型患者对比差异有统计学意义(P0.05)。多因素Logistic回归分析显示基因C型、核酸定量、家属病史、吸烟为导致HBV隐匿性感染的独立危险因素(P0.05)。结论:青海地区献血者HBV感染隐匿风险相对比较低,多为基因C型,基因C型为导致HBV隐匿性感染的独立危险因素。     

H2AX May Function as an Anchor to Hold Broken Chromosomal DNA Ends in Close Proximity

The histone H2A variant, H2AX, is a core component of chromatin that is phosphorylated in chromatin flanking DNA double strand breaks (DSBs). Here, we summarize H2AX functions and outline a specific "anchoring" model, that can explain the translocation prone phenotype of H2AX-deficient and H2AX/p53-deficient mice. We also discuss how this model of H2AX function could account for some aspects of the genomic instability and cancer prone human phenotypes associated with Ataxia Telangiectasia (AT), Nijmegen Breakage Syndrome (NBS), Ataxia Telangiectasia Like Disorder (ATLD), and Bloom's Syndrome (BS).     

The Viable But Nonculturable State of Ralstonia solanacearum May Be Involved in Long-Term Survival and Plant Infection

The role of the dormant-like viable but nonculturable (VBNC) condition in the etiology of bacterial infection was examined using a plant system. The plant-pathogenic bacterium Ralstonia solanacearum was first shown to enter into the VBNC state both in response to cupric sulfate when in a saline solution and when placed in autoclaved soil. To determine if the VBNC condition is related to pathogenesis, the physiological status of bacteria recovered from different regions of inoculated tomato plants was determined at different stages of infection. The fraction of in planta bacteria that were VBNC increased during infection and became greater than 99% by the late stage of disease. The possibility that soil-dwelling VBNC bacteria may resuscitate and infect plants was also examined. When tomato seeds were germinated in sterile soil that contained VBNC but no detectable culturable forms of R. solanacearum cells, resuscitation was observed to occur in soil adjacent to plant roots; these resuscitated bacteria were able to infect plants. This is the first report of R. solanacearum entering the VBNC state and of resuscitation of any VBNC plant-pathogenic bacteria and provides evidence that the VBNC state may be involved in explaining the persistent nature of some infections.     

Sheep May Not Be an Important Zoonotic Reservoir for Cryptosporidium and Giardia Parasites

Little is known of the prevalence of Cryptosporidium and Giardia parasites in sheep and the genotypes that they harbor, although potentially sheep may contribute significantly to contamination of watersheds. In the present study, conducted in Western Australia, a total of 1,647 sheep fecal samples were screened for the presence of Cryptosporidium and Giardia spp. using microscopy, and a subset (n = 500) were screened by PCR and genotyped. Analysis revealed that although both parasites were detected in a high proportion of samples by PCR (44% and 26% for Giardia and Cryptosporidium spp., respectively), with the exception of one Cryptosporidium hominis isolate, the majority of isolates genotyped are not commonly found in humans. These results suggest that the public health risk of sheep-derived Cryptosporidium and Giardia spp. in catchment areas and effluent may be overestimated and warrant further investigation.     

Specific Amino Acid Substitutions in the S Protein Prevent Its Excretion In Vitro and May Contribute to Occult Hepatitis B Virus Infection

Occult hepatitis B virus (HBV) infection (OBI) is defined as low plasma level of HBV DNA with undetectable HBV surface antigen (HBsAg) outside the preseroconversion window period. The mechanisms leading to OBI remain largely unknown. The potential role of specific amino acid substitutions in the S protein from OBI in HBsAg production and excretion was examined in vitro. HBsAg was quantified in culture supernatants and cell extracts of HuH-7 cells transiently transfected with plasmids containing the S gene of eight HBsAg⁺ controls and 18 OBI clones. The intracellular (IC)/extracellular (EC) HBsAg production ratio was ∼1.0 for the majority of controls. Three IC/EC HBsAg patterns were observed in OBI strains clones: pattern 1, an IC/EC ratio of 1.0, was found in 5/18 OBI clones, pattern 2, detectable IC but low or undetectable EC HBsAg (IC/EC, 7.0 to 800), was found in 6/18 OBIs, and pattern 3, low or undetectable IC and EC HBsAg, was found in 7/18 clones. Intracellular immunofluorescence staining showed that in pattern 2, HBsAg was concentrated around the nucleus, suggesting retention in the endoplasmic reticulum. The substitution M75T, Y100S, or P178R was present in 4/6 pattern 2 OBI clones. Site-directed-mutagenesis-corrected mutations reversed HBsAg excretion to pattern 1 and, when introduced into a control clone, induced pattern 2 except for Y100S. In a control and several OBIs, variants of a given quasispecies expressed HBsAg according to different patterns. However, the P178R substitution present in all cloned sequences of two OBI strains may contribute significantly to the OBI phenotype.     

Hydroxyapatite-Coated Sillicone Rubber Enhanced Cell Adhesion and It May Be through the Interaction of EF1β and γ-Actin

Silicone rubber (SR) is a common soft tissue filler material used in plastic surgery. However, it presents a poor surface for cellular adhesion and suffers from poor biocompatibility. In contrast, hydroxyapatite (HA), a prominent component of animal bone and teeth, can promote improved cell compatibility, but HA is an unsuitable filler material because of the brittleness in mechanism. In this study, using a simple and economical method, two sizes of HA was applied to coat on SR to counteract the poor biocompatibility of SR. Surface and mechanical properties of SR and HA/SRs confirmed that coating with HA changes the surface topology and material properties. Analysis of cell proliferation and adhesion as well as measurement of the expression levels of adhesion related molecules indicated that HA-coated SR significantly increased cell compatibility. Furthermore, mass spectrometry proved that the biocompatibility improvement may be related to elongation factor 1-beta (EF1β)/γ-actin adjusted cytoskeletal rearrangement.     

Fecal Occult Blood and Fecal Calprotectin as Point-of-Care Markers of Intestinal Morbidity in Ugandan Children with Schistosoma mansoni Infection

Background

Calprotectin is a calcium-binding cytoplasmic protein found in neutrophils and increasingly used as a marker of bowel inflammation. Fecal occult blood (FOB) is also a dependable indicator of bowel morbidity. The objective of our study was to determine the applicability of these tests as surrogate markers of Schistosoma mansoni intestinal morbidity before and after treatment with praziquantel (PZQ).

Methods

216 children (ages 3–9 years old) from Buliisa District in Lake Albert, Uganda were examined and treated with PZQ at baseline in October 2012 with 211 of them re-examined 24 days later for S. mansoni and other soil transmitted helminths (STH). POC calprotectin and FOB assays were performed at both time points on a subset of children. Associations between the test results and infection were analysed by logistic regression.

Results

Fecal calprotectin concentrations of 150–300 µg/g were associated with S. mansoni egg patent infection both at baseline and follow up (OR: 12.5 P = 0.05; OR: 6.8 P = 0.02). FOB had a very strong association with baseline anemia (OR: 9.2 P = 0.03) and medium and high egg intensity schistosomiasis at follow up (OR: 6.6 P = 0.03; OR: 51.3 P = 0.003). Both tests were strongly associated with heavy intensity S. mansoni infections. There was a significant decrease in FOB and calprotectin test positivity after PZQ treatment in those children who had egg patent schistosomiasis at baseline.

Conclusions

Both FOB and calprotectin rapid assays were found to correlate positively and strongly with egg patent S. mansoni infection with a positive ameloriation response after PZQ treatment indicative of short term reversion of morbidity. Both tests were appropriate for use in the field with excellent operational performance and reliability. Due to its lower-cost which makes its scale-up of use affordable, FOB could be immediately adopted as a monitoring tool for PC campaigns for efficacy evaluation before and after treatment.     

Pyrrolidine Dithiocarbamate Inhibits Herpes Simplex Virus 1 and 2 Replication,and Its Activity May Be Mediated through Dysregulation of the Ubiquitin-Proteasome System

Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF-κB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus, and influenza virus. In this paper, we report that PDTC could inhibit the replication of herpes simplex virus 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediate early (IE) and late (membrane protein gD) genes and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn²⁺. Although PDTC could potently block reactive oxygen species (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting the mitogen-activated protein kinase (MAPK) pathway activation induced by viral infection that was vital for the virus''s propagation. We found that PDTC modulated cellular ubiquitination and, furthermore, influenced HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced PML stability in the nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of the cellular ubiquitin-proteasome system (UPS).     

Colon Cancer-Specific Antigen-2 May Be Used as a Detecting and Prognostic Marker in Colorectal Cancer: A Preliminary Observation

Background

A specific and sensitive serum marker for colorectal cancer (CRC) detection and surveillance is central to effective treatment. It was preliminarily reported that some nuclear matrix proteins may be served as a specific blood based marker for colon cancer. The objective of this study is to evaluate the value of serum CCSA-2 detection in diagnosis, prognostic estimation and surveillance for CRC.

Method

Serum CCSA-2 protein was measured in 181 various patient populations and 20 healthy donors before surgery. For 106 CRC patients, it was also measured on day 7 after surgery. Among them, 49 CRC patients'' CCSA-2 protein were measured during the follow-up period according to NCCN Guideline.

Results

The serum CCSA-2 concentration in CRC patients was significantly higher than which in other patients and healthy individuals. Serum CCSA-2, at the cut-off point of 64.10 ng/mL, had a sensitivity of 98.10% and a specificity of 97.90% in separating CRC populations from all other individuals. The CCSA-2 assay was significantly more sensitive than CEA and CA19-9 assay in CRC detection. After surgery, the serum CCSA-2 level of CRC patients declined significantly, but it rebounded to a high level when recurrences occurred. The pre-operative serum CCSA-2 level in patients who had a relapse within the follow-up period was significantly higher than which in patients without relapse.

Conclusions

Serum CCSA-2 not only may be a potential biomarker using in screening and surveillance of CRC, but also may be an independent prognostic marker for CRC patients. Further clinical trials need to be performed in a larger population of patients to ulteriorly confirm these results.     

As Well as Physiological States, Pathological States and Therapeutical Problems May Be a Gushing Spring for Biological Theory - and Conversely

New class of therapies, including bipolar therapies (BPT) and paradoxical unipolar therapies (PUT) were firstly proposed in relation to a clinical insight and to some results of biological investigations, then they gave rise to mathematical modeling which brought a justification of these therapies, at least from a theoretical point of view. After recalling the mathematical model for the regulation of agonistic antagonistic couples, and reporting the fundamental types of control simulation by means of it, we point out the validity of therapeutical applications inferred from this model. These therapy modalities, including BPT and PUT, now concern the following diseases: astrocytomas, epilepsia and trials on multiple sclerosis. Even if such attempts are in their early stage, noticeably for the last case where biological changes have mainly been studied, it seems that a large span of treatments is open to BPT and PUT. Improvement of these techniques in the future depends, in our opinion, on a parallel working on the dynamics of the mathematical model and the dynamics, perceived by clinical insight and confirmed by biological investigations, of the body reactions to such strategies. Justification of BPT and PUT was given, by resorting to the notion of pathological homeostasis which, too often, intervenes in order to nullify the effects of unilateral (not paradoxical) therapies. This research has elicited some therapies which use two agents with antagonistic effects or only an agent with effects similar to the agent already in excess in the body - in both cases at nearly physiological doses.     

管家基因GAPDH在肿瘤与衰老组织中作为内参应慎重

甘油醛-3-磷酸脱氢酶（glyceraldehyde 3-phosphate dehydrogenase,GAPDH）是糖酵解过程中的一个酶,编码该酶的基因为管家基因,几乎在所有组织中呈高水平、恒定表达,常用作蛋白质、RNA、DNA等分子生物学相关实验的标准化内参。但近年来,GAPDH作为内参受到质疑,特别是在肿瘤组织、衰老组织。大量研究证实,GAPDH在多种肿瘤中表达上调,衰老的骨骼肌中下调。其中GAPDH在肿瘤中的高表达可能与肿瘤的侵袭性转移和细胞增殖相关。本文就GAPDH在肿瘤、衰老组织或细胞中的表达情况以及可能机制作一综述,旨在更全面地了解管家基因GAPDH在肿瘤与衰老组织、细胞中是否恒定表达,以便在研究中可以选择最优的内参做参照。     

Maternal Effects May Act as an Adaptation Mechanism for Copepods Facing pH and Temperature Changes

Acidification of the seas, caused by increased dissolution of CO₂ into surface water, and global warming challenge the adaptation mechanisms of marine organisms. In boreal coastal environments, temperature and pH vary greatly seasonally, but sometimes also rapidly within hours due to upwelling events. We studied if copepod zooplankton living in a fluctuating environment are tolerant to climate change effects predicted for 2100, i.e., a temperature increase of 3°C and a pH decrease of 0.4. Egg production of the copepod Acartia sp. was followed over five consecutive days at four temperature and pH conditions (17°C/ambient pH; 17°C/low pH; 20°C/ambient pH; 20°C/low pH). Egg production was higher in treatments with warmer temperature but the increase was smaller when copepods were simultaneously exposed to warmer temperature and lowered pH. To reveal if maternal effects are important in terms of adaptation to a changing environment, we conducted an egg transplantation experiment, where the produced eggs were moved to a different environment and egg hatching was monitored for three days. When pH changed between the egg production and hatching conditions, it resulted in lower hatching success, but the effect was diminished over the course of the experiment possibly due to improved maternal provisioning. Warmer egg production temperature induced a positive maternal effect and increased the egg hatching rate. Warmer hatching temperature resulted also in earlier hatching. However, the temperature effects appear to be dependent on the ambient sea temperature. Our preliminary results indicate that maternal effects are an important mechanism in the face of environmental change.     

A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients

We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along V_H4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS⁺ antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS⁺ rhAbs to bind brain tissue antigens. AGS⁺ rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS⁺ rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS⁺ antibodies from early and established RRMS patients, as AGS⁺ antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS⁺ antibodies that bind to these cell types may be an indicator of gray matter-directed autoimmunity in early and established RRMS patients.     

Identification of Wb123 as an Early and Specific Marker of Wuchereria bancrofti Infection

Background

The current antibody tests used for monitoring in lymphatic filariasis (LF) elimination programs suffer from poor specificity because of the considerable geographical overlap with other filarial infections such as Loa loa (Ll), Onchocerca volvulus (Ov), and Mansonella perstans (Mp).

Methods

Using bioinformatics to assemble into contigs 2048 expressed sequence tags (ESTs) from the L3 infective larvae of W. bancrofti (Wb), these were next assessed for homology to known proteins and nucleotides and to similar assemblies of L3 larval ESTs of B. malayi (Bm – n = 5068), Ov (n = 4166), and Ll (n = 3315). Nineteen potential L3- and Wb- and/or Bm-specific antigens were identified. Sixteen of the 19 antigens could be expressed as fusion proteins with Renilla luciferase (Ruc); these were used in a rapid Luciferase Immunopreciptation System (LIPS) assay.

Results

One of the 16 expressed antigens (Wb123) was both highly immunogenic and specific for Wb. Using Wb123-based IgG and IgG4 LIPS assays on well-defined sera from normal North Americans and those infected exclusively with intestinal helminths, we could detect all of the Wb-infected individuals (from diverse geographic regions) with 100% sensitivity and 100% specificity. Using sera from exclusively Ll-infected, Ov-infected Mp-infected or Bm-infected subjects as the negative comparator, the sensitivities were between 98–100% and the specificities ranged between 84–100% (for IgG anti-Wb123) and between 98–100% (for IgG4 anti-Wb123). Blinded assessments using panels of sera from various Wb-, Bm- or non-Wb helminth-infected subjects demonstrated equally high degrees of sensitivity and specificity.

Significance

We have identified a Wb-encoded antigen that can be used both as a rapid, high throughput tool to diagnose individual Wb infections and as a sensitive method for early detection of recrudescent infections in areas of control and for mapping new areas of Wb transmission.     

Both Loved and Feared: Third Party Punishers Are Viewed as Formidable and Likeable,but These Reputational Benefits May Only Be Open to Dominant Individuals

Third party punishment can be evolutionarily stable if there is heterogeneity in the cost of punishment or if punishers receive a reputational benefit from their actions. A dominant position might allow some individuals to punish at a lower cost than others and by doing so access these reputational benefits. Three vignette-based studies measured participants'' judgements of a third party punisher in comparison to those exhibiting other aggressive/dominant behaviours (Study 1), when there was variation in the success of punishment (Study 2), and variation in the status of the punisher and the type of punishment used (Study 3). Third party punishers were judged to be more likeable than (but equally dominant as) those who engaged in other types of dominant behaviour (Study 1), were judged to be equally likeable and dominant whether their intervention succeeded or failed (Study 2), and participants believed that only a dominant punisher could intervene successfully (regardless of whether punishment was violent or non-violent) and that subordinate punishers would face a higher risk of retaliation (Study 3). The results suggest that dominance can dramatically reduce the cost of punishment, and that while individuals can gain a great deal of reputational benefit from engaging in third party punishment, these benefits are only open to dominant individuals. Taking the status of punishers into account may therefore help explain the evolution of third party punishment.