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Koala (Phascolarctos cinereus) populations in southern Australia have a history of bottlenecks – earlier this century the species became extinct in South Australia, and almost so in Victoria. Subsequently large numbers of animals from island populations (founded from very few animals) have been translocated back to mainland sites and to other islands in the region. As part of a larger study of the genetic structure of koala populations in southern Australia, we have undertaken a survey of mitochondrial DNA restriction fragment length polymorphism (mtDNA-RFLP) variability. Genomic DNA from 91 koalas from five populations was examined using 23 restriction enzymes, and mtDNA fragments were detected using a domestic cat full-length mtDNA clone. Only one of the enzymes, TaqI, revealed polymorphism – a relatively low amount of variation compared with other mammals, although low mtDNA-RFLP variation has also been reported in Queensland koalas. French Island and populations established predominantly from French Island immigrant koalas, either directly or via other island populations, were indistinguishable by haplotype frequencies. The mtDNA data are thus consistent with the interpretation that the koala translocation programme has homogenized gene frequencies amongst those populations involved. South Gippsland is not recorded as having received translocated koalas directly, and has significantly different mtDNA-RFLP haplotype frequencies from all other populations examined. The fact that this distinction was not previously observed in nuclear gene frequencies may reflect predominantly male-mediated dispersal in koalas.

BACKGROUND: Despite the excellent total knee arthroplasty (TKA) results reported using traditional outcome measures, dissatisfaction rates of up to 30% are reported following surgery. Although several preoperative factors have been identified as possible predictors of satisfaction, there is conflicting evidence. Identification of dissatisfaction in the early postoperative assessment may therefore be an alternative consideration. METHODS: We examined the relationship between 12-month satisfaction, and early post-operative outcomes in a cohort of 486 TKA patients. Preoperative, and postoperative outcome measures at 3- and 12-months (Oxford knee score, pain score, SF12, and knee motion), were analysed and compared between patients who were satisfied and dissatisfied at 12-months following TKA. Mean scores, and postoperative change in scores were calculated. Postoperative outcomes were examined for correlation with satisfaction, and multivariate logistic regression models used to identify potential predictors of dissatisfaction. RESULTS: Overall satisfaction was 77.0%. No preoperative differences were observed between groups. Dissatisfaction was associated with worse postoperative status across all outcome measures (p

During knee arthroscopy, narrowness and tightness maybe encountered in the medial compartment that does not allow sufficient visualization or instrumentation. When this occurs, our team has found it helpful to perform a percutaneous clysis of the deep portion of the medial collateral ligament with a spinal needle. With the knee positioned in 10° to 20° of flexion and a valgus stress is applied. A spinal needle (18 Gauge) is passed percutaneously through the medial collateral ligament between the tibial plateau and undersurface of the medial meniscus. Several passes are made with the spinal needle with the bevel of the needle angled to selectively divide the fibers while keeping the medial collateral ligament under tension. Then with controlled valgus force, the medial compartment will progressively open allowing improved visualization to the posteromedial corner of the knee. This increase in space gives an enhanced visual field and further allows more room for arthroscopic instrumentation.

The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience

HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p, eLife digest Developing treatments or vaccines for HIV is challenging because the genetic makeup of the virus is constantly changing in an effort to outwit the human immune system. Moreover, the immune system is highly variable as a result of the long-standing co-evolution of humans and microbes. Each individual will try to oppose the invading virus in a unique way, forcing the virus to acquire specific mutations that can be interpreted as the genetic signature of this one-against-one battle. To explore the influence of co-evolution on HIV, Bartha et al. took samples of both human and viral genomes from 1071 individuals infected with HIV, the AIDS virus, and used genotyping and sequencing technology to obtain a comprehensive description of the genetic variation in both. Computational techniques were then used to search for links between variants in the human DNA sequences and variants in the viral sequences. The most common type of genetic variation found in the human genome is a single nucleotide polymorphism, or SNP for short: a SNP is produced when a single nucleotide – an A, C, G or T – is replaced by a different nucleotide. Bartha et al. found that SNPs within the human DNA sequences in their study were linked to variations in 48 amino acids in HIV. Moreover, all these SNPs were found within a group of genes known as the HLA (human leukocyte antigen) system, which encodes for proteins that play a vital role in the immune response. This work identified the areas of the human genome that put pressure on the AIDS virus, and the regions of the virus that serve to escape human control. The approach developed by Bartha et al. allows the interactions between a microbe and a human host to be studied by looking at the genome of the microbe and the genome of the infected person. It also differentiates host-induced mutations that limit the capacity of the virus to do harm from those that are tolerated by the pathogen. A similar strategy could be used to study other infectious diseases. DOI: http://dx.doi.org/10.7554/eLife.01123.002

Tigers and their close relatives (Panthera) are some of the world’s most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats’ hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species., Tigers are an endangered species and therefore understanding their genetic architecture could aid conservation efforts. Here, the authors report the first genome sequence of the Amur tiger and, through close species comparative genomic analysis, provide insight into the genome organization, evolutionary divergence and diversity of big cats.

Objectives: Effective treatment of Biceps-Labral (B-L) Complex lesions is predicated upon accurate diagnosis. Diagnostic algorithms include both physical examination and MRI. We sought to evaluate the contribution of MRI and physical examination to the accurate diagnosis of B-L Complex lesions. Methods: A retrospective review of 273 surgical cases of lesions of the B-L Complex was performed comparing the preoperative documented clinical "Three Pack" examination to the preoperative Radiologist's MRI reading in accurately predicting lesions of the B-L Complex seen at the time of surgery, and as documented by intraoperative photos and videos. After the completion of this retrospective review, an additional 145 patients(116 symptomatic, 29 matched controls) were enrolled in a prospective validation study of the "Three Pack" examination. All patients were examined independently and separately by three examiners without contamination: the senior surgeon, the sports medicine fellow, and the senior surgeon' s PA. Results were adjusted for order of examination.All B-L Complex Lesions were documented at surgery by digital photos and or video. Results: In the retrospective review, the MRI accurately described the labral tears found at surgery in only 45% of the cases. Of the documented biceps lesions, only 28% of the time was the biceps read on MRI as abnormal. When the preop ACT was positive, a positive"arthroscopic"ACT (where the biceps incarcerates between the humeral head and glenoid) or labral tear was noted in 88% of the cases. There were no cases where the preop ACT was negative and the "arthroscopic" ACT was positive. However, when the "arthroscopic"ACT was positive, 46% of the time there was no tear of the labrum. The average age of the patients with a positive "arthroscopic" ACT was 34 yo. In the subsequent prospective validation of the "Three Pack", The interobserver reliability for the "three pack" evaluation was quite strong with Kappa values between.700 to.850 for all tests, indicating substantial (.61-.80) to almost perfect (.81-1.00) agreement categories. This was in contrast to other "traditional" tests performed (Speed's, Yergason's, full and empty can tests), where only moderate agreement at best (.41-.60) was noted. Tenderness to BGP had a high sensitivity and specificity of.978 and.703 respectively for groove lesions; a positive throwing test had a moderate sensitivity of.694 and higher specificity of.745; the ACT (O'Brien Sign) had a very high sensitivity for labral tears and biceps incarceration,.897 and.914 respectively, with moderate specificities of.562 and.602 respectively. Seventy percent of patients had more than 1 site of pain and pathology confirmed at surgery. 88% of patients had a positive ACT in the symptomatic shoulder vs 11% in the unaffected shouder (and 18% of controls) for a p valueConclusion: The "Three Pack" Examination is a highly reliable approach for evaluating painful lesions of the B- L Complex, with strong interobserver reliability. This more comprehensive approach to the B-L complex is also important as many patients have more than one site of pain and pathology. A positive Active Compression Test appears to be a normal finding as well, seen in 18% of patients who have never had shoulder pain, and had never felt that pain before.

Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.

Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size., Author Summary Comparing the frequency differences between common DNA variants in disease-affected cases and in unaffected controls has been successful in uncovering the genetic component of multiple diseases. This approach is most effective when large samples of cases and controls are available. Here we combine information from multiple studies of HIV infected patients, including more than 6,300 HIV+ individuals, with data from 7,200 general population samples of European ancestry to test nearly 8 million common DNA variants for an impact on HIV acquisition. With this large sample we did not observe any single common genetic variant that significantly associated with HIV acquisition. We further tested 22 variants previously identified by smaller studies as influencing HIV acquisition. With the exception of a deletion polymorphism in the CCR5 gene (CCR5Δ32) we found no convincing evidence to support these previous associations. Taken together these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

Approximately one-third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base-pair insertion (8+ allele) at the 3′ end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8+ (the 3 allele). Significantly longer times to 1% and 0 1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8+8+ or 8+N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8+ and 3 (NN, 18%) showed the best outcomes overall. Thus, while SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so. Refereed/Peer-reviewed

Background Longer operation times, poorer patient outcomes and increased early post-operative complications are reasons cited for not undertaking Total Knee Arthroplasty (TKA) on morbidly obese patients. This study tests the hypothesis that there is no difference in intra-operative parameters between morbidly obese and non-obese patients, and no difference in patient outcome. Methods Intra-operative parameters, post-operative complications, patient outcomes and knee range of motion were compared between morbidly obese patients (BMI>40kg/m 2 ) and individually age and gender matched non-obese patients (BMI 2 ) undergoing cementless rotating platform TKA. Results Anaesthetic times and length of hospital stay were not significantly different between the morbidly obese and non-obese patients. Surgical time was significantly greater in morbidly obese patients. Improvements in patient outcomes following TKA were not significantly different between the morbidly obese and non-obese patients at early and short-term follow-up. Conclusions In contrast to previous studies, post-operative complication rates within three months of surgery and up to one year post-operatively were not significantly higher for morbidly obese patients. Level of evidence III

Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts clinical outcomes for patients with chronic myeloid leukemia. In this work, we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6-month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary, early intervention strategies can be based robustly just on the transcript level at 3 months. This trial was registered at www.clinicaltrials.gov as # NCT01460693.

The Cementless Oxford Unicompartmental Knee Replacement (OUKR) was developed to address problems related to cementation, and has been demonstrated in a randomised study to have similar clinical outcomes with fewer radiolucencies than observed with the cemented device. However, before its widespread use it is necessary to clarify contraindications and assess the complications. This requires a larger study than any previously published.We present a prospective multicentre series of 1000 cementless OUKRs in 881 patients at a minimum follow-up of one year. All patients had radiological assessment aligned to the bone–implant interfaces and clinical scores. Analysis was performed at a mean of 38.2 months (19 to 88) following surgery. A total of 17 patients died (comprising 19 knees (1.9%)), none as a result of surgery; there were no tibial or femoral loosenings. A total of 19 knees (1.9%) had significant implant-related complications or required revision. Implant survival at six years was 97.2%, and there was a partial radiolucency at the bone–implant interface in 72 knees (8.9%), with no complete radiolucencies. There was no significant increase in complication rate compared with cemented fixation (p = 0.87), and no specific contraindications to cementless fixation were identified.Cementless OUKR appears to be safe and reproducible in patients with end-stage anteromedial osteoarthritis of the knee, with radiological evidence of improved fixation compared with previous reports using cemented fixation.Cite this article: Bone Joint J 2013;95-B:181–7.

Eight papers arising from a colloquium on Warfare and Society in the Ancient Eastern Mediterranean held at the University of Liverpool, 13th June 2008.

The KK.Cg-A (y) /J (KK-A (y) ) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK-A (y) mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK-a/a controls, 26-week-old KK-A (y) mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK-A (y) mice also exhibited elevated serum BUN and reduced glomerular filtration, indicating that reduction in renal mass leads to more severe impairment in renal function. Glomerular hypertrophy and hypercellularity, mesangial matrix expansion, podocyte effacement, and basement membrane thickening were present in both binephric and uninephrectomized cohorts. Glomerular size was increased in both groups, but podocyte density was reduced only in the Unx animals. Consistent with functional and histological evidence of increased injury, fibrotic (fibronectin 1, MMP9, and TGF β 1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK-A (y) mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK-A (y) mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4 + T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele ( CKR5Δ32 ) was identified that is present at a frequency of ∼0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Δ32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

The incorporation of precise definitions for taxonomic units into wildlife legislation has necessitated the reevaluation of the taxonomy of endangered and threatened species. We used the subspecies recognition criteria proposed by Avise and Ball (1990) and O’Brien and Mayr (1991) to examine the infraspecific taxonomy of the leopard, Panthera pardus, a geographically widespread species with 27 currently recognized trinomial designations. Samples from named subspecies revealed appreciable genetic diversity using three molecular methods: allozymes, mitochondrial DNA restriction sites, and feline-specific minisatellites. Continental populations and subspecies from Africa and Asia possessed the highest amount of molecular genetic variation, whereas relatively lower amounts of diversity were present in island populations. Molecular data were analyzed using three phylogenetic methods (distance-matrix, maximum parsimony, and maximum likelihood) to resolve genetic differentiation below the species level The combined results revealed phylogenetic distinction of six geographically isolated groups of leopards: (1) African, (2) central Asian, (3) Indian, (4) Sri Lankan, (5) Javan, and (6) east Asian. Based on the combined molecular analyses and supporting morphological data (Miththapala 1992), u,e recommend that subspecific leopard taxonomy be revised to comprise eight subspecies: (1) P. p. pardus, Africa; (2) P. p. saxicolor, central Asia; (3) P. p. fusca, Indian subcontinent; (4) P. p. kotiya, Sri Lanka; (5) P. p. melas, Java; (6) P. p. orientalis, Amur; (7) P. p. japonensis, northern China; and (8) P. p. delacouri, southern China. In most cases, designated subspecies conform to historic geological barriers that would have facilitated allopatric genetic divergence. La incorporacion de definiciones precisas para unidades taxonomicas en legislacion de la vida silvestre ha necesitado de la re-evaluacion de la taxonomia de especies amenazadas y en peligo de extincion. Utilizamos los criterios de reconocimiento de subespecies propuestos por Avise y Ball (1990) y O’Brien y Mayr (1991) para examinar la taxonomia intraespecifica del leopardo Panthera pardus, una especie ampliamente dispersa con 27 designaciones trinomiales reconocidas. Muestras de supuestas subespecies revelaron una diversidad genetica apreciable, usando tres metodos moleculares: Alozimas, sitios de restriccion en ADN mitocondrial y minisatelites felino-especificos: Poblaciones continentales y subespecies de Africa y Asia poseen la mas alta cantidad de variacion genetica molecular, mientras que en poblaciones insulares estuvieron presentes cantidades relativamente bajas de diversidad. Los datos moleculares fueron analizados utilizando tres metodos filogeneticos (Matriz de distancia, maxima parsimonia y maxima proximidad) para resolver diferenciaciones geneticas por debajo del nivel de especie. Los resultados combinados revelaron la distincion filo-genetica de seis grupos de leopardos geograficamente aislados: 1) Africano, 2) Centro asiatico, 3) Hindu, 4) Sri Lankano, 5) Javano y, 6) Este asiatico. Basados en el analisis molecular combinado y soportados en datos morfologicos (Miththapala, 1992), recomendamos la revision taxonomica a nivel de subespecie que comprende ocho subespecies: 1) P. p. pardus, Africa; 2) P. p. saxicolor, Asia central; 3) P. p. fusca, subcontinente Hindu; 4) P. p. kotiya, Sri Lanka; 5) P. p. melas, Java; 6) P. p. orientalis, Amur; 7) P. p. japonensis, norte Chino; 8) P. p. delacouri, sur Chino. En la mayoria de los casos las subespecies designadas estan conformadas por barreras geologicas historicas que pudieron haber facilitado divergencia genetica alopatrica.

PURPOSE: To prospectively assess the accuracy of unenhanced magnetic resonance (MR) imaging in the detection and localization of labral injuries. MATERIALS AND METHODS: One hundred three patients with clinically suspected shoulder injuries were prospectively examined with unenhanced MR imaging. A combination of gradient-echo and high-resolution fast-spin-echo axial pulse sequences were used. Surgical correlation was obtained in all patients. RESULTS: At surgery, 37 torn anterior, 36 torn superior, and 19 torn posterior labral were identified. The sensitivity for detection of these tears with MR imaging was 100%, 86%, and 74%, respectively; the specificity was 95%, 100%, and 95%, respectively. Overall, unenhanced MR imaging was 95% accurate in the detection of labral injuries. CONCLUSION: With appropriate pulse sequences, unenhanced MR imaging of the shoulder is an accurate technique for the detection and localization of labral injuries.

Patterns of mitochondrial restriction fragment length polymorphism (RFLP) variation were used to resolve more recent relationships among the species of the Felidae ocelot lineage, domestic cat lineage, and pantherine lineage. Twenty-five of 28 restriction enzymes revealed site variation in at least 1 of 21 cat species. The ocelot lineage was resolved into three separate sistertaxa groups: Geoffroy's cat (Oncifelis geoffroyi) and kodkod (O. guigna), ocelot (Leopardus pardalis) and margay (L. wiedii), and pampas cat (Lynchailurus colocolo) and most of the tigrina samples (Leopardus tigrina). Within the domestic cat lineage, domestic cat (Felis catus), European wild cat (F. silvestris), and African wild cat (F. libyca) formed a monophyletic trichotomy, which was joined with sand cat (F. margarita) to a common ancestor. Jungle cat (F. chaus) and black-footed cat (F. nigripes) mtDNAs diverged earlier than those of the other domestic cat lineage species and are less closely related. Within the pantherine lineage, phylogenetic analysis identified two distinct groups, uniting lion (P. leo) with leopard (P. pardus) and tiger (P. tigris) with snow leopard (P. uncia).

CANINE distemper virus (CDV) is thought to have caused several fatal epidemics in canids within the Serengeti–Mara ecosystem of East Africa, affecting silver-backed jackals (Canis mesomelas) and bat-eared foxes (Otocyon megalotis) in 1978 (ref. 1), and African wild dogs (Lycaon pictus) in 1991 (refs 2, 3). The large, closely monitored Serengeti lion population4,5 was not affected in these epidemics. However, an epidemic caused by a morbillivirus closely related to CDV emerged abruptly in the lion population of the Serengeti National Park, Tanzania, in early 1994, resulting in fatal neurological disease characterized by grand mal seizures and myoclonus; the lions that died had encephalitis and pneumonia. Here we report the identification of CDV from these lions, and the close phylogenetic relationship between CDV isolates from lions and domestic dogs. By August 1994, 85% of the Serengeti lion population had anti-CDV antibodies, and the epidemic spread north to lions in the Maasai Mara National reserve, Kenya, and uncounted hyaenas, bat-eared foxes, and leopards were also affected.

The highly endangered solenodons, endemic to Cuba (Solenodon cubanus) and Hispaniola (S. paradoxus), comprise the only two surviving species of West Indian insectivores1,2. Combined gene sequences (13.9 kilobases) from S. paradoxus established that solenodons diverged from other eulipotyphlan insectivores 76 million years ago in the Cretaceous period, which is consistent with vicariance, though also compatible with dispersal. A sequence of 1.6 kilobases of mitochondrial DNA from S. cubanus indicated a deep divergence of 25 million years versus the congeneric S. paradoxus, which is consistent with vicariant origins as tectonic forces separated Cuba and Hispaniola3,4. Efforts to prevent extinction of the two surviving solenodon species would conserve an entire lineage as old or older than many mammalian orders.

The emergence of pathogenic viruses in new species offers an unusual opportunity to monitor the coadaptation of viruses and their hosts in a dynamic ongoing process of intense biological selection. Tracking lentivirus epidemics in man, monkeys and cats reveals genomic struggles at three levels: quasispecies divergence within an individual; coadaptation of virus and host genomes subsequent to disease outbreaks; and transmission, spread and pathogenesis in related host species. Aspects of each level are revealed by examining the genetic diversity of feline immunodeficiency virus in domestic and wild cat species. This approach has been facilitated by the recent genetic characterization of a novel lentivirus in lions.

African horse sickness (AHS) is a disease that affects equids, and is principally transmitted by Culicoides spp. that are biological vectors of AHS viruses (AHSV). The repeated spread of AHSV from sub-Saharan Africa to the Middle East, northern Africa and the Iberian peninsula indicate that a better understanding of AHS epizootiology is needed. African horse sickness has long been known to infect and cause mortality among domestic dogs that ingest virus contaminated meat, but it is uncertain what role carnivores play in transmission of the virus. We present evidence of widespread natural AHS infection among a diversity of African carnivore species. We hypothesize that such infection resulted from ingestion of meat and organs from AHS-infected prey species. The effect of AHS on the carnivores is unknown, as is their role in the maintenance cycle of the disease.

The phylogenetic placement of the red panda (Ailurus fulgens) and the giant panda (Ailuropoda melanoleuca) has been an evolutionary enigma since their original descriptions in the nineteenth century. A series of recent molecular analyses led to a consensus that the giant panda's ancestors were derived from early bears (Ursidae), but left unsettled the phylogenetic relationship of the red panda. Previous molecular and morphological phylogenies were inconclusive and varied among placement of the red panda within the raccoon family (Procyonidae), within the bear family (Ursidae), or in a separate family of carnivores equidistant between the two. To examine a relatively ancient (circa 20-30 million years before the present, MYBP) phylogenetic divergence, we used two slowly evolving genetic markers: mitochondrial 12S rRNA sequence and 592 fibroblast proteins resolved by two dimensional gel electrophoresis. Four different carnivore outgroup species, including dog (Canidae: Canis familiaris), cat (Felidae: Felis catus), fanaloka (Viverridae: Fossa fossa), and mongoose (Herpestidae: Galidia elegans), were selected to identify the root of the phylogenetic topologies. Phylogenetic reconstruction by distance-based methods, maximum parsimony, and maximum likelihood clearly indicate a distinct bifurcation forming the Ursidae and the Procyonidae. Further, our data consistently place the red panda as an early divergence within the Procyonidae radiation and confirm the inclusion of giant panda in the Ursidae lineage.

The increasing use of shoulder arthroscopy in the early 1980s has contributed significantly to the diagnosis, treatment, and understanding of shoulder instability. Shoulder instability is recognized as a spectrum, spanning from occult subluxation to frank dislocation. Arthroscopy assumes a more significant diagnostic role in the case of subtle shoulder instability. A description of the authors' preferred method of examination under anesthesia is included. The arthroscopic findings associated with shoulder instability are described, together with a brief review of the structures important for shoulder stability. Descriptions of normal arthroscopic shoulder anatomy and some of the more common normal variants also are discussed.

PURPOSE: To determine the value of magnetic resonance (MR) imaging in the clinical management of chronic refractory lateral epicondylitis. MATERIALS AND METHODS: Coronal three-dimensional Fourier transform, multiplanar gradient-recalled-echo, and fat-suppressed sagittal images were obtained in 33 patients. Twenty of these patients underwent surgical debridement and/or primary tendon repair and were included in the correlative study. Surgical and pathologic reports were reviewed to determine the location and gross characteristics of the tissue. RESULTS: Findings at MR imaging correlated with the surgical findings of primary degeneration of the extensor carpi radialis brevis (n = 20). Histopathologic examination demonstrated neovascularization, disruption of collagen, and mucoid degeneration without inflammation. CONCLUSION: The use of MR imaging in patients with recalcitrant lateral epicondylitis assists in surgical planning. The definition of tendon degeneration and degree of tear, as depicted on MR image...

In Fig 1, the numbers (n) of subjects are missing from the bars of the bar graph. Please see corrected Fig 1 here. Fig 1 Intraocular pressure in glaucomatous and normal cats.

Pangolins (order Pholidota) are the only mammals covered by scales. We have recently sequenced and analyzed the genomes of two critically endangered Asian pangolin species, namely the Malayan pangolin (Manis javanica) and the Chinese pangolin (Manis pentadactyla). These complete genome sequences will serve as reference sequences for future research to address issues of species conservation and to advance knowledge in mammalian biology and evolution. To further facilitate the global research effort in pangolin biology, we developed the Pangolin Genome Database (PGD), as a future hub for hosting pangolin genomic and transcriptomic data and annotations, and with useful analysis tools for the research community. Currently, the PGD provides the reference pangolin genome and transcriptome data, gene sequences and functional information, expressed transcripts, pseudogenes, genomic variations, organ-specific expression data and other useful annotations. We anticipate that the PGD will be an invaluable platform for researchers who are interested in pangolin and mammalian research. We will continue updating this hub by including more data, annotation and analysis tools particularly from our research consortium. Database URL: http://pangolin-genome.um.edu.my

In the article 'Genome empowerment for the Puerto Rican parrot - Amazona vittata. GigaScience 2012 1:13' [1] the leadership of avian phylogenomic project [2] mentioned in commentary should have been Guojie Zhang, Erich Jarvis, and Tom Gilbert [2]. We regret this omission.

Aim Obesity is an established risk factor for endometrial cancer. Associations tend to be stronger for the endometrioid subtype. The role of adult weight change and weight cycling is uncertain. Our study aimed to determine whether there is an association between different adult weight trajectories, weight cycling and risk of endometrial cancer overall, and by subtype. Methods We analysed data from the Australian National Endometrial Cancer study, a population-based case–control study that collected self-reported information on height, weight at three time points (age 20, maximum and 1 year prior to diagnosis [recent]), intentional weight loss/regain (weight cycling) from 1398 women with endometrial cancer and 1538 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. Results Relative to women who maintained a stable weight during adulthood, greater weight gain after the age of 20 was associated with increased risk of endometrial cancer (OR for gain 40+kg all subtypes 5.3, 95% CI 3.9–7.3; endometrioid 6.5, 95% CI 4.7–9.0). The strongest associations were observed among women who were continually overweight from the age of 20 (all subtypes OR 3.6, 95% CI 2.6–5.0). Weight cycling was associated with increased risk, particularly among women who had ever been obese (OR 2.9 95% CI 1.8–4.7), with ∼3-fold risks seen for both endometrioid and non-endometrioid tumour subtypes. Women who had intentionally lost weight and maintained that weight loss were not at increased risk. Conclusion These results suggest that higher adult weight gain, and perhaps weight cycling, independently increase the risk of endometrial cancer, however women who lost weight and kept that weight off were not at increased risk.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China., Author Summary NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.

Twelve fresh-frozen cadaver shoulders were dissected to study the anatomy and histology of the coracohumeral ligament. Based on the gross and microscopic anatomy, the ligament was found in three variations. In the most common pattern (nine of 12 specimens), the coracohumeral ligament represented a folded portion of glenohumeral joint capsule in the rotator interval between subscapularis and supraspinatus. Because of its inverted "v"-shaped origin from the coracoid base, tension on this structure creates the appearance of a prominent ligamentous structure. However, histologic cross-sections of this pattern of coracohumeral ligament reveal that it is lined by synovium on its undersurface and contains no discretely organized collagen bundles representative of a ligament. The second pattern (two of 12 specimens) was similar, except that the capsular reflection representing the ligament was fused together, giving the structure a more clearly definable anterior edge. In only one specimen was the ligament a truly ligamentous structure. In its normal state the coracohumeral ligament usually appears as a capsular reflection on the coracoid base, and though it courses toward the superior aspect of the intertubercular groove, it is not a true ligamentous structure. These findings support the position of those authors who state that the coracohumeral ligament is unlikely to play a significant role as a suspensory structure in its physiologic state.

The mechanosensory lateral line, found only in fishes and amphibians, is an important sense organ associated with aquatic life. Lateral line patterns differ among teleost, the most diverse vertebrate taxa, hypothetically in response to selective pressures from different aquatic habitats. In this article, we conduct evolutionary genomic analyses of 34 genes associated with lateral line system development in teleosts to elucidate the significance of contrasting evolutionary rates and changes in the protein coding sequences. We find that duplicated copies of these genes are preferentially retained in the teleost genomes and that episodic events of positive selection have occurred in 22 of the 30 postduplication branches. In general, teleost genes evolved at a faster rate relative to their tetrapod counterparts, and the mutation rates of 26 of the 34 genes differed among teleosts and tetrapods. We conclude that following whole genome duplication, evolutionary rates and episodic events of positive selection on the lateral line system development genes might have been one of the factors favoring the subsequent adaptive radiation of teleosts into diverse habitats. These results provide the foundation for further detailed explorations into lateral line system genes and the evolution of diverse phenotypes and adaptations.

The recent rise in speed and efficiency of new sequencing technologies have facilitated high-throughput sequencing, assembly and analyses of genomes, advancing ongoing efforts to analyze genetic sequences across major vertebrate groups. Standardized procedures in acquiring high quality DNA and RNA and establishing cell lines from target species will facilitate these initiatives. We provide a legal and methodological guide according to four standards of acquiring and storing tissue for the Genome 10K Project and similar initiatives as follows: four-star (banked tissue/cell cultures, RNA from multiple types of tissue for transcriptomes, and sufficient flash-frozen tissue for 1 mg of DNA, all from a single individual); three-star (RNA as above and frozen tissue for 1 mg of DNA); two-star (frozen tissue for at least 700 μg of DNA); and one-star (ethanol-preserved tissue for 700 μg of DNA or less of mixed quality). At a minimum, all tissues collected for the Genome 10K and other genomic projects should consider each species’ natural history and follow institutional and legal requirements. Associated documentation should detail as much information as possible about provenance to ensure representative sampling and subsequent sequencing. Hopefully, the procedures outlined here will not only encourage success in the Genome 10K Project but also inspire the adaptation of standards by other genomic projects, including those involving other biota.

Dasatinib is effective therapy for newly diagnosed patients with chronic myeloid leukemia, but not all patients respond well. We analyzed the outcome of patients treated with dasatinib as first-line therapy to identify patients who are more likely to fare poorly. The 8.6% of patients who at 3 months had a BCR-ABL1/ABL1 ratio > 10% had a significantly worse 2-year cumulative incidence of complete cytogenetic response (58.8% vs 96.6%, P < .001) and molecular responses than the remaining patients with a lower transcript levels. The predictive value of the 3-month transcript level could be improved using the dasatinib-specific transcript level cut-offs, namely, 2.2%, 0.92%, and 0.57% for complete cytogenetic response, 3 log and 4.5 log reductions in the transcript level, respectively. The study was registered at www.clinicaltrials.gov as #NCT01460693.

Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate

The Genome 10K project aims to sequence the genomes of 10,000 vertebrates, representing approximately one genome for each vertebrate genus. Since fishes (cartilaginous fishes, ray-finned fishes and lobe-finned fishes) represent more than 50% of extant vertebrates, it is planned to target 4,000 fish genomes. At present, nearly 60 fish genomes are being sequenced at various public funded labs, and under a Genome 10K and BGI pilot project. An additional 100 fishes have been identified for sequencing in the next phase of Genome 10K project.

Cysteine-rich secretory proteins (CRISPs) are glycoproteins found exclusively in vertebrates and have broad diversified functions. They are hypothesized to play important roles in mammalian reproduction and in reptilian venom, where they disrupt homeostasis of the prey through several mechanisms, including among others, blockage of cyclic nucleotide-gated and voltage-gated ion channels and inhibition of smooth muscle contraction. We evaluated the molecular evolution of CRISPs in toxicoferan reptiles at both nucleotide and protein levels relative to their nonvenomous mammalian homologs. We show that the evolution of CRISP gene in these reptiles is significantly influenced by positive selection and in snakes (x 5 3.84) more than in lizards (x 5 2.33), whereas mammalian CRISPs were under strong negative selection (CRISP1 5 0.55, CRISP2 5 0.40, and CRISP3 5 0.68). The use of ancestral sequence reconstruction, mapping of mutations on the threedimensional structure, and detailed evaluation of selection pressures suggests that the toxicoferan CRISPs underwent accelerated evolution aided by strong positive selection and directional mutagenesis, whereas their mammalian homologs are constrained by negative selection. Gene and protein-level selection analyses identified 41 positively selected sites in snakes and 14 sites in lizards. Most of these sites are located on the molecular surface (nearly 76% in snakes and 79% in lizards), whereas the backbone of the protein retains a highly conserved structural scaffold. Nearly 46% of the positively selected sites occur in the cysteine-rich domain of the protein. This directional mutagenesis, where the hotspots of mutations are found on the molecular surface and functional domains of the protein, acts as a diversifying mechanism for the exquisite biological targeting of CRISPs in toxicoferan reptiles. Finally, our analyses suggest that the evolution of toxicoferan-CRISP venoms might have been influenced by the specific predatory mechanism employed by the organism. CRISPs in Elapidae, which mostly employ neurotoxins, have experienced less positive selection pressure (x 5 2.86) compared with the ‘‘nonvenomous’’ colubrids (x 5 4.10) that rely on grip and constriction to capture the prey, and the Viperidae, a lineage that mostly employs haemotoxins (x 5 4.19). Relatively lower omega estimates in Anguimorph lizards (x 5 2.33) than snakes (x 5 3.84) suggests that lizards probably depend more on pace and powerful jaws for predation than venom.

A simple tandem repeat (STR) PCR-based typing system developed for the genetic individualization of domestic cat samples has been used to generate a population genetic database of domestic cat breeds. A panel of 10 tetranucleotide STR loci and a gender-identifying sequence tagged site (STS) were co-amplified in genomic DNA of 1043 individuals representing 38 cat breeds. The STR panel exhibits relatively high heterozygosity in cat breeds, with an average 10-locus heterozygosity of 0.71, which represents an average of 38 breed-specific heterozygosities for the 10-member panel. When the entire set of breed individuals was analyzed as a single population, a heterozygosity of 0.87 was observed. Heterozygosities obtained for the 10 loci range from 0.72 to 0.96. The power for genetic individualization of domestic cat samples of the multiplex is high, with a probability of match (p(m)) of 6.2E-14, using a conservative θ = 0.05.

Sixteen isozyme markers have been assigned to the chromosome complement of the neotropical primate species Ateles paniscus chamek using three somatic cell hybrid panels. Several genetic associations were found to be common between humans and this species, despite the fact that Ateles is a karyologically rearranged taxon. Conversely, several human gene clusters were disrupted, resulting in gene associations not previously found in other primates. A comparison with other primates and mammalian orders, for which gene maps are available, was carried out for a comprehensive evaluation of genome evolution in these disparate taxa.

Bluetongue is an International Office of Epizootics List A disease described as the century's most economically devastating affliction of sheep. Bluetongue (BLU) viruses were thought to infect only ruminants, shrews, and some rodents, but recently, inadvertent administration of BLU virus-contaminated vaccine resulted in mortality and abortion among domestic dogs. We present evidence of natural BLU virus infection among African carnviores that dramatically widens the spectrum of susceptible hosts. We hypothesize that such infection occurred after ingestion of meat and organs from BLU virus-infected prey species. The effect of BLU virus on endangered carnivores such as the cheetah and African wild dog requires urgent investigation. Also, the role of carnivores in the epizootiology of this disease needs elucidation.

Recent advances in human gene mapping technologies have led to increased emphasis in developing representative genetic maps for several species, particularly domestic plants and animals. These maps are being compiled with two distinct goals: to provide a resource for genetic analysis, and to help dissect the evolution of genome organization by comparing linkage relationships of homologous genes. We recently proposed a list of reference anchor loci suitable for comparative gene mapping in mammals and other vertebrate classes. The comparative anchors, which are Type I (coding gene) loci, provide a comparative framework, but the addition of Type II (microsatellite) loci is also necessary for mapping phenotypes in animal gene maps. Strategies for combining the advantages of Type I and Type II locus markers are presented with emphasis on application of these concepts to the construction of a gene map of the domestic cat.

Feline immunodeficiency virus (FIV) is a novel lentivirus that is genetically homologous and functionally analogous to the human AIDS viruses, human immunodeficiency virus types 1 and 2. FIV causes immunosuppression in domestic cats by destroying the CD4 T-lymphocyte subsets in infected hosts. A serological survey of over 400 free-ranging African and Asian lions (Panthera leo) for antibodies to FIV revealed endemic lentivirus prevalence with an incidence of seropositivity as high as 90%. A lion lentivirus (FIV-Ple) was isolated by infection of lion lymphocytes in vitro. Seroconversion was documented in two Serengeti lions, and discordance of mother-cub serological status argues against maternal transmission (in favor of horizontal spread) as a major route of infection among lions. A phylogenetic analysis of cloned FIV-Ple pol gene sequences from 27 lions from four African populations (from the Serengeti reserve, Ngorongoro Crater, Lake Manyara, and Kruger Park) revealed remarkably high intra- and interindividual genetic diversity at the sequence level. Three FIV-Ple phylogenetic clusters or clades were resolved with phenetic, parsimony, and likelihood analytical procedures. The three clades, which occurred not only together in the same population but throughout Africa, were as divergent from each other as were homologous pol sequences of lentivirus isolated from distinct feline species, i.e., puma and domestic cat. The FIV-Ple clades, however, were more closely related to each other than to other feline lentiviruses (monophyletic for lion species), suggesting that the ancestors of FIV-Ple evolved in allopatric (geographically isolated) lion populations that converged recently. To date, there is no clear evidence of FIV-Ple-associated pathology, raising the possibility of a historic genetic accommodation of the lion lentivirus and its host leading to a coevolved host-parasite symbiosis (or commensalism) in the population similar to that hypothesized for endemic simian immunodeficiency virus without pathology in free-ranging African monkey species.

Phylogenetic associations among six closely related South American felid species were defined by changes in protein-encoding gene loci. We analyzed proteins isolated from skin fibroblasts using two-dimensional electrophoresis and allozymes extracted from blood cells. Genotypes were determined for multiple individuals of ocelot, margay, tigrina, Geoffroy's cat, kodkod, and pampas cat at 548 loci resolved by two-dimensional electrophoresis and 44 allozyme loci. Phenograms were constructed using the methods of Fitch-Margoliash and neighbor-joining on a matrix of Nei's unbiased genetic distances for all pairs of species. Results of a relative-rate test indicate changes in two-dimensional electrophoresis data are constant among all South American felids with respect to a hyena outgroup. Allelic frequencies were transformed to discrete character states for maximum parsimony analysis. Phylogenetic reconstruction indicates a major split occurred approximately 5-6 million years ago, leading to three groups within the ocelot lineage. The earliest divergence led to Leopardus tigrina, followed by a split between an ancestor of an unresolved trichotomy of three species (Oncifelis guigna, O. geoffroyi, and Lynchailuris colocolo) and a recent common ancestor of Leopardus pardalis and L. wiedii. The results suggest that modern South American felids are monophyletic and evolved rapidly after the formation of the Panama land bridge between North and South America.

The mitochondrial DNA of plant and animal cells is a transcriptionally active genome that traces its origins to a symbiotic infection of eucaryotic cells by bacterial progenitors. As prescribed by the Serial Endosymbiosis Theory, symbiotic organelles have gradually transferred their genes to the eucaryotic genome, producing a functional interaction of nuclear and mitochondrial genes in organelle function. We report here a recent remarkable transposition of 7.9 kb of a typically 17.0-kb mitochondrial genome to a specific nuclear chromosomal position in the domestic cat. The intergrated segment has subsequently become amplified 38-76 times and now occurs as a tandem repeat macrosatellite with multiple-length alleles resolved by pulse-field gel electrophoresis (PFGE) segregating in cat populations. Sequence determination of the nuclear mitochondrial DNA segment, Numt, revealed a d(CA)-rich 8-bp motif [ACACACGT] repeated imperfectly five times at the deletion junction that is a likely target for recombination. The extent and pattern of sequence divergence of Numt genes from the cytoplasmic mtDNA homologues plus the occurrence of Numt in other species of the family Felidae allowed an estimate for the origins of Numt at 1.8-2.0 million years ago in an ancestor of four modern species in the genus Felis. Numt genes do not function in cats; rather, the locus combines properties of nuclear minisatellites and pseudogenes. These observations provide an empirical glimpse of historic genomic events that may parallel the accommodation of organelles in eucaryotes.