Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis and cancer treatment. In this review, we first discuss how the activation of this pathway is determined. We then provide up-to-date statistics on the cancers ALT activity is detected. Additionally, we discussed the relationship between ALT positivity and prognosis as well as the pathogenetics of the ALT positive cancers. Finally, we evaluated the pre-clinical and clinical investigation of potential therapy for ALT cancers.Abstract: Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.

No vertebrate, living or extinct, is known to have possessed an odd number of limbs. Despite this ‘forbidden phenotype’, gaits that use odd numbers of limbs (e.g. tripedalism or pentapedalism) have evolved in both avian and mammalian lineages. Tripedal locomotion is commonly employed by parrots during climbing, who use their beaks as an additional support. However, it is unclear whether the beak functions simply as a stabilizing hook, or as a propulsive limb. Here, we present data on kinetics of tripedal climbing in six rosy-faced lovebirds ( Agapornis roseicollis ). Our findings demonstrate that parrots use cyclical tripedal gaits when climbing and the beak and hindlimbs generate comparable propulsive and tangential substrate reaction forces and power. Propulsive and tangential forces generated by the beak are of magnitudes equal to or greater than those forces generated by the forelimbs of humans and non-human primates during vertical climbing. We conclude that the feeding apparatus and neck flexors of parrots have been co-opted to function biomechanically as a propulsive third limb during vertical climbing. We hypothesize that this exaptation required substantive alterations to the neuromuscular system including enhanced force-generating capabilities of the neck flexors and modifications to locomotor central pattern generators.

Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function.

Living sloths exhibit numerous anatomical specializations towards inverted quadrupedalism, however, previous studies have noted a more varied locomotor repertoire than previously anticipated. In this study, we present spatiotemporal gait characteristics and triaxial kinetic data from the brown‐throated three‐toed sloth (Bradypus variegatus) across three locomotor modes: terrestrial quadrupedal “crawling”, suspensory walking, and vertical climbing. Compared to quadrupedal crawling and suspensory walking, B. variegatus adopted longer contact times and stride durations, larger duty factors, and greater speed during vertical climbing. Net fore‐aft impulses were significantly greater during vertical climbing in both limb pairs than in quadrupedal crawling and suspensory walking. Functionally, during quadrupedal crawling and vertical climbing, both limb pairs served propulsive roles, while differentiation between a propulsive forelimb and braking hindlimb was observed during suspension. Net tangential forces differentiated vertical climbing kinetics from the other modes of locomotion, with the introduction of bidirectional pulling and pushing forces in the forelimb and hindlimb, respectively. The net mediolateral impulses were similar in vertical climbing and quadrupedal crawling as both limb pairs directed forces in one direction, whereas during suspensory walking, the laterally dominant forelimb was opposed by the medially dominant hindlimb. In total, this study provides novel data on the diverse locomotor dynamics in a slow‐moving arboreal tetrapod and posits new testable hypotheses about the neuroplasticity and ease of transitioning between locomotor behaviors. The strikingly similar kinetic profiles of quadrupedal crawling and suspensory walking compared to vertical climbing suggest shared neuromuscular and mechanical demands between these mirrored locomotor modes.

Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed.