Orangutan information broadcast via consonant-like and vowel-like calls breaches mathematical models of linguistic evolution

The origin of language is one of the most significant evolutionary milestones of life on Earth, but one of the most persevering scientific unknowns. Two decades ago, game theorists and mathematicians predicted that the first words and grammar emerged as a response to transmission errors and information loss in language's precursor system, however, empirical proof is lacking. Here, we assessed information loss in proto-consonants and proto-vowels in human pre-linguistic ancestors as proxied by orangutan consonant-like and vowel-like calls that compose syllable-like combinations. We played back and re-recorded calls at increasing distances across a structurally complex habitat (i.e. adverse to sound transmission). Consonant-like and vowel-like calls degraded acoustically over distance, but no information loss was detected regarding three distinct classes of information (viz. individual ID, context and population ID). Our results refute prevailing mathematical predictions and herald a turning point in language evolution theory and heuristics. Namely, explaining how the vocal–verbal continuum was crossed in the hominid family will benefit from future mathematical and computational models that, in order to enjoy empirical validity and superior explanatory power, will be informed by great ape behaviour and repertoire

Implanted Radio Telemetry in Orangutan Reintroduction and Post-release Monitoring and its Application in Other Ape Species

Designed as a new method to facilitate the reintroduction and post-release monitoring of orangutans and other apes, implanted radio-telemetry (IRT) was developed and first deployed in 2009. Since that time, it has been necessary to collate and review information on its uptake and general efficacy to inform its ongoing development and that of other emerging tracking technologies. We present here technical specifications and the surgical procedure used to implant miniaturized radio transmitters, as well as a formal testing procedure for measuring detectable transmission distances of implanted devices. Feedback from IRT practitioners (veterinarians and field managers) was gathered through questionnaires and is also presented. To date, IRT has been used in at least 250 individual animals (mainly orangutans) from four species of ape in both Asia and Africa. Median surgical and wound healing times were 30 min and 15 days, respectively, with implants needing to be removed on at least 36 separate occasions. Confirmed failures within the first year of operation were 18.1%, while longer distances were reported from positions of higher elevation relative to the focal animal. IRT has been a transformational technology in facilitating the relocation of apes after their release, resulting in much larger amounts of post-release data collection than ever before. It is crucial however, that implant casings are strengthened to prevent the requirement for recapture and removal surgeries, especially for gradually adapting apes. As with all emerging technological solutions, IRT carries with it inherent risk, especially so due to the requirement for subcutaneous implantation. These risks must, however, be balanced with the realities of releasing an animal with no means of relocation, as has historically been, and is still, the case with orangutans and gorillas

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Fully transformer-based biomarker prediction from colorectal cancer histology: a large-scale multicentric study

Background: Deep learning (DL) can extract predictive and prognostic biomarkers from routine pathology slides in colorectal cancer. For example, a DL test for the diagnosis of microsatellite instability (MSI) in CRC has been approved in 2022. Current approaches rely on convolutional neural networks (CNNs). Transformer networks are outperforming CNNs and are replacing them in many applications, but have not been used for biomarker prediction in cancer at a large scale. In addition, most DL approaches have been trained on small patient cohorts, which limits their clinical utility. Methods: In this study, we developed a new fully transformer-based pipeline for end-to-end biomarker prediction from pathology slides. We combine a pre-trained transformer encoder and a transformer network for patch aggregation, capable of yielding single and multi-target prediction at patient level. We train our pipeline on over 9,000 patients from 10 colorectal cancer cohorts. Results: A fully transformer-based approach massively improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training on a large multicenter cohort, we achieve a sensitivity of 0.97 with a negative predictive value of 0.99 for MSI prediction on surgical resection specimens. We demonstrate for the first time that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem. Interpretation: A fully transformer-based end-to-end pipeline trained on thousands of pathology slides yields clinical-grade performance for biomarker prediction on surgical resections and biopsies. Our new methods are freely available under an open source license

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of superenhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods: An international collaboration, exome sequencing, molecular modeling, yeast twohybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability

Hepatitis C infection: eligibility for antiviral therapies

peer reviewedBackground Current treatments of chronic hepatitis C virus (HCV) are effective, but expensive and susceptible to induce significant side effects. Objectives To evaluate the proportion of HCV patients who are eligible for a treatment. Methods In a database comprising 1726 viraemic HCV patients, the files of 299 patients who presented to the same hepatologist for an initial appointment between 1996 and 2003 were reviewed. Results Patients' characteristics were age 43.1 +/- 15.6 years, 53% male and 92% Caucasian. The main risk factors were transfusion (43%) and drug use (22%). Genotypes were mostly genotype 1 (66%), genotype 3 (12%) and genotype 2 (10%). These characteristics were not different from those of the whole series of 1726 patients. A total of 176 patients (59%) were not treated, the reasons for non-treatment being medical contraindications (34%), non-compliance (25%) and normal transaminases (24%). In addition, 17% of patients declined therapy despite being considered as eligible, mainly due to fear of adverse events. Medical contraindications were psychiatric (27%), age (22%), end-stage liver disease (15%), willingness for pregnancy (13%), cardiac contraindication (7%) and others (16%). Only 123 patients (41%) were treated. A sustained viral response was observed in 41%. The treatment was interrupted in 16% for adverse events. Conclusions The majority of HCV patients are not eligible for treatment. This implies that, with current therapies, only 17% of patients referred for chronic HCV become sustained responders. Some modifications of guidelines could extend the rate of treatment (patients with normal transaminases), but an important barrier remains the patients' and the doctors' fear of adverse events

In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells

The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV

Chewing Through the Miocene: An Examination of the Feeding Musculature in the Ground Sloth Hapalops from South America (Mammalia: Pilosa)

Hapalops, a smaller-sized and early sloth of the Megatheroidea, appeared in the middle Miocene Santa Cruz formation of Argentina. This genus is part of the group from which later, larger megatheroids arose, i.e., Nothrotheriops and Megatherium. Many cranial characters support this idea; however Hapalops is not merely a smaller antecedent of the later forms. Specifically, Hapalops retains short anterior caniniform teeth, and a temporomandibular joint elevated above the cheek tooth row; a combination distinct among sloths. An elevated temporomandibular joint occurs in Bradypus, a tree sloth with anterior chisel-shaped teeth instead of caniniforms, and the tree sloth Choloepus, which is aligned with the megalonychids, has anterior caniniforms. Hapalops has an elongated zygomatic ascending process that is reminiscent of that in Bradypus; however, the Bradypus skull is extremely foreshortened while that of Hapalops is elongated, as in nothrotheres, but not deepened as in megatheres. Previous work identified many sloth cranial character complexes, and functional limitations on skull feature combinations. The unique Hapalops character patterns indicate a selective feeder with a mediolaterally oriented grinding stroke during mastication