Is strongyloidiasis a zoonosis from dogs?

Strongyloides stercoralis infection remains a major veterinary and public health challenge globally. This chronic and potentially lifelong disease has fatal outcomes in immunosuppressed people and dogs. Currently, the role of dogs in the transmission cycle of human strongyloidiasis remains enigmatic. While zoonotic transmission to humans from companion animals has been proposed, this has not been confirmed. Modern molecular methods have allowed greater opportunity to explore the genotypes of S. stercoralis in dogs and humans. Work thus far has demonstrated that at least two distinct lineages exist, one apparently confined to canine hosts and one found in canine, feline, human and non-human primate hosts. Although genotyping of dog and human isolates from the same village has demonstrated identical genotypes in both species, coprophagia of human waste by dogs confounds interpretation. It remains unclear if dogs act as a zoonotic reservoir for human infection, or vice versa, or if this occurs only in some regions of the world and not in others. These questions must be answered before effective control strategies for strongyloidiasis can be instituted. This review explores the evidence for and against cross-species transmission of S. stercoralis between dogs and humans and summarizes future directions for research in this area. This article is part of the Theo Murphy meeting Issue 'Strongyloides: omics to worm-free populations'.

Strongyloides in non-human primates: significance for public health control.

Primates are an important source of infectious disease in humans. Strongyloidiasis affects an estimated 600 million people worldwide, with a global distribution and hotspots of infection in tropical and subtropical regions. Recently added to the list of neglected tropical diseases, global attention has been demanded in the drive for its control. Through a literature review of Strongyloides in humans and non-human primates (NHP), we analysed the most common identification methods and gaps in knowledge about this nematode genus. The rise of molecular-based methods for Strongyloides detection is evident in both humans and NHP and provides an opportunity to analyse all data available from primates. Dogs were also included as an important host species of Strongyloides and a potential bridge host between humans and NHP. This review highlights the lack of molecular data across all hosts-humans, NHP and dogs-with the latter highly underrepresented in the database. Despite the cosmopolitan nature of Strongyloides, there are still large gaps in our knowledge for certain species when considering transmission and pathogenicity. We suggest that a unified approach to Strongyloides detection be taken, with an optimized, repeatable molecular-based method to improve our understanding of this parasitic infection. This article is part of the Theo Murphy meeting issue 'Strongyloides: omics to worm-free populations'.

Characterization of long-term ex vivo expansion of tree shrew spermatogonial stem cells.

Tree shrews ( Tupaia belangeri chinensis) share a close relationship to primates and have been widely used in biomedical research. We previously established a spermatogonial stem cell (SSC)-based gene editing platform to generate transgenic tree shrews. However, the influences of long-term expansion on tree shrew SSC spermatogenesis potential remain unclear. Here, we examined the in vivo spermatogenesis potential of tree shrew SSCs cultured across different passages. We found that SSCs lost spermatogenesis ability after long-term expansion (>50 passages), as indicated by the failure to colonize the seminiferous epithelium and generate donor spermatogonia (SPG)-derived spermatocytes or spermatids marking spermatogenesis. RNA sequencing (RNA-seq) analysis of undifferentiated SPGs across different passages revealed significant gene expression changes after sub-culturing primary SPG lines for more than 40 passages on feeder layers. Specifically, DNA damage response and repair genes (e.g., MRE11, SMC3, BLM, and GEN1) were down-regulated, whereas genes associated with mitochondrial function (e.g., NDUFA9, NDUFA8, NDUFA13, and NDUFB8) were up-regulated after expansion. The DNA damage accumulation and mitochondrial dysfunction were experimentally validated in high-passage cells. Supplementation with nicotinamide adenine dinucleotide (NAD +) precursor nicotinamide riboside (NR) exhibited beneficial effects by reducing DNA damage accumulation and mitochondrial dysfunction in SPG elicited by long-term culture. Our research presents a comprehensive analysis of the genetic and physiological attributes critical for the sustained expansion of undifferentiated SSCs in tree shrews and proposes an effective strategy for extended in vitro maintenance.

Novel machine-learning analysis of SARS-CoV-2 infection in a subclinical nonhuman primate model using radiomics and blood biomarkers.

Detection of the physiological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is challenging in the absence of overt clinical signs but remains necessary to understand a full subclinical disease spectrum. In this study, our objective was to use radiomics (from computed tomography images) and blood biomarkers to predict SARS-CoV-2 infection in a nonhuman primate model (NHP) with inapparent clinical disease. To accomplish this aim, we built machine-learning models to predict SARS-CoV-2 infection in a NHP model of subclinical disease using baseline-normalized radiomic and blood sample analyses data from SARS-CoV-2-exposed and control (mock-exposed) crab-eating macaques. We applied a novel adaptation of the minimum redundancy maximum relevance (mRMR) feature-selection technique, called mRMR-permute, for statistically-thresholded and unbiased feature selection. Through performance comparison of eight machine-learning models trained on 14 feature sets, we demonstrated that a logistic regression model trained on the mRMR-permute feature set can predict SARS-CoV-2 infection with very high accuracy. Eighty-nine percent of mRMR-permute selected features had strong and significant class effects. Through this work, we identified a key set of radiomic and blood biomarkers that can be used to predict infection status even in the absence of clinical signs. Furthermore, we proposed and demonstrated the utility of a novel feature-selection technique called mRMR-permute. This work lays the foundation for the prediction and classification of SARS-CoV-2 disease severity.

Estimating prevalence of Enterovirus D111 in human and non-human primate populations using cross-sectional serology.

Enteroviruses primarily affect young children with a varying severity of disease. Recent outbreaks of severe respiratory and neurological disease due to EV-D68 and EV-A71, as well as atypical hand-foot-and-mouth-disease due to CVA6, have brought to light the potency of enteroviruses to emerge as severe human pathogens. Enterovirus D111 (EV-D111) is an enteric pathogen initially detected in Central Africa in human and wildlife samples and was recently detected in environmental samples. The natural history and epidemiology of EV-D111 are poorly studied. Here, the presence of serum neutralizing antibodies to EV-D111 was estimated in human and wildlife samples from five countries. We report high prevalence of neutralizing antibodies measured against EV-D111 in human populations (range, 55-83 %), a proxy for previous infection, which indicates active virus circulation in absence of detection in clinical cases and a high number of undiagnosed infections. Notably, seroprevalence in samples from the UK varied by age and was higher in children and older adults (1-5 and >60 years old), but lower in ages 11-60. EV-D111 seroprevalence in apes and Old World monkeys was 50 % (33-66 %), which also suggests prior exposure and supports existing knowledge of enterovirus circulation in wild and captive apes and Old World monkeys. Generally, reported cases of infection likely underestimate the prevalence of infection particularly when the knowledge of community transmission is limited. Continued serologic surveillance and detection of EV-D111 in clinical and environmental samples will allow for a more robust assessment of EV-D111 epidemiology.

Detection of coinfection with Primate Erythroparvovirus 1 and arboviruses (DENV, CHIKV and ZIKV) in individuals with acute febrile illness in the state of Rio Grande do Norte in 2016.

BACKGROUND: Arthropod-borne viruses, known as arboviruses, pose substantial risks to global public health. Dengue (DENV), Chikungunya (CHIKV) and Zika (ZIKV) viruses stand out as significant concerns in Brazil and worldwide. Their overlapping clinical manifestations make accurate diagnosis a challenge, underscoring the need for reliable laboratory support. This study employs a comprehensive molecular diagnostic approach to track viral infections in individuals with acute febrile illness, a period marked by widespread outbreaks of DENV, CHIKV and ZIKV. METHODS: Between January and August 2016, we received a total of 713 serum samples obtained from individuals with acute febrile illness, previously tested for DENV, CHIKV or ZIKV, with initial negative results, from LACEN-NATAL. Of the total 713 samples, 667 were from females (354 of them pregnant) and 46 from males. Molecular diagnosis was conducted using the Multiplex RT-qPCR technique for simultaneous detection of DENV, CHIKV and ZIKV. Additionally, we performed differential diagnosis by RT-qPCR for other viruses of the Flavivirus, Alphavirus Enterovirus genera and qPCR for Primate Erythroparvovirus 1 (B19V) species, in accordance with Ministry of Health guidelines. RESULTS: Among the 713 cases, 78.2% tested positive for viral infections, including 48% with CHIKV viremia, 0.6% with DENV and 0.1% with ZIKV. Arboviral coinfections totaled 2.4%, including DENV-CHIKV (1.7%) and CHIKV-ZIKV (0.7%). Moreover, 8% exhibited B19V viremia. Simultaneous infections were identified in 17.5%, encompassing B19V-CHIKV (17.1%), B19V-DENV (0.1%), and B19V-ZIKV (0.3%) Triple infections were observed in 1.3% of cases with B19V-DENV-CHIKV (1%) and B19V-CHIKV-ZIKV (0.3%). CONCLUSION: Molecular testing demonstrated high efficacy in diagnosing prevalent arboviruses and detecting multiple coinfections. This approach helps to elucidate etiologies for symptomatic cases, especially during arbovirus outbreaks, and aids comprehensive surveillance. Our findings underscore the importance of monitoring co-circulating pathogens, such as B19V, with implications for clinical management, particularly in pregnant individuals. This study enhances our understanding of arbovirus epidemiology and reinforces the critical role of molecular diagnosis in disease surveillance and control.

LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification.

The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type-specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.

Corvids optimize working memory by categorizing continuous stimuli.

Working memory (WM) is a crucial element of the higher cognition of primates and corvid songbirds. Despite its importance, WM has a severely limited capacity and is vulnerable to noise. In primates, attractor dynamics mitigate the effect of noise by discretizing continuous information. Yet, it remains unclear whether similar dynamics are seen in avian brains. Here, we show jackdaws (Corvus monedula) have similar behavioral biases as humans; memories are less precise and more biased as memory demands increase. Model-based analysis reveal discrete attractors are evenly spread across the stimulus space. Altogether, our comparative approach suggests attractor dynamics in primates and corvids mitigate the effect of noise by systematically drifting towards specific attractors. By demonstrating this effect in an evolutionary distant species, our results strengthen attractor dynamics as general, adaptive biological principle to efficiently use WM.

A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates.

Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-TFH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM BPC) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.

Phylogenetic comparative analysis of the cerebello-cerebral system in 34 species highlights primate-general expansion of cerebellar crura I-II.

The reciprocal connections between the cerebellum and the cerebrum have been suggested to simultaneously play a role in brain size increase and to support a broad array of brain functions in primates. The cerebello-cerebral system has undergone marked functionally relevant reorganization. In particular, the lateral cerebellar lobules crura I-II (the ansiform) have been suggested to be expanded in hominoids. Here, we manually segmented 63 cerebella (34 primate species; 9 infraorders) and 30 ansiforms (13 species; 8 infraorders) to understand how their volumes have evolved over the primate lineage. Together, our analyses support proportional cerebellar-cerebral scaling, whereas ansiforms have expanded faster than the cerebellum and cerebrum. We did not find different scaling between strepsirrhines and haplorhines, nor between apes and non-apes. In sum, our study shows primate-general structural reorganization of the ansiform, relative to the cerebello-cerebral system, which is relevant for specialized brain functions in an evolutionary context.

ELOA3: A primate-specific RNA polymerase II elongation factor encoded by a tandem repeat gene cluster.

The biological role of the repetitive DNA sequences in the human genome remains an outstanding question. Recent long-read human genome assemblies have allowed us to identify a function for one of these repetitive regions. We have uncovered a tandem array of conserved primate-specific retrogenes encoding the protein Elongin A3 (ELOA3), a homolog of the RNA polymerase II (RNAPII) elongation factor Elongin A (ELOA). Our genomic analysis shows that the ELOA3 gene cluster is conserved among primates and the number of ELOA3 gene repeats is variable in the human population and across primate species. Moreover, the gene cluster has undergone concerted evolution and homogenization within primates. Our biochemical studies show that ELOA3 functions as a promoter-associated RNAPII pause-release elongation factor with distinct biochemical and functional features from its ancestral homolog, ELOA. We propose that the ELOA3 gene cluster has evolved to fulfil a transcriptional regulatory function unique to the primate lineage that can be targeted to regulate cellular hyperproliferation.

Investigating the dietary niches of fossil Plio-Pleistocene European macaques: The case of Macaca majori Azzaroli, 1946 from Sardinia.

The genus Macaca includes medium- to large-bodied monkeys and represents one of the most diverse primate genera, also having a very large geographic range. Nowadays, wild macaque populations are found in Asia and Africa, inhabiting a wide array of habitats. Fossil macaques were also present in Europe from the Late Miocene until the Late Pleistocene. Macaques are considered ecologically flexible monkeys that exhibit highly opportunistic dietary strategies, which may have been critical to their evolutionary success. Nevertheless, available ecological information regarding fossil European species is very sparse, limiting our knowledge of their evolutionary history in this geographic area. To further our understanding of fossil European macaque ecology, we investigated the dietary ecology of Macaca majori, an insular endemic species from Sardinia. In particular, we characterized the dental capabilities and potential dietary adaptations of M. majori through dental topographic and enamel thickness analyses of two M2s from the Early Pleistocene site of Capo Figari (1.8 Ma). We also assessed its diet through dental microwear texture analysis, while the microwear texture of M. majori was also compared with microwear textures from other European fossil macaques from mainland Europe. The dental topographic and enamel thickness analyses suggest that M. majori frequently consumes hard/mechanically challenging and/or abrasive foods. The results of the dental microwear analysis are consistent with this interpretation and further suggest that M. majori probably exhibited more durophagous dietary habits than mainland Plio-Pleistocene macaques. Overall, our results indicate that M. majori probably occupied a different dietary niche compared to its mainland fossil relatives, which suggests that they may have inhabited different paleoenvironments.

Truly pattern: Nonlinear integration of motion signals is required to account for the responses of pattern cells in rat visual cortex.

A key feature of advanced motion processing in the primate dorsal stream is the existence of pattern cells-specialized cortical neurons that integrate local motion signals into pattern-invariant representations of global direction. Pattern cells have also been reported in rodent visual cortex, but it is unknown whether the tuning of these neurons results from truly integrative, nonlinear mechanisms or trivially arises from linear receptive fields (RFs) with a peculiar geometry. Here, we show that pattern cells in rat primary (V1) and lateromedial (LM) visual cortex process motion direction in a way that cannot be explained by the linear spatiotemporal structure of their RFs. Instead, their tuning properties are consistent with and well explained by those of units in a state-of-the-art neural network model of the dorsal stream. This suggests that similar cortical processes underlay motion representation in primates and rodents. The latter could thus serve as powerful model systems to unravel the underlying circuit-level mechanisms.

Architecture of the brain's visual system enhances network stability and performance through layers, delays, and feedback.

In the visual system of primates, image information propagates across successive cortical areas, and there is also local feedback within an area and long-range feedback across areas. Recent findings suggest that the resulting temporal dynamics of neural activity are crucial in several vision tasks. In contrast, artificial neural network models of vision are typically feedforward and do not capitalize on the benefits of temporal dynamics, partly due to concerns about stability and computational costs. In this study, we focus on recurrent networks with feedback connections for visual tasks with static input corresponding to a single fixation. We demonstrate mathematically that a network's dynamics can be stabilized by four key features of biological networks: layer-ordered structure, temporal delays between layers, longer distance feedback across layers, and nonlinear neuronal responses. Conversely, when feedback has a fixed distance, one can omit delays in feedforward connections to achieve more efficient artificial implementations. We also evaluated the effect of feedback connections on object detection and classification performance using standard benchmarks, specifically the COCO and CIFAR10 datasets. Our findings indicate that feedback connections improved the detection of small objects, and classification performance became more robust to noise. We found that performance increased with the temporal dynamics, not unlike what is observed in core vision of primates. These results suggest that delays and layered organization are crucial features for stability and performance in both biological and artificial recurrent neural networks.

Gene expression in the primate orbitofrontal cortex related to anxious temperament.

Anxiety disorders are among the most prevalent psychiatric disorders, causing significant suffering and disability. Relative to other psychiatric disorders, anxiety disorders tend to emerge early in life, supporting the importance of developmental mechanisms in their emergence and maintenance. Behavioral inhibition (BI) is a temperament that emerges early in life and, when stable and extreme, is linked to an increased risk for the later development of anxiety disorders and other stress-related psychopathology. Understanding the neural systems and molecular mechanisms underlying this dispositional risk could provide insight into treatment targets for anxiety disorders. Nonhuman primates (NHPs) have an anxiety-related temperament, called anxious temperament (AT), that is remarkably similar to BI in humans, facilitating the design of highly translational models for studying the early risk for stress-related psychopathology. Because of the recent evolutionary divergence between humans and NHPs, many of the anxiety-related brain regions that contribute to psychopathology are highly similar in terms of their structure and function, particularly with respect to the prefrontal cortex. The orbitofrontal cortex plays a critical role in the flexible encoding and regulation of threat responses, in part through connections with subcortical structures like the amygdala. Here, we explore individual differences in the transcriptional profile of cells within the region, using laser capture microdissection and single nuclear sequencing, providing insight into the molecules underlying individual differences in AT-related function of the pOFC, with a particular focus on previously implicated cellular systems, including neurotrophins and glucocorticoid signaling.

Change detection in the primate auditory cortex through feedback of prediction error signals.

Although cortical feedback signals are essential for modulating feedforward processing, no feedback error signal across hierarchical cortical areas has been reported. Here, we observed such a signal in the auditory cortex of awake common marmoset during an oddball paradigm to induce auditory duration mismatch negativity. Prediction errors to a deviant tone presentation were generated as offset calcium responses of layer 2/3 neurons in the rostral parabelt (RPB) of higher-order auditory cortex, while responses to non-deviant tones were strongly suppressed. Within several hundred milliseconds, the error signals propagated broadly into layer 1 of the primary auditory cortex (A1) and accumulated locally on top of incoming auditory signals. Blockade of RPB activity prevented deviance detection in A1. Optogenetic activation of RPB following tone presentation nonlinearly enhanced A1 tone response. Thus, the feedback error signal is critical for automatic detection of unpredicted stimuli in physiological auditory processing and may serve as backpropagation-like learning.

Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus.

The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader-Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the GOLGA cores and HERC segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.

Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.