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The cerebral cortex contains multiple, distinct areas that individually perform specific computations. A particular strength of the cortex is the communication of signals between cortical areas that allows the outputs of these compartmentalized computations to influence and build on each other, thereby dramatically increasing the processing power of the cortex and its role in sensation, action, and cognition. Determining how the cortex communicates signals between individual areas is, therefore, critical for understanding cortical function. Historically, corticocortical communication was thought to occur exclusively by direct anatomical connections between areas that often sequentially linked cortical areas in a hierarchical fashion. More recently, anatomical, physiological, and behavioral evidence is accumulating indicating a role for the higher-order thalamus in corticocortical communication. Specifically, the transthalamic pathway involves projections from one area of the cortex to neurons in the higher-order thalamus that, in turn, project to another area of the cortex. Here, we consider the evidence for and implications of having two routes for corticocortical communication with an emphasis on unique processing available in the transthalamic pathway and the consequences of disorders and diseases that affect transthalamic communication., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Competing Interests: Competing interests: None declared.

In 1998, Jones suggested a classification of thalamocortical projections into core and matrix divisions (Jones, 1998). In this classification, core projections are specific, topographical, innervate middle cortical layers, and serve to transmit specific information to the cortex for further analysis; matrix projections, in contrast, are diffuse, much less topographic, innervate upper layers, especially Layer 1, and serve a more global, modulatory function, such as affecting levels of arousal. This classification has proven especially influential in studies of thalamocortical relationships. Whereas it may be the case that a clear subset of thalamocortical connections fit the core motif, since they are specific, topographic, and innervate middle layers, we argue that there is no clear evidence for any single class that encompasses the remainder of thalamocortical connections as is claimed for matrix. Instead, there is great morphological variation in connections made by thalamocortical projections fitting neither a core nor matrix classification. We thus conclude that the core/matrix classification should be abandoned, because its application is not helpful in providing insights into thalamocortical interactions and can even be misleading. As one example of the latter, recent suggestions indicate that core projections are equivalent to first-order thalamic relays (i.e., those that relay subcortical information to the cortex) and matrix to higher-order relays (i.e., those that relay information from one cortical area to another), but available evidence does not support this relationship. All of this points to a need to replace the core/matrix grouping with a more complete classification of thalamocortical projections., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Objective: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC)., Methods: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication., Results: We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10 - 8 , with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A (P = 0.012) in healthy colon mucosa., Conclusions: Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms., (© 2024. The Author(s).)

First-order thalamic nuclei receive feedforward signals from peripheral receptors and relay these signals to primary sensory cortex. Primary sensory cortex, in turn, provides reciprocal feedback to first-order thalamus. Because the vast majority of sensory thalamocortical inputs target primary sensory cortex, their complementary corticothalamic neurons are assumed to be similarly restricted to primary sensory cortex. We upend this assumption by characterizing morphologically diverse neurons in multiple mid-level visual cortical areas of the primate ( Macaca mulatta ) brain that provide direct feedback to the primary visual thalamus, the dorsal lateral geniculate nucleus (LGN). Although the majority of geniculocortical neurons project to primary visual cortex (V1), a minority, located mainly in the koniocellular LGN layers, provide direct input to extrastriate visual cortex. These "V1-bypassing" projections may be implicated in blindsight. We hypothesized that geniculocortical inputs directly targeting extrastriate cortex should be complemented by reciprocal corticogeniculate circuits. Using virus-mediated circuit tracing, we discovered corticogeniculate neurons throughout three mid-level extrastriate areas: MT, MST, and V4. Quantitative morphological analyses revealed nonuniform distributions of unique cell types across areas. Many extrastriate corticogeniculate neurons had spiny stellate morphology, suggesting possible targeting of koniocellular LGN layers. Importantly though, multiple morphological types were observed across areas. Such morphological diversity could suggest parallel streams of V1-bypassing corticogeniculate feedback at multiple stages of the visual processing hierarchy. Furthermore, the presence of corticogeniculate neurons across visual cortex necessitates a reevaluation of the LGN as a hub for visual information rather than a simple relay., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Adusei et al.)

Industrial plasma fractionation, a complex and highly regulated technology, remains largely inaccessible to many low- and middle-income countries (LMICs). This, combined with the limited availability and high cost of plasma-derived medicinal products (PDMPs), creates deficiency of access to adequate treatment for patients in resource-limited countries, and leads to their suffering. Meanwhile, an increasing number of LMICs produce surplus plasma, as a by-product of red blood cell preparation from whole blood, that is discarded because of the lack of suitability for fractionation. This article reviews pragmatic technological options for processing plasma collected from LMICs into therapies and supports a realistic stepwise approach aligned with recent World Health Organization guidance and initiatives launched by the Working Party for Global Blood Safety of the International Society of Blood Transfusion. When industrial options based on contract or toll plasma fractionation programme and, even more, domestic fractionation facilities require larger volumes of quality plasma than is produced, alternative methods should be considered. In-bag minipool or small-scale production procedures implementable in blood establishments or national service centres are the only realistic options available to gradually reduce plasma wastage, provide safer treatments for patients currently treated with non-pathogen-reduced blood products and concurrently improve Good Manufacturing Practice (GMP) levels with minimum capital investment. As a next step, when the available volume of quality-assured plasma reaches the necessary thresholds, LMICs could consider engaging with an established fractionator in a fractionation agreement or a contract in support of a domestic fractionation facility to improve the domestic PDMP supply and patients' treatment., (© 2023 International Society of Blood Transfusion.)

Studies investigating neural information processing often implicitly ask both, which processing strategy out of several alternatives is used and how this strategy is implemented in neural dynamics. A prime example are studies on predictive coding. These often ask whether confirmed predictions about inputs or prediction errors between internal predictions and inputs are passed on in a hierarchical neural system-while at the same time looking for the neural correlates of coding for errors and predictions. If we do not know exactly what a neural system predicts at any given moment, this results in a circular analysis-as has been criticized correctly. To circumvent such circular analysis, we propose to express information processing strategies (such as predictive coding) by local information-theoretic quantities, such that they can be estimated directly from neural data. We demonstrate our approach by investigating two opposing accounts of predictive coding-like processing strategies, where we quantify the building blocks of predictive coding, namely predictability of inputs and transfer of information, by local active information storage and local transfer entropy. We define testable hypotheses on the relationship of both quantities, allowing us to identify which of the assumed strategies was used. We demonstrate our approach on spiking data collected from the retinogeniculate synapse of the cat (N = 16). Applying our local information dynamics framework, we are able to show that the synapse codes for predictable rather than surprising input. To support our findings, we estimate quantities applied in the partial information decomposition framework, which allow to differentiate whether the transferred information is primarily bottom-up sensory input or information transferred conditionally on the current state of the synapse. Supporting our local information-theoretic results, we find that the synapse preferentially transfers bottom-up information., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2023 Wollstadt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC)., Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I ( A , B , and C ) and HLA class -II loci ( DQB1 , DRB1 , and DPB1 ) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357)., Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p = 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p = 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p = 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant., Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC., Competing Interests: GI: receives/received research funding from Myriad Genetics and Laboratories. JG: consultant for Guardant Health. VM: owns stock in Aniling. SG: Co-founder of Brogent International LLC with equity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsai, Qu, Bonner, Sanz-Pamplona, Lindsey, Melas, McDonnell, Idos, Walker, Tsang, Da Silva, Moratalla-Navarro, Maoz, Rennert, Kast, Greenson, Moreno, Rennert, Gruber and Schmit.)

Burst activity is a ubiquitous feature of thalamic neurons and is well documented for visual neurons in the lateral geniculate nucleus (LGN). Although bursts are often associated with states of drowsiness, they are also known to convey visual information to cortex and are particularly effective in evoking cortical responses. The occurrence of thalamic bursts depends on (1) the inactivation gate of T-type Ca 2+ channels (T-channels), which become de-inactivated following periods of increased membrane hyperpolarization, and (2) the opening of the T-channel activation gate, which has voltage-threshold and rate-of-change (δv/δt) requirements. Given the time/voltage relationship for the generation of Ca 2+ potentials that underlie burst events, it is reasonable to predict that geniculate bursts are influenced by the luminance contrast of drifting grating stimuli, with the null phase of higher contrast stimuli evoking greater hyperpolarization followed by a larger dv/dt than the null phase of lower contrast stimuli. To determine the relationship between stimulus contrast and burst activity, we recorded the spiking activity of cat LGN neurons while presenting drifting sine-wave gratings that varied in luminance contrast. Results show that burst rate, reliability, and timing precision are significantly greater with higher contrast stimuli compared with lower contrast stimuli. Additional analysis from simultaneous recordings of synaptically connected retinal ganglion cells and LGN neurons further reveals the time/voltage dynamics underlying burst activity. Together, these results support the hypothesis that stimulus contrast and the biophysical properties underlying the state of T-type Ca 2+ channels interact to influence burst activity, presumably to facilitate thalamocortical communication and stimulus detection., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W. Martin Usrey reports financial support was provided by 10.13039/100000002National Institutes of Health., (© 2023 The Authors.)

The aim of this study was to classify the diversity of anal HPV and non-HPV sexually transmitted infections (STIs) and compare the concordance between anal and genital infections in HIV-infected and uninfected women living in the Tapajós region, Amazon, Brazil. A cross-sectional study was performed with 112 HIV-uninfected and 41 HIV-infected nonindigenous women. Anal and cervical scrapings were collected and analyzed for HPV, Chlamydia trachomatis (CT) , Neisseria gonorrheae (NG), Trichomonas vaginalis (TV), Mycoplasma genitalium (MG), and Human alphaherpesvirus 2 (HSV-2). The Kappa test evaluated the concordance between anal and genital infections. The overall prevalence of anal HPV infection was 31.3% in HIV-uninfected and 97.6% in HIV-infected women. The most frequent anal high-risk HPV (hrHPV) types were HPV18 and HPV16 in HIV-uninfected women and HPV51, HPV59, HPV31, and HPV58 in HIV-infected women. Anal HPV75 Betapapillomavirus was also identified. Anal non-HPV STIs were identified in 13.0% of all participants. The concordance analysis was fair for CT, MG, and HSV-2, almost perfect agreement for NG, moderate for HPV, and variable for the most frequent anal hrHPV types. Thus, a high prevalence of anal HPV infection with moderate and fair concordance between anal and genital HPV and non-HPV STIs was observed in our study.

Determinants of parental HPV vaccine hesitancy, including medical mistrust and exposure to negative vaccine information, are understudied in racial/ethnic minority communities where vaccine uptake is low. We conducted a cross-sectional survey (March 2021) among parents of adolescents, ages 9-17 years, from an academic enrichment program serving low-income, first-generation, underrepresented minority families in Los Angeles to understand determinants of parental HPV vaccine hesitancy. Parents completed self-administered surveys, including a 9-item HPV vaccine hesitancy scale, in either English, Spanish, or Chinese. Logistic regression was used to identify individual and interpersonal factors associated with parental hesitancy and adolescent HPV vaccination. One-fifth of parents (n = 357) reported high HPV vaccine hesitancy and > 50% reported concerns about safety or side effects. High medical mistrust was associated with high parental HPV vaccine hesitancy (adjusted-OR 1.69, 95% CI: 1.13, 2.37). Community-tailored and multilevel strategies to increase vaccine confidence are needed to improve HPV and other adolescent vaccinations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Human papillomavirus (HPV) vaccine hesitancy is a growing concern in the United States, yet understudied among racial/ethnic minority parents. We conducted qualitative research to understand parental HPV vaccine hesitancy and inform community-specific, multilevel approaches to improve HPV vaccination among diverse populations in Los Angeles., Methods: We recruited American Indian/Alaska Native (AI/AN), Hispanic/Latino/a (HL) and Chinese parents of unvaccinated children (9-17 years) from low-HPV vaccine uptake regions in Los Angeles for virtual focus groups (FGs). FGs were conducted in English (2), Mandarin (1), and Spanish (1) between June-August 2021. One English FG was with AI/AN-identifying parents. FGs prompted discussions about vaccine knowledge, sources of information/hesitancy, logistical barriers and interpersonal, healthcare and community interactions regarding HPV vaccination. Guided by the social-ecological model, we identified multilevel emergent themes related to HPV vaccination., Results: Parents (n = 20) in all FGs reported exposure to HPV vaccine information from the internet and other sources, including in-language media (Mandarin) and health care providers (Spanish). All FGs expressed confusion around the vaccine and had encountered HPV vaccine misinformation. FGs experienced challenges navigating relationships with children, providers, and friends/family for HPV vaccine decision-making. At the community-level, historical events contributed to mistrust (e.g., forced community displacement [AI/AN]). At the societal-level, transportation, and work schedules (Spanish, AI/AN) were barriers to vaccination. Medical mistrust contributed to HPV vaccine hesitancy across the analysis levels., Conclusion: Our findings highlight the importance of multilevel influences on parental HPV vaccine hesitancy and decision-making and the need for community-specific messaging to combat medical mistrust and other barriers to HPV vaccination among racial/ethnic minority communities., (© 2023. The Author(s).)

Competing Interests: Declaration of interests The authors disclose no conflicts.

Objective: We assessed the association between gendered racism, the simultaneous experience of sexism and racism, depression, and psychological distress in Black college women using an intersectional instrument, the gendered racial microaggression scale. Participants: Black college women enrolled at a predominantly white institution (PWI) in the southeastern U.S. (N = 164, response rate = 77%, mean age 21.67). Methods: We used a cross-sectional survey to explore the impact of stress appraisal and frequency of gendered racial microaggressions on depression and psychological distress using validated scales. Results: 30% reported depression and 54% reported severe psychological distress. Correlations indicate significant relationships between gendered racism, depression and psychological distress, with the strongest relation reported between the frequency of gendered racism to depression. Regression analyses suggest significant relationships between gendered racism, depression and psychological distress. Conclusion: Gendered racism has significant bearing on the mental health of Black college women attending a PWI. Implications for interventions are discussed.

Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of the vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using a HPV16E7E6 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8 + T cell response with at minimum a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.

This document provides a commentary and further elaboration on the conclusions reached during a recent international workshop on plasma protein therapies organized by the Working Party for Global Safety of the International Society of Blood Transfusion (ISBT). The workshop addressed the profound deficiency in access to safe plasma protein therapies that persists in low- and middle-income countries (LMICs). We provide additional factual economic and technological information that highlights why local production of small-scale virus-inactivated concentrates of clotting factors and immune globulins from domestic recovered plasma through stepwise introduction of available validated technologies is a pragmatic approach to gradually improve the care of patients with bleeding disorders and immune deficiencies in LMIC while supporting progress toward fractionation of plasma. This strategy is in line with a recent WHO guidance. We stress that the active involvement of international blood donor and blood transfusion organizations, patient organizations, governments and industry will be essential in supporting stepwise and sustainable improvements in access to safe, effective, and quality assured plasma protein therapies., Competing Interests: Declaration of competing interest The authors declare that the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

Before visual information from the retina reaches primary visual cortex (V1), it is dynamically filtered by the lateral geniculate nucleus (LGN) of the thalamus, the first location within the visual hierarchy at which nonretinal structures can significantly influence visual processing. To explore the form and dynamics of geniculate filtering we used data from monosynpatically connected pairs of retinal ganglion cells (RGCs) and LGN relay cells in the cat that, under anesthetized conditions, were stimulated with binary white noise and/or drifting sine-wave gratings to train models of increasing complexity to predict which RGC spikes were relayed to cortex, what we call "relay status." In addition, we analyze and compare a smaller dataset recorded in the awake state to assess how anesthesia might influence our results. Consistent with previous work, we find that the preceding retinal interspike interval (ISI) is the primary determinate of relay status with only modest contributions from longer patterns of retinal spikes. Including the prior activity of the LGN cell further improved model predictions, primarily by indicating epochs of geniculate burst activity in recordings made under anesthesia, and by allowing the model to capture gain control-like behavior within the awake LGN. Using the same modeling framework, we further demonstrate that the form of geniculate filtering changes according to the level of activity within the early visual circuit under certain stimulus conditions. This finding suggests a candidate mechanism by which a stimulus specific form of gain control may operate within the LGN., (Copyright © 2022 Alexander et al.)

Competing Interests: Competing interests: None declared.

Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Throughout the brain, parallel processing streams compose the building blocks of complex neural functions. One of the most salient models for studying the functional specialization of parallel visual streams in the primate brain is the lateral geniculate nucleus (LGN) of the dorsal thalamus, through which the parvocellular and magnocellular channels, On-center and Off-center channels, and ipsilateral and contralateral eye channels are maintained and provide the foundation for cortical processing. We examined three aspects of neural processing in these streams: (1) the relationship between extraclassical surround suppression, a widespread visual computation thought to represent a canonical neural computation, and the parallel channels of the LGN; (2) the magnitude of binocular interaction in the parallel streams; and (3) the magnitude of suppression elicited by perceptual competition (binocular rivalry) in each stream. Our results show that surround suppression is almost exclusive to Off channel cells; further, we found evidence for two different components of monocular surround suppression-an early-stage suppression exhibited by all magnocellular cells, and a late-stage suppression exhibited only by Off cells in both the parvocellular and magnocellular pathways. This finding indicates that stream-specific circuits contribute to surround suppression in the primate LGN and suggests a distinct role for suppression in the Off channel to the cortex. We also examined the responses of LGN neurons in alert macaque monkeys to determine whether neurons that supply the cortex with visual information are influenced by stimulation of both eyes. Our results demonstrate that LGN neurons are not influenced by stimulation of the non-dominant eye. This was the case when dichoptic stimuli were presented to classical receptive fields of neurons, extraclassical receptive fields of neurons, and when stimuli were appropriate to produce the perception of binocular rivalry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lankow and Usrey.)

Telerehabilitation is becoming increasingly valuable as a method for expanding medical services. The smartphone-based mHealth platform (SMPT) has been developed to provide high-quality remote rehabilitation through a smartphone and inertial measurement units. The SMPT uses smartphone as a main platform with connection to medical backend server to provide telerehabilitation. Patients would be referred to therapists to receive a tutorial of exercise technique prior to conducting their home exercise. Once patients begin their home exercises, they can report any problems instantly through the SMPT. The medical staff can adjust the exercise program according to patient feedback and the data collected by the SMPT. After completing the exercise program, patients visit their clinician for re-evaluation. A Service User Technology Acceptability Questionnaire from both medical professional and public perspective revealed a high level of agreement on enhanced care, increased accessibility, and satisfaction and a moderate level of agreement on the use of this platform as a substitute for traditional rehabilitation. Concerns about privacy and discomfort were low in the medical professional and public groups. Concerns about care personnel were also significantly different between the two groups. The SMPT is a promising system for providing telerehabilitation as an adjunct to traditional rehabilitation, which may result in improved outcomes compared with those achieved when using traditional rehabilitation alone.

For animals to survive, they must interact with their environment, taking in sensory information and making appropriate motor responses. Early on during vertebrate evolution, this was accomplished with neural circuits located mostly within the spinal cord and brainstem. As the cerebral cortex evolved, it provided additional and powerful advantages for assessing environmental cues and guiding appropriate responses. Importantly, the cerebral cortex was added onto an already functional nervous system. Moreover, every cortical area, including areas traditionally considered sensory, provides input to the subcortical motor structures that are bottlenecks for driving action. These facts have important ramifications for cognitive aspects of motor control. Here we consider the evolution of cortical mechanisms for attention from the perspective of having to work through these subcortical bottlenecks. From this perspective, many features of attention can be explained, including the preferential engagement of some cortical areas at the cost of disengagement from others to improve appropriate behavioral responses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The lack of definitive treatment or preventative options for COVID-19 led many clinicians early on to consider convalescent plasma (CCP) as potentially therapeutic. Regulators, blood centres and hospitals worldwide worked quickly to get CCP to the bedside. Although response was admirable, several areas have been identified to help improve future pandemic management., Materials and Methods: A multidisciplinary, multinational subgroup from the ISBT Working Group on COVID-19 was tasked with drafting a manuscript that describes the lessons learned pertaining to procurement and administration of CCP, derived from a comprehensive questionnaire within the subgroup., Results: While each country's responses and preparedness for the pandemic varied, there were shared challenges, spanning supply chain disruptions, staffing, impact of social distancing on the collection of regular blood and CCP products, and the availability of screening and confirmatory SARS-CoV-2 testing for donors and patients. The lack of a general framework to organize data gathering across clinical trials and the desire to provide a potentially life-saving therapeutic through compassionate use hampered the collection of much-needed safety and outcome data worldwide. Communication across all stakeholders was identified as being central to reducing confusion., Conclusion: The need for flexibility and adaptability remains paramount when dealing with a pandemic. As the world approaches the first anniversary of the COVID-19 pandemic with rising rates worldwide and over 115 million cases and 2·55 million deaths, respectively, it is important to reflect on how to better prepare for future pandemics as we continue to combat the current one., (© 2021 International Society of Blood Transfusion.)

Gain-control mechanisms adjust neuronal responses to accommodate the wide range of stimulus conditions in the natural environment. Contrast gain control and extraclassical surround suppression are two manifestations of gain control that govern the responses of neurons in the early visual system. Understanding how these two forms of gain control interact has important implications for the detection and discrimination of stimuli across a range of contrast conditions. Here, we report that stimulus contrast affects spatial integration in the lateral geniculate nucleus of alert macaque monkeys (male and female), whereby neurons exhibit a reduction in the strength of extraclassical surround suppression and an expansion in the preferred stimulus size with low-contrast stimuli compared with high-contrast stimuli. Effects were greater for magnocellular neurons than for parvocellular neurons, indicating stream-specific interactions between stimulus contrast and stimulus size. Within the magnocellular pathway, contrast-dependent effects were comparable for ON-center and OFF-center neurons, despite ON neurons having larger receptive fields, less pronounced surround suppression, and more pronounced contrast gain control than OFF neurons. Together, these findings suggest that the parallel streams delivering visual information from retina to primary visual cortex, serve not only to broaden the range of signals delivered to cortex, but also to provide a substrate for differential interactions between stimulus contrast and stimulus size that may serve to improve stimulus detection and stimulus discrimination under pathway-specific lower and higher contrast conditions, respectively. SIGNIFICANCE STATEMENT Stimulus contrast is a salient feature of visual scenes. Here we examine the influence of stimulus contrast on spatial integration in the lateral geniculate nucleus (LGN). Our results demonstrate that increases in contrast generally increase extraclassical suppression and decrease the size of optimal stimuli, indicating a reduction in the extent of visual space from which LGN neurons integrate signals. Differences between magnocellular and parvocellular neurons are noteworthy and further demonstrate that the feedforward parallel pathways to cortex increase the range of information conveyed for downstream cortical processing, a range broadened by diversity in the ON and OFF pathways. These results have important implications for more complex visual processing that underly the detection and discrimination of stimuli under varying natural conditions., (Copyright © 2021 the authors.)

DPX is a unique T cell activating formulation that generates robust immune responses (both clinically and preclinically) which can be tailored to various cancers via the use of tumor-specific antigens and adjuvants. While DPX-based immunotherapies may act complementary with checkpoint inhibitors, combination therapy is not always easily predictable based on individual therapeutic responses. Optimizing these combinations can be improved by understanding the mechanism of action underlying the individual therapies. Magnetic Resonance Imaging (MRI) allows tracking of cells labeled with superparamagnetic iron oxide (SPIO), which can yield valuable information about the localization of crucial immune cell subsets. In this work, we evaluated the use of a multi-echo, single point MRI pulse sequence, TurboSPI, for tracking and quantifying cytotoxic T lymphocytes (CTLs) and myeloid lineage cells (MLCs). In a subcutaneous cervical cancer model (C3) we compared untreated mice to mice treated with either a single therapy (anti-PD-1 or DPX-R9F) or a combination of both therapies. We were able to detect, using TurboSPI, significant increases in CTL recruitment dynamics in response to combination therapy. We also observed differences in MLC recruitment to therapy-draining (DPX-R9F) lymph nodes in response to treatment with DPX-R9F (alone or in combination with anti-PD-1). We demonstrated that the therapies presented herein induced time-varying changes in cell recruitment. This work establishes that these quantitative molecular MRI techniques can be expanded to study a number of cancer and immunotherapy combinations to improve our understanding of longitudinal immunological changes and mechanisms of action., Competing Interests: At the time of writing this manuscript, MLT, GW, and MS were employees of IMV Inc., who manufactures DPX-based immunotherapies. KDB also had a research contract with IMV for an unrelated project., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment., Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot., Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16 + patients and in 2 of 3 HPV18 + patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival., Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response., (©2020 American Association for Cancer Research.)

Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and β defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes., (Copyright © 2020 Skeate, Segerink, Garcia, Fernandez, Prins, Lühen, Voss, Da Silva and Kast.)

Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8 + T cells stimulated with TAP low dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer., (©2020 American Association for Cancer Research.)

Tumor necrosis factor superfamily member 14 (LIGHT) has been in pre-clinical development for over a decade and shows promise as a modality of enhancing treatment approaches in the field of cancer immunotherapy. To date, LIGHT has been used to combat cancer in multiple tumor models where it can be combined with other immunotherapy modalities to clear established solid tumors as well as treat metastatic events. When LIGHT molecules are delivered to or expressed within tumors they cause significant changes in the tumor microenvironment that are primarily driven through vascular normalization and generation of tertiary lymphoid structures. These changes can synergize with methods that induce or support anti-tumor immune responses, such as checkpoint inhibitors and/or tumor vaccines, to greatly improve immunotherapeutic strategies against cancer. While investigators have utilized multiple vectors to LIGHT-up tumor tissues, there are still improvements needed and components to be found within a human tumor microenvironment that may impede translational efforts. This review addresses the current state of this field., (Copyright © 2020 Skeate, Otsmaa, Prins, Fernandez, Da Silva and Kast.)

Langerhans cells (LC) are the resident antigen presenting cells of the mucosal epithelium and play an essential role in initiating immune responses. LC are the only cells in the body to contain Birbeck granules (BG), which are unique cytoplasmic organelles comprised of c-type lectin langerin. Studies of BG have historically focused on morphological characterizations, but BG have also been implicated in viral antigen processing which suggests that they can serve a function in antiviral immunity. This study focused on investigating proteins that could be involved in BG formation to further characterize their structure using transmission electron microscopy (TEM). Here, we report a critical role for the protein annexin A2 (anxA2) in the proper formation of BG structures. When anxA2 expression is downregulated, langerin expression decreases, cytoplasmic BG are nearly ablated, and the presence of malformed BG-like structures increases. Furthermore, in the absence of anxA2, we found langerin was no longer localized to BG or BG-like structures. Taken together, these results indicate an essential role for anxA2 in facilitating the proper formation of BG.

Background: The eighth international symposium for sentinel node biopsy (SNB) in head and neck cancer was held in 2018. This consensus conference aimed to deliver current multidisciplinary guidelines. This document focuses on the surgical aspects of SNB for oral cancer., Method: Invited expert faculty selected topics requiring guidelines. Topics were reviewed and evidence evaluated where available. Data were presented at the consensus meeting, with live debate from panels comprising expert, nonexpert, and patient representatives followed by voting to assess the level of support for proposed recommendations. Evidence review, debate, and voting results were all considered in constructing these guidelines., Results/conclusion: A range of topics were considered, from patient selection to surgical technique and follow-up schedule. Consensus was not achieved in all areas, highlighting potential issues that would benefit from prospective studies. Nevertheless these guidelines represent an up-to-date pragmatic recommendation based on current evidence and expert opinion., (© 2019 Wiley Periodicals, Inc.)

Retinal signals are transmitted to cortex via neurons in the lateral geniculate nucleus (LGN), where they are processed in burst or tonic response mode. Burst mode occurs when LGN neurons are sufficiently hyperpolarized for T-type Ca 2+ channels to deinactivate, allowing them to open in response to depolarization, which can trigger a high-frequency sequence of Na + -based spikes (i.e., burst). In contrast, T-type channels are inactivated during tonic mode and do not contribute to spiking. Although burst mode is commonly associated with sleep and the disruption of retinogeniculate communication, bursts can also be triggered by visual stimulation, thereby transforming the retinal signals relayed to the cortex. To determine how burst mode affects retinogeniculate communication, we made recordings from monosynaptically connected retinal ganglion cells and LGN neurons in male/female cats during visual stimulation. Our results reveal a robust augmentation of retinal signals within the LGN during burst mode. Specifically, retinal spikes were more effective and often triggered multiple LGN spikes during periods likely to have increased T-type Ca 2+ channel activity. Consistent with the biophysical properties of T-type Ca 2+ channels, analysis revealed that effect magnitude was correlated with the duration of the preceding thalamic interspike interval and occurred even in the absence of classically defined bursts. Importantly, the augmentation of geniculate responses to retinal input was not associated with a degradation of visual signals. Together, these results indicate a graded nature of response mode and suggest that, under certain conditions, bursts facilitate the transmission of visual information to the cortex by amplifying retinal signals. SIGNIFICANCE STATEMENT The thalamus is the gateway for retinal information traveling to the cortex. The lateral geniculate nucleus, like all thalamic nuclei, has two classically defined categories of spikes-tonic and burst-that differ in their underlying cellular mechanisms. Here we compare retinogeniculate communication during burst and tonic response modes. Our results show that retinogeniculate communication is enhanced during burst mode and visually evoked thalamic bursts, thereby augmenting retinal signals transmitted to cortex. Further, our results demonstrate that the influence of burst mode on retinogeniculate communication is graded and can be measured even in the absence of classically defined thalamic bursts., (Copyright © 2019 the authors.)

Persistent human papillomavirus (HPV) infection is causally linked to the development of several human cancers, including cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancers. To address the need for a therapeutic vaccine against HPV-associated diseases, here we test and compare the immunogenicity and therapeutic efficacy of a bacterial exotoxin fusion protein covalently linked to the HPV16 E7 oncoprotein adjuvanted with CpG or GPI-0100 in the C3.43 preclinical HPV16-transformed tumor model. We show that TVGV-1 protein vaccine adjuvanted with either CpG or GPI-0100 adjuvant induces a high frequency of E7-specific CD8 + T cells, and both adjuvants are able to assist the immune response in inducing polyfunctional cytokine-secreting lytic T cells that show therapeutic efficacy against well-established C3.43 tumors. CpG-adjuvanted TVGV-1 resulted in higher frequencies of IFNγ secreting and degranulating E7-specific T cells compared to GPI-0100-adjuvanted TVGV-1, resulting in marginally increased in vivo efficacy. Despite minor differences in immune response outcomes, we consider both CpG ODN and GPI-0100 to be promising vaccine adjuvants to increase the immunogenicity and therapeutic efficacy of the TVGV-1 protein for HPV16-driven cancers., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Visual information processed in the retina is transmitted to primary visual cortex via relay cells in the lateral geniculate nucleus (LGN) of the dorsal thalamus. Although retinal ganglion cells are the primary source of driving input to LGN neurons, not all retinal spikes are transmitted to the cortex. Here, we investigate the relationship between stimulus contrast and retinogeniculate communication and test the hypothesis that both the time course and strength of retinogeniculate interactions are dynamic and dependent on stimulus contrast. By simultaneously recording the spiking activity of synaptically connected retinal ganglion cells and LGN neurons in the cat, we show that the temporal window for retinogeniculate integration and the effectiveness of individual retinal spikes are inversely proportional to stimulus contrast. This finding provides a mechanistic understanding for the phenomenon of augmented contrast gain control in the LGN-a nonlinear receptive field property of LGN neurons whereby response gain during low-contrast stimulation is enhanced relative to response gain during high-contrast stimulation. In addition, these results support the view that network interactions beyond the retina play an essential role in transforming visual signals en route from retina to cortex., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Pyramidal cells in cortical Layers 5 and 6 are the only cells in the cerebral cortex with axons that leave the cortex to influence the thalamus. Layer 6 cells provide modulatory feedback input to all thalamic nuclei. Layer 5 cells provide driving input to higher-order thalamic nuclei and do not innervate first-order nuclei, which get their driving inputs from subcortical sources. Higher-order nuclei innervated by Layer 5 cells thus seem to be involved with cortico-thalamo-cortical communication. The Layer 5 axons branch to also target additional subcortical structures that mediate interactions with the external environment. These corticofugal pathways represent the only means by which the cortex influences the rest of the neuraxis and thus are essential for proper cortical function and species survival. Here we review current understanding of the corticofugal pathways from Layers 5 and 6 and speculate on their functional contributions to neural processing and behavior., (© 2018 Wiley Periodicals, Inc.)

Attention is a critical component of visual perception; however, the mechanisms of attention at the granular level are poorly understood. One possible mechanism by which attention modulates neuronal activity is to control the efficacy of communication between connected neurons; however, it is unclear whether attention alters communication efficacy across a variety of neuronal circuits. In parallel, attentional modulation of neuronal firing rate is not uniform but depends upon the match between neuronal feature selectivity and the feature required for successful task completion. Here we tested whether modulation of communication efficacy is a viable mechanism of attention by assessing whether it is consistent across a variety of neuronal circuits and dependent upon the type of information conveyed in each circuit. We identified monosynaptically connected pairs of V1 neurons through cross-correlation of neuronal spike trains recorded in adult female macaque monkeys performing attention-demanding contrast-change detection tasks. Attention toward the stimulus in the receptive field of recorded neurons significantly facilitated the efficacy of communication among connected pairs of V1 neurons. The amount of attentional enhancement depended upon neuronal physiology, with larger facilitation for circuits conveying information about task-relevant features. Furthermore, presynaptic activity was more determinant of attentional enhancement of communication efficacy than postsynaptic activity, and feedforward local circuits often displayed the largest facilitation with attention. Together, these findings highlight attentional modulation of communication efficacy as a generalized mechanism of attention and demonstrate that attentional modulation at the granular level depends on the relevance of feature-specific information conveyed by neuronal circuits. SIGNIFICANCE STATEMENT How we pay attention to objects and locations in the visual environment has a profound impact on visual perception. Individual neurons in the visual cortex are similarly regulated by shifts in visual attention; however, the rules that govern whether and how attention alters neuronal activity are not known. In this study, we explored whether attention regulates communication between connected pairs of neurons in the primary visual cortex. We observed robust attentional facilitation of communication among these circuits. Furthermore, the extent to which the circuits were facilitated by attention depended on whether the information they conveyed was relevant for the particular attention task., (Copyright © 2019 the authors 0270-6474/19/391066-11$15.00/0.)

Viral life cycles consist of three main phases: (1) attachment and entry, (2) genome replication and expression, and (3) assembly, maturation, and egress. Each of these steps is intrinsically reliant on host cell factors and processes including cellular receptors, genetic replication machinery, endocytosis and exocytosis, and protein expression. Annexin A2 (AnxA2) is a membrane-associated protein with a wide range of intracellular functions and a recurrent host factor in a variety of viral infections. Spatially, AnxA2 is found in the nucleus and cytoplasm, vesicle-bound, and on the inner and outer leaflet of the plasma membrane. Structurally, AnxA2 exists as a monomer or in complex with S100A10 to form the AnxA2/S100A10 heterotetramer (A2t). Both AnxA2 and A2t have been implicated in a vast array of cellular functions such as endocytosis, exocytosis, membrane domain organization, and translational regulation through RNA binding. Accordingly, many discoveries have been made involving AnxA2 in viral pathogenesis, however, the reported work addressing AnxA2 in virology is highly compartmentalized. Therefore, the purpose of this mini review is to provide information regarding the role of AnxA2 in the lifecycle of multiple epithelial cell-targeting viruses to highlight recurrent themes, identify discrepancies, and reveal potential avenues for future research.

Background: Prior small studies have shown increased expression of sperm protein 17 (Sp17) in epithelial ovarian cancer (EOC) tissue and suggest Sp17 as a potential biomarker for EOC. However, how Sp17 expression varies with histology, grade, and stage of EOC and its expression in other ovarian neoplasms has not been defined. It is unknown whether patients with EOC have elevated serum Sp17 levels or if Sp17 expression is associated with survival outcomes., Methods: The study included 982 patients with benign, borderline, and malignant ovarian neoplasms and normal ovary. There were 878 patients with tissue only, 39 with serum only, and 65 with matching serum and tissue. Immunohistochemical (IHC) staining with anti-Sp17 antibody was performed on tissue specimens and the intensity scored as weak, moderate, or strong. A sandwich enzyme-linked immunosorbent assay (ELISA) was performed to measure Sp17 sera concentrations., Results: Sp17 expression was most commonly seen in serous cystadenomas (83%) and serous borderline tumors (100%). Of the 773 EOC specimens, 223 (30%) expressed Sp17. Grade and histology were significantly associated with Sp17 expression among EOC specimens (p < 0.001) on both univariate and multivariable analysis, with grade 1 serous adenocarcinomas showing the highest expression (51%). Sp17 expression was limited in other benign and non-epithelial malignant neoplasms. Neither Sp17 tissue expression nor serum concentration correlated with survival outcomes. Serum concentrations were higher in patients with Sp17 tissue expression, and the highest concentrations were noted among patients with serous and clear cell adenocarcinomas., Conclusions: Sp17 is highly expressed in benign, borderline, and low grade malignant serous ovarian neoplasms and can be quantified in serum. Sp17 expression may have diagnostic significance in this subset of patients.

Objective: We evaluated acceptability of cervico-vaginal self-collection (CVSC) and prevalence of human papillomavirus (HPV) in Human immunodeficiency virus (HIV)-infected and HIV-uninfected women living in the Tapajós region, Amazon, Brazil., Methods: Cross-sectional study recruited 153 non-indigenous women (HIV-uninfected, n = 112 and HIV-infected, n = 41) who voluntarily sought assistance in health services. Peripheral blood for HIV screening and cervical scraping (CS) for HPV detection were collected. Women who accepted to perform CVSC received instructions and individual collection kits. Risk factors for high-risk HPV genotypes (hrHPV) were identified by uni- and multivariate analyses., Results: The overall acceptability of CVSC was 87%. Only HIV-infected women had cytological abnormalities (12.2%). Prevalence of any HPV and hrHPV infection was 42.9% and 47.9% for HIV-uninfected and 97.6% and 77.5% for HIV-infected women, respectively. There was significant agreement in the detection of HPV (88%, 0.76, 95% confidence interval [CI], 0.65-0.87) and hrHPV (79.7%, 0.56, 95% CI, 0.41-0.71) between self-collected and clinician-collected samples. The most prevalent hrHPV types were HPV16 and HPV18 in HIV-uninfected and HPV16, HPV51 and HPV59 in HIV-infected women. HIV-infected women with hrHPV infection had multiple hrHPV infections (p = 0.005) and lower CD4 count (p = 0.018). Risk factors for hrHPV infection included being HIV-infected and having five or more sexual partners., Conclusions: CVSC had high acceptability and high prevalence of hrHPV types in women living in the Tapajós region, Amazon, Brazil., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Human papillomavirus (HPV) entry into epithelial cells is independent of canonical endocytic pathways. Upon interaction with host cells, HPV establishes infection by traversing through an endocytic pathway that is clathrin- and caveolin-independent, but dependent on the annexin A2/S100A10 heterotetramer (A2t). We examined the contribution of monomeric annexin A2 (AnxA2) vs. A2t in HPV infection and endocytosis, and further characterized the role of these molecules in protein trafficking. We specifically show that cell surface A2t is not required for HPV attachment, and in the absence of A2t virion internalization remains clathrin-independent. Without A2t, viral progression from early endosomes to multivesicular endosomes is significantly inhibited, capsid uncoating is dramatically reduced, and lysosomal degradation of HPV is accelerated. Furthermore, we present evidence that AnxA2 forms a complex with CD63, a known mediator of HPV trafficking. Overall, the observed reduction in infection is less significant in the absence of S100A10 alone compared to full A2t, supporting an independent role for monomeric AnxA2. More broadly, we show that successful infection by multiple oncogenic HPV types is dependent on A2t. These findings suggest that A2t is a central mediator of high-risk HPV intracellular trafficking post-entry and pre-viral uncoating.