CD20 deficiency in humans results in impaired T cell-independent antibody responses.

CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in "cryptic" splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell-independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses.

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer.

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Common genetic variation and the control of HIV-1 in humans.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

Small-bodied humans from Palau, Micronesia.

UNLABELLED: Newly discovered fossil assemblages of small bodied Homo sapiens from Palau, Micronesia possess characters thought to be taxonomically primitive for the genus Homo. BACKGROUND: Recent surface collection and test excavation in limestone caves in the rock islands of Palau, Micronesia, has produced a sizeable sample of human skeletal remains dating roughly between 940-2890 cal ybp. PRINCIPLE FINDINGS: Preliminary analysis indicates that this material is important for two reasons. First, individuals from the older time horizons are small in body size even relative to "pygmoid" populations from Southeast Asia and Indonesia, and thus may represent a marked case of human insular dwarfism. Second, while possessing a number of derived features that align them with Homo sapiens, the human remains from Palau also exhibit several skeletal traits that are considered to be primitive for the genus Homo. SIGNIFICANCE: These features may be previously unrecognized developmental correlates of small body size and, if so, they may have important implications for interpreting the taxonomic affinities of fossil specimens of Homo.

Gene expression signatures of radiation response are specific, durable and accurate in mice and humans.

BACKGROUND: Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. METHODS AND FINDINGS: We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100% specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90% and 81%, respectively. CONCLUSIONS: We conclude that PB gene expression profiles can be identified in mice and humans that are accurate in predicting medical conditions, are specific to each condition and remain highly accurate over time.

Same-sex gaze attraction influences mate-choice copying in humans.

Mate-choice copying occurs when animals rely on the mating choices of others to inform their own mating decisions. The proximate mechanisms underlying mate-choice copying remain unknown. To address this question, we tracked the gaze of men and women as they viewed a series of photographs in which a potential mate was pictured beside an opposite-sex partner; the participants then indicated their willingness to engage in a long-term relationship with each potential mate. We found that both men and women expressed more interest in engaging in a relationship with a potential mate if that mate was paired with an attractive partner. Men and women's attention to partners varied with partner attractiveness and this gaze attraction influenced their subsequent mate choices. These results highlight the prevalence of non-independent mate choice in humans and implicate social attention and reward circuitry in these decisions.

Hyperpolarized Xe MR imaging of alveolar gas uptake in humans.

BACKGROUND: One of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange. METHODS AND PRINCIPAL FINDINGS: Here we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) (129)Xe to probe the regional uptake of alveolar gases by directly imaging HP (129)Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP (129)Xe magnetization is rapidly replenished by diffusive exchange with alveolar (129)Xe. The dissolved HP (129)Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs. CONCLUSIONS: The features observed in dissolved-phase (129)Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP (129)Xe imaging reports on pulmonary function at a fundamental level.

A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.

Antibiotic resistance-the need for global solutions.

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Of mice, birds, and men: the mouse ultrasonic song system has some features similar to humans and song-learning birds.

Humans and song-learning birds communicate acoustically using learned vocalizations. The characteristic features of this social communication behavior include vocal control by forebrain motor areas, a direct cortical projection to brainstem vocal motor neurons, and dependence on auditory feedback to develop and maintain learned vocalizations. These features have so far not been found in closely related primate and avian species that do not learn vocalizations. Male mice produce courtship ultrasonic vocalizations with acoustic features similar to songs of song-learning birds. However, it is assumed that mice lack a forebrain system for vocal modification and that their ultrasonic vocalizations are innate. Here we investigated the mouse song system and discovered that it includes a motor cortex region active during singing, that projects directly to brainstem vocal motor neurons and is necessary for keeping song more stereotyped and on pitch. We also discovered that male mice depend on auditory feedback to maintain some ultrasonic song features, and that sub-strains with differences in their songs can match each other's pitch when cross-housed under competitive social conditions. We conclude that male mice have some limited vocal modification abilities with at least some neuroanatomical features thought to be unique to humans and song-learning birds. To explain our findings, we propose a continuum hypothesis of vocal learning.

New World Gold Cultural Anxiety and Monetary Disorder in Early Modern Spain

Elvira Vilches examines economic treatises, stories of travel and conquest, moralist writings, fiction, poetry, and drama to reveal that New World gold ultimately became a problematic source of power that destabilized Spain’s sense of ...

Response to Comment on "Whole-genome analyses resolve early branches in the tree of life of modern birds".

Mitchell et al. argue that divergence-time estimates for our avian phylogeny were too young because of an "inappropriate" maximum age constraint for the most recent common ancestor of modern birds and that, as a result, most modern bird orders diverged before the Cretaceous-Paleogene mass extinction event 66 million years ago instead of after. However, their interpretations of the fossil record and timetrees are incorrect.