Clones assemble! The clonal complexity of blood during ontogeny and disease.

Hematopoietic stem and progenitor cells (HSPCs) govern the daily expansion and turnover of billions of specialized blood cells. Given their clinical utility, much effort has been made toward understanding the dynamics of hematopoietic production from this pool of stem cells. An understanding of hematopoietic stem cell clonal dynamics during blood ontogeny could yield important insights into hematopoietic regulation, especially during aging and repeated exposure to hematopoietic stress-insults that may predispose individuals to the development of hematopoietic disease. Here, we review the current state of research regarding the clonal complexity of the hematopoietic system during embryogenesis, adulthood, and hematologic disease

Prelimbic cortex maintains attention to category-relevant information and flexibly updates category representations

Category learning groups stimuli according to similarity or function. This involves finding and attending to stimulus features that reliably inform category membership. Although many of the neural mechanisms underlying categorization remain elusive, models of human category learning posit that prefrontal cortex plays a substantial role. Here, we investigated the role of the prelimbic cortex (PL) in rat visual category learning by administering excitotoxic lesions before category training and then evaluating the effects of the lesions with computational modeling. Using a touchscreen apparatus, rats (female and male) learned to categorize distributions of category stimuli that varied along two continuous dimensions. For some rats, categorizing the stimuli encouraged selective attention towards a single stimulus dimension (i.e., 1D tasks). For other rats, categorizing the stimuli required divided attention towards both stimulus dimensions (i.e., 2D tasks). Testing sessions then examined generalization to novel exemplars. PL lesions impaired learning and generalization for the 1D tasks, but not the 2D tasks. Then, a neural network was fit to the behavioral data to examine how the lesions affected categorization. The results suggest that the PL facilitates category learning by maintaining attention to category-relevant information and updating category representations

Comparison of respondent-reported and sensor-recorded latrine utilization measures in rural Bangladesh: a cross-sectional study.

Background: Health improvements realized through sanitation are likely achieved through high levels of facilities utilization by all household members. However, measurements of sanitation often rely on either the presence of latrines, which does not guarantee use, or respondent-reported utilization of sanitation facilities, which is prone to response bias. Overstatement of sanitation metrics limits the accuracy of program outcome measures, and has implications for the interpretation of related health impact data. Methods: We conducted a cross-sectional study of 213 households in 14 village water, sanitation and hygiene committee clusters throughout rural Bangladesh and used a combined data- and relationship-scale approach to assess agreement between respondent-reported latrine utilization and sensor-recorded measurement. Results: Four-day household-level respondent-reported defecation averaged 28 events (inter-quartile range [IQR] 20-40), while sensor-recorded defecation averaged 17 events (IQR 11-29). Comparative analyses suggest moderately high accuracy (bias correction factor=0.84), but imprecision in the data (broad scatter of data, Pearson's r=0.35) and thus only weak concordance between measures (ρc=0.29 [95% BCa CI 0.15 to 0.43]). Conclusions: Respondent-reported latrine utilization data should be interpreted with caution, as evidence suggests use is exaggerated. Coupling reported utilization data with objective measures of use may aid in the estimation of latrine use

Selective attention in rat visual category learning

A prominent theory of category learning, COVIS, posits that new categories are learned with either a declarative or procedural system, depending on the task. The declarative system uses the prefrontal cortex (PFC) to learn rule-based (RB) category tasks in which there is one relevant sensory dimension that can be used to establish a rule for solving the task, whereas the procedural system uses corticostriatal circuits for information integration (II) tasks in which there are multiple relevant dimensions, precluding use of explicit rules. Previous studies have found faster learning of RB versus II tasks in humans and monkeys but not in pigeons. The absence of a learning rate difference in pigeons has been attributed to their lacking a PFC. A major gap in this comparative analysis, however, is the lack of data from a nonprimate mammalian species, such as rats, that have a PFC but a less differentiated PFC than primates. Here, we investigated RB and II category learning in rats. Similar to pigeons, RB and II tasks were learned at the same rate. After reaching a learning criterion, wider distributions of stimuli were presented to examine generalization. A second experiment found equivalent RB and II learning with wider category distributions. Computational modeling revealed that rats extract and selectively attend to category-relevant information but do not consistently use rules to solve the RB task. These findings suggest rats are on a continuum of PFC function between birds and primates, with selective attention but limited ability to utilize rules relative to primates

A generalised random encounter model for estimating animal density with remote sensor data

Summary: Wildlife monitoring technology is advancing rapidly and the use of remote sensors such as camera traps and acoustic detectors is becoming common in both the terrestrial and marine environments. Current methods to estimate abundance or density require individual recognition of animals or knowing the distance of the animal from the sensor, which is often difficult. A method without these requirements, the random encounter model (REM), has been successfully applied to estimate animal densities from count data generated from camera traps. However, count data from acoustic detectors do not fit the assumptions of the REM due to the directionality of animal signals. We developed a generalised REM (gREM), to estimate absolute animal density from count data from both camera traps and acoustic detectors. We derived the gREM for different combinations of sensor detection widths and animal signal widths (a measure of directionality). We tested the accuracy and precision of this model using simulations of different combinations of sensor detection widths and animal signal widths, number of captures and models of animal movement. We find that the gREM produces accurate estimates of absolute animal density for all combinations of sensor detection widths and animal signal widths. However, larger sensor detection and animal signal widths were found to be more precise. While the model is accurate for all capture efforts tested, the precision of the estimate increases with the number of captures. We found no effect of different animal movement models on the accuracy and precision of the gREM. We conclude that the gREM provides an effective method to estimate absolute animal densities from remote sensor count data over a range of sensor and animal signal widths. The gREM is applicable for count data obtained in both marine and terrestrial environments, visually or acoustically (e.g. big cats, sharks, birds, echolocating bats and cetaceans). As sensors such as camera traps and acoustic detectors become more ubiquitous, the gREM will be increasingly useful for monitoring unmarked animal populations across broad spatial, temporal and taxonomic scales

Selective attention in rat visual category learning

A prominent theory of category learning, COVIS, posits that new categories are learned with either a declarative or procedural system, depending on the task. The declarative system uses the prefrontal cortex (PFC) to learn rule-based (RB) category tasks in which there is one relevant sensory dimension that can be used to establish a rule for solving the task, whereas the procedural system uses corticostriatal circuits for information integration (II) tasks in which there are multiple relevant dimensions, precluding use of explicit rules. Previous studies have found faster learning of RB versus II tasks in humans and monkeys but not in pigeons. The absence of a learning rate difference in pigeons has been attributed to their lacking a PFC. A major gap in this comparative analysis, however, is the lack of data from a nonprimate mammalian species, such as rats, that have a PFC but a less differentiated PFC than primates. Here, we investigated RB and II category learning in rats. Similar to pigeons, RB and II tasks were learned at the same rate. After reaching a learning criterion, wider distributions of stimuli were presented to examine generalization. A second experiment found equivalent RB and II learning with wider category distributions. Computational modeling revealed that rats extract and selectively attend to category-relevant information but do not consistently use rules to solve the RB task. These findings suggest rats are on a continuum of PFC function between birds and primates, with selective attention but limited ability to utilize rules relative to primates

Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador

Background: We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era. Methods: Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (householdcontact characteristics). Results: Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was ,18 months and had vomiting, with household contact ,10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission. Conclusion: Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees

Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up

<b>Background</b> High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis.<p></p> <b>Methods</b> We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay.<p></p> <b>Results</b> 650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score[greater than or equal to]8) prostate cancer incidence (n=119). The association was greatest among men in the 4th highest quintile for cholesterol, 6.1 to <6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of <5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status.<p></p> <b>Conclusions</b> Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer

Impact of Circulating Cholesterol Levels on Growth and Intratumoral Androgen Concentration of Prostate Tumors

Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR

Sheldon-Hall syndrome

Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate. Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature. Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive. SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic. Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers. The diagnosis of SHS is based on clinical criteria. Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome). Prenatal diagnosis by ultrasonography is feasible at 18–24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible. There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery. Life expectancy and cognitive abilities are normal