A solution to the single-question crowd wisdom problem.

Once considered provocative, the notion that the wisdom of the crowd is superior to any individual has become itself a piece of crowd wisdom, leading to speculation that online voting may soon put credentialed experts out of business. Recent applications include political and economic forecasting, evaluating nuclear safety, public policy, the quality of chemical probes, and possible responses to a restless volcano. Algorithms for extracting wisdom from the crowd are typically based on a democratic voting procedure. They are simple to apply and preserve the independence of personal judgment. However, democratic methods have serious limitations. They are biased for shallow, lowest common denominator information, at the expense of novel or specialized knowledge that is not widely shared. Adjustments based on measuring confidence do not solve this problem reliably. Here we propose the following alternative to a democratic vote: select the answer that is more popular than people predict. We show that this principle yields the best answer under reasonable assumptions about voter behaviour, while the standard 'most popular' or 'most confident' principles fail under exactly those same assumptions. Like traditional voting, the principle accepts unique problems, such as panel decisions about scientific or artistic merit, and legal or historical disputes. The potential application domain is thus broader than that covered by machine learning and psychometric methods, which require data across multiple questions.

Essential Role of Neutrophils in the Protective Immune Response Induced by a Live Attenuated Leishmania Vaccine.

No licensed vaccine exists against visceral leishmaniasis (VL), a disease caused by the Leishmania donovani parasite. We have previously reported both macrophages and dendritic cells play important role in the protection induced by a live attenuated centrin gene-deleted L. donovani (LdCen-/- ) parasite vaccine. The role of neutrophils in orchestrating the initial innate response to pathogens is widely recognized. To investigate the early interaction of LdCen-/- with neutrophils, we immunized mice intradermally in the ear pinna with LdCen-/- Compared with LdWT infection, LdCen-/- parasites induced higher recruitment of neutrophils to the ear dermis and ear draining lymph nodes (dLN) as early as 6-18 h after immunization, which were predominantly proinflammatory in nature. Neutrophils from ear dLN of LdCen-/- -immunized mice exhibited heightened expression of costimulatory molecules and attenuated expression of coinhibitory molecules necessary for higher T cell activation. Further phenotypic characterization revealed heterogeneous neutrophil populations containing Nα and Nß subtypes in the ear dLN. Of the two, the parasitized Nα subset from LdCen-/- -immunized mice exhibited much stronger Ag-specific CD4+ T cell proliferation ex vivo. Adoptive transfer of neutrophils bearing LdCen-/- parasites induced an increased Th1 response in naive mice. Importantly, neutrophil depletion significantly abrogated Ag-specific CD4+ T cell proliferation in LdCen-/- -immunized mice and impaired protection against virulent challenge. Conversely, replenishing of neutrophils significantly restored the LdCen-/- -induced host-protective response. These results suggest that neutrophils are indispensable for protective immunity induced by LdCen-/- parasite vaccine.

Student Evaluation of a Learning Community Model Adapted to Student and Curriculum Needs.

The Neuroscience Learning Community (LC) that Stonehill introduced to its curriculum grew out of the Great Recession of 2008 and the need for our students to gain hands-on, high-impact learning experiences, despite limited resources. This learning model was first reported in 2013, and since then it has undergone changes that were necessary due to the number of credits and amount of time required for that model. Curriculum changes are common, and Stonehill College changed its credit requirements for LCs to meet students' needs. As a result, the new Neuroscience LC model that we describe here reduced credit hours while leveraging new faculty expertise, collaborations, and new community partnerships. This paper reports student evaluations of an LC model adapted to demand fewer credits and less time, but to retain the community-based learning aspect and to increase faculty collaboration, while maintaining a high standard of learning fundamental neuroscience topics. Evaluations suggest that students valued the updated Neuroscience LC because it helped them understand neuroscience concepts and the impact of neuroscience in our world.

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani (LdCen-/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen-/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen-/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen-/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen-/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen-/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R-/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen-/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen-/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.

Gruneisen parameters of bead-spring chains: MD simulation and theory.

Molecular Dynamics (MD) simulations were carried out in a microcanonical ensemble to compute the Gruneisen parameter (denoted as γ) of a liquid of bead-spring chains having 10 beads/chain. γ was studied over a wide range of temperatures below and above the glass transition temperature. We found that the Gruneisen parameter varied in the range of 2.1-3.1 and was significantly higher than typically observed experimentally in real polymers. In the glass, a theory was developed for γ using a cell model in which the beads are harmonically bound to their respective cell centers. The resulting Gruneisen parameter is predicted to increase slightly with temperature. Above the glass transition temperature, we employed the generalized Flory dimer equation-of-state and the polymer reference interaction model theory to calculate γ. In these calculations, we found that γ decreased with temperature in the liquid. The theoretical predictions for γ were found to be in good qualitative agreement with our MD simulations, without any adjustable parameters, both above and below Tg. In experiments on real polymers, γ undergoes a sharp discontinuity at the glass transition. By contrast, in our MD simulations, γ varies smoothly over a broad transition region.

Androgen sensitivity gateway to COVID-19 disease severity.

In this communication, we present arguments for androgen sensitivity as a likely determinant of COVID-19 disease severity. The androgen sensitivity model explains why males are more likely to develop severe symptoms while children are ostensibly resistant to infection. Further, the model explains the difference in COVID-19 mortality rates among different ethnicities. Androgen sensitivity is determined by genetic variants of the androgen receptor. The androgen receptor regulates transcription of the transmembrane protease, serine 2 (TMPRSS2), which is required for SARS-CoV-2 infectivity. TMPRSS2 primes the Spike protein of the virus, which has two consequences: diminishing viral recognition by neutralizing antibodies and activating SARS-CoV-2 for virus-cell fusion. Genetic variants that have been associated with androgenetic alopecia, prostate cancer, benign prostatic hyperplasia and polycystic ovary syndrome could be associated with host susceptibility. In addition to theoretical epidemiological and molecular mechanisms, there are reports of high rates of androgenetic alopecia of from hospitalized COVID-19 patients due to severe symptoms. Androgen sensitivity is a likely determinant of COVID-19 disease severity. We believe that the evidence presented in this communication warrants the initiation of trials using anti-androgen agents.

A rodent cage change insomnia model disrupts memory consolidation.

Insomnia involves disruption of sleep initiation, maintenance and/or overall quality, and may interfere with cognition. Here, we evaluated memory impairment produced by rodent mild (acute) insomnia models. Insomnia models consisted of either single or repeated exposure to cages previously occupied (dirtied) by an unfamiliar rat for 5-7 days. Rats were trained in the Morris water maze to remember the platform location (acquisition), and were then exposed to: (a) 6 hr of undisturbed baseline; (b) dirty cage change-induced insomnia (animal placed into a cage dirtied by another rat for 6 hr); or (c) double-dirty cage change-induced insomnia (animal placed into a cage dirtied by another rat for 3 hr, and then another dirty cage 3 hr later). The animal's memory for the platform location was then evaluated in a probe trial. Double-dirty cage change-induced insomnia significantly disrupted sleep, although the effects of dirty cage change-induced insomnia were overall not significant. In the fourth hour of double-dirty cage change-induced insomnia (following the second cage change), sleep episode number and duration alterations indicated sleep fragmentation. Furthermore, power spectral analysis revealed diminished wake and, to a lesser extent, rapid eye movement theta power (indicated by trend difference) in the last 3 hr of exposure. Significant deficits were noted for measures of water maze performance following double-dirty cage change-induced insomnia, indicating impaired memory. In summary, one variant of the rodent insomnia model, double-dirty cage change-induced insomnia, disrupted sleep and attenuated memory consolidation, indicating this paradigm may be useful to evaluate the effects of hypnotics on memory consolidation.

Frontal pattern hair loss among Chinese women is frequently associated with ponytail hairstyle.

Female alopecia patients in China often present with a frontal pattern hair loss. This feature is seen less frequently in western women. Women in China frequently style their hair in a ponytail. Thus, we hypothesized that the high prevalence of frontal pattern hair loss in Chinese women is due to traction alopecia. To better understand this, we studied 43 women presenting frontal alopecia at a hair clinic. Among the women presenting frontal alopecia, 79% reported styling their hair in a ponytail four or more days per week for an average period of 10 years. To our knowledge, this is the first study to elucidate the cause of frequent frontal alopecia in Chinese women. Although cultural style changes are difficult to change, we believe that awareness of the medical implications of frequent ponytail styling will reduce the rate of frontal alopecia among Chinese women.

Tretinoin enhances minoxidil response in androgenetic alopecia patients by upregulating follicular sulfotransferase enzymes.

Minoxidil sulfate is the active metabolite required to exert the vasodilatory and hair growing effects of minoxidil. For hair growth, sulfotransferase enzymes expressed in outer root sheath of the hair follicle sulfonate minoxidil. The large intra-subject variability in follicular sulfotransferase was found to predict minoxidil response and thus explain the low response rate to topical minoxidil in the treatment of androgenetic alopecia. A method to increase minoxidil response would be of significant clinical utility. Retinoids have been reported to increase minoxidil response. The purported mechanism of action was retinoid modulation of skin permeation to minoxidil; however, evidence to the contrary supports retinoids increase dermal thickness. In order to elucidate the effect of topical retinoids on minoxidil response, we studied the effect of topical tretinoin on follicular sulfotransferase. In this study, we demonstrate that topical tretinoin application influences the expression of follicular sulfotransferase. Of clinical significance, in our cohort, 43% of subjects initially predicted to be nonresponders to minoxidil were converted to responders following 5 days of topical tretinoin application. To the best of our knowledge, this is the first study to elucidate the interaction mechanism between topical minoxidil and retinoids and thus provides a pathway for the development of future androgenetic alopecia treatments.

Calreticulin is a secreted BMP antagonist, expressed in Hensen's node during neural induction.

Hensen's node is the "organizer" of the avian and mammalian early embryo. It has many functions, including neural induction and patterning of the ectoderm and mesoderm. Some of the signals responsible for these activities are known but these do not explain the full complexity of organizer activity. Here we undertake a functional screen to discover new secreted factors expressed by the node at this time of development. Using a Signal Sequence Trap in yeast, we identify several candidates. Here we focus on Calreticulin. We show that in addition to its known functions in intracellular Calcium regulation and protein folding, Calreticulin is secreted, it can bind to BMP4 and act as a BMP antagonist in vivo and in vitro. Calreticulin is not sufficient to account for all organizer functions but may contribute to the complexity of its activity.

Styling without shedding: Novel topical formula reduces hair shedding by contracting the arrector pili muscle.

Approximately 40% of women experience excessive hair shedding during styling (e.g., hair brushing). Previously, we demonstrated that topically applied phenylephrine, a potent α1 adrenergic receptor agonist, can be used to contract the arrector pili muscle of the follicular unit; thus, increasing the force required to pluck hair and reducing shedding during brushing. While demonstrating efficacy, phenylephrine has several drawbacks when applied to the scalp, including the possibility cardiovascular events. We hypothesized that a high concentration of a weak α1 agonist would allow for: (a) rapid penetration through the stratum corneum eliciting a quick response; (b) a low probability of cardiac adverse events owing to the low receptor binding affinity; and (c) an efficacy of the weak α1 agonist similar to that of phenylephrine at the local site of application. Accordingly, we developed a novel topical solution, AB-102, containing a high concentration of a weak α1 agonist. Several studies were conducted to test the safety and efficacy of AB-102. In a dose escalating safety study, utilizing a wearable holter monitor, we observed no cardiac or hemodynamic adverse events. In addition, in a controlled efficacy study, AB-102 reduced the number of hairs shed during brushing by up to 77% (average of 38%).

Characterization of follicular minoxidil sulfotransferase activity in a cohort of pattern hair loss patients from the Indian Subcontinent.

Several studies have established that sulfotransferase enzyme activity in the outer root sheath of plucked hair follicles predicts response to topical minoxidil in the treatment of pattern hair loss. However, the prevalence of this enzyme activity among Indian patients has not been studied. Additionally, no reports in the literature characterize sulfotransferase activity based on sex, age, duration of hair loss, grade of hair loss, and family history. In this study we utilized a sulfotransferase activity assay first reported by Goren et al. We characterize the follicular sulfotransferase activity of 120 pattern hair loss patients visiting a dermatology outpatient clinic in India. Overall, 40.8% of patients with pattern hair loss had low levels of sulfotransferase. Surprisingly, 49.3% of men had low levels of sulfotransferase compared to 26.6% of women. No correlation was found between sulfotransferase activity and age, duration of hair loss, grade of hair loss, or family history. A sub-analysis of patient reported outcomes (PRO) validated previous findings that sulfotransferase enzyme activity is a predictive marker for minoxidil response in pattern hair loss patients.

Partnerships in Neuroscience Research Between Small Colleges and Large Institutions: A Case Study.

There are advantages and limitations associated with a science, technology, engineering and math (STEM) education at small, liberal arts colleges relative to larger universities. While there may be increased opportunity for personal attention and access to faculty, students at liberal arts colleges may not always have the opportunity to gain experience with state-of-the-art equipment and technology. Herein, we describe a case study of an inter-institutional partnership between Stonehill College and two neuroscience research laboratories which are part of the Veterans Affairs Boston Healthcare System (VABHS). Both laboratories are affiliated with Harvard Medical School (HMS). We discuss the benefits as well as the challenges associated with the development and maintenance of this partnership. The experience with the use of sophisticated instrumentation and technology available in these laboratories may give students a competitive edge when applying to graduate school programs. However, we contend that the most important advantage of this research experience is the development of a sense of self-esteem and professional competence that will allow students to meet the many challenges that lie ahead in graduate school and beyond.

Prevalence of hair shedding among women.

Hair shedding in female patients is a frequent complaint in dermatological, endocrinological, and gynecological consults. Previously, the Sinclair Hair Shedding Scale was developed to assess normal versus excessive hair shedding in female pattern hair loss (FPHL) subjects. However, the prevalence of hair shedding in females not suffering from FPHL is unknown. To gain better understanding of hair shedding in the general population, we recruited 300 subjects visiting a public hospital for conditions other than alopecia. Of the 300 subjects recruited, 263 did not suffer from FPHL. Among those subjects, approximately 40% reported experiencing excessive hair shedding (as defined by the Sinclair Hair Shedding Scale) on hair washing days. In comparison, in our subject population, approximately 60% of subjects with FPHL reported excessive hair shedding on hair washing days. To best of our knowledge, this is the first study to quantify the prevalence of hair shedding in women. While, no treatment currently exists for this condition, we hope that this study would encourage physicians and researchers to address this frequent concern.

The glass transition temperature of thin films: A molecular dynamics study for a bead-spring model.

Molecular dynamics simulations were carried out on free-standing liquid films of different thicknesses h using a bead-spring model of 10 beads per chain. The glass transition temperatures, Tg, of the various films were determined from plots of the internal energy versus temperature. We used these simulations to test the validity of our earlier conjecture that the glass transition of a confined liquid could be approximated by pre-averaging over the non-uniform density profile of the film. Using the density profiles from our simulations, we computed the average density of the free-standing films as a function of temperature. In all our film simulations we found, within the error of the simulation, that Tg of the film occurred at the same density (or packing fraction) as the bulk system at the bulk glass transition temperature TgB. By equating these densities at their respective glass transition temperatures, as suggested by the simulations, we deduced that Tg/TgB is proportional to h0/h. This is consistent with previous simulations and experimental data. Moreover, the parameter h0 is determinable in our model from the density profile of the films.

Characterization of cross-protection by genetically modified live-attenuated Leishmania donovani parasites against Leishmania mexicana.

Previously, we showed that genetically modified live-attenuated Leishmania donovani parasite cell lines (LdCen(-/-) and Ldp27(-/-)) induce a strong cellular immunity and provide protection against visceral leishmaniasis in mice. In this study, we explored the mechanism of cross-protection against cutaneous lesion-causing Leishmania mexicana. Upon challenge with wild-type L. mexicana, mice immunized either for short or long periods showed significant protection. Immunohistochemical analysis of ears from immunized/challenged mice exhibited significant influx of macrophages, as well as cells expressing MHC class II and inducible NO synthase, suggesting an induction of potent host-protective proinflammatory responses. In contrast, substantial inhibition of IL-10, IL-4, and IL-13 expression and the absence of degranulated mast cells and less influx of eosinophils within the ears of immunized/challenged mice suggested a controlled anti-inflammatory response. L. mexicana Ag-stimulated lymph node cell culture from the immunized/challenged mice revealed induction of IFN-γ secretion by the CD4 and CD8 T cells compared with non-immunized/challenged mice. We also observed suppression of Th2 cytokines in the culture supernatants of immunized/challenged lymph nodes compared with non-immunized/challenged mice. Adoptively transferred total T cells from immunized mice conferred strong protection in recipient mice against L. mexicana infection, suggesting that attenuated L. donovani can provide protection against heterologous L. mexicana parasites by induction of a strong T cell response. Furthermore, bone marrow-derived dendritic cells infected with LdCen(-/-) and Ldp27(-/-) parasites were capable of inducing a strong proinflammatory response leading to the proliferation of Th1 cells. These studies demonstrate the potential of live-attenuated L. donovani parasites as pan-Leishmania species vaccines.

α1 -AR agonist induced piloerection protects against the development of traction alopecia.

Traction alopecia is hair loss that occurs after persistent pulling (e.g., during cosmetic procedures) on the roots of hair over time. Unlike plucking, which is painful, persistent pulling may go unnoticed until a patient presents with either bald spots or diffuse telogen shedding. Each hair follicle in the scalp contains an arrector pili muscle that, when contracted, erects the hair. The smooth muscle in the arrector pili expresses α1 adrenergic receptors (α1 -AR). As such, we hypothesized that contraction of the arrector pili muscle via an α1 -AR agonist would increase the threshold of force required to pluck hair during cosmetic procedures. Female subjects, ages 18-40, were recruited to study the effect of topically applied phenylephrine, a selective α1 -AR agonist, on epilation force and hair shedding during cosmetic procedures. In our blinded study, 80% of subjects demonstrated reduced shedding on days using phenylephrine compared to days using a placebo solution. The average reduction in hair loss was approximately 42%. In addition, the force threshold required for epilation increased by approximately 172% following topical phenylephrine application. To our knowledge this is the first study demonstrating the utility of α1 -AR agonists in the treatment of traction alopecia and hair shedding during cosmetic procedures.

Management of chronic pruritus with a UV filtering topical cream.

Chronic pruritus is a common dermatological condition affecting 10-13% of the general population. UVB phototherapy has been demonstrated to be effective in relieving the symptoms of pruritus. However, phototherapy is rarely administered because the treatment is time-consuming and expensive, when compared to other topical drugs. In previous works, it has been reported that a topical cream, which selectively filters solar UVB can be used as a convenient alternative to traditional phototherapy. Here, we report the results of a pilot study aimed at assessing the effectiveness of the cream for treating pruritus. Seven patients with pruritus symptoms were included in the study. After 3 months of treatment (3 sessions per week), all patients noted improvement in pruritus symptoms. These preliminary results demonstrate that the novel topical cream could provide a convenient, low cost treatment for chronic pruritus patients.

Circular dichroism and site-directed spin labeling reveal structural and dynamical features of high-pressure states of myoglobin.

Excited states of proteins may play important roles in function, yet are difficult to study spectroscopically because of their sparse population. High hydrostatic pressure increases the equilibrium population of excited states, enabling their characterization [Akasaka K (2003) Biochemistry 42:10875-85]. High-pressure site-directed spin-labeling EPR (SDSL-EPR) was developed recently to map the site-specific structure and dynamics of excited states populated by pressure. To monitor global secondary structure content by circular dichroism (CD) at high pressure, a modified optical cell using a custom MgF2 window with a reduced aperture is introduced. Here, a combination of SDSL-EPR and CD is used to map reversible structural transitions in holomyoglobin and apomyoglobin (apoMb) as a function of applied pressure up to 2 kbar. CD shows that the high-pressure excited state of apoMb at pH 6 has helical content identical to that of native apoMb, but reversible changes reflecting the appearance of a conformational ensemble are observed by SDSL-EPR, suggesting a helical topology that fluctuates slowly on the EPR time scale. Although the high-pressure state of apoMb at pH 6 has been referred to as a molten globule, the data presented here reveal significant differences from the well-characterized pH 4.1 molten globule of apoMb. Pressure-populated states of both holomyoglobin and apoMb at pH 4.1 have significantly less helical structure, and for the latter, that may correspond to a transient folding intermediate.

Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice.

Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modified Leishmania donovani parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice both in vitro and in vivo. In vitro infection of macrophages with live attenuated parasites (compared to that with wild-type [WT] L. donovani parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], gamma interferon [IFN-γ], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1α/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4(+) T cell activation in vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1ß, TNF-α, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT L. donovani-infected mice. Furthermore, an ex vivo antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-γ and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4(+) T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB/c mice.