Search

In humans, skin blood flux (SkBF) and eccrine sweating are tightly coupled, suggesting common neural control and regulation. This study was designed to separate these two sympathetic nervous system end-organ responses via nonadrenergic SkBF-decreasing mechanical perturbations during heightened sudomotor drive. We induced sweating physiologically via whole body heat stress using a high-density tube-lined suit ( protocol 1; 2 women, 4 men), and pharmacologically via forearm intradermal microdialysis of two steady-state doses of a cholinergic agonist, pilocarpine ( protocol 2; 4 women, 3 men). During sweating induction, we decreased SkBF via three mechanical perturbations: arm and leg dependency to engage the cutaneous venoarteriolar response (CVAR), limb venous occlusion to engage the CVAR and decrease perfusion pressure, and limb arterial occlusion to cause ischemia. In protocol 1, heat stress increased arm cutaneous vascular conductance and forearm sweat rate (capacitance hygrometry). During heat stress, despite decreases in SkBF during each of the acute (3 min) mechanical perturbations, eccrine sweat rate was unaffected. During heat stress with extended (10 min) ischemia, sweat rate decreased. In protocol 2, both pilocarpine doses (ED50 and EMAX) increased SkBF and sweat rate. Each mechanical perturbation resulted in decreased SkBF but minimal changes in eccrine sweat rate. Taken together, these data indicate that a wide range of acute decreases in SkBF do not appear to proportionally decrease either physiologically- or pharmacologically induced eccrine sweating in peripheral skin. This preservation of evaporative cooling despite acutely decreased SkBF could have consequential impacts for heat storage and balance during changes in body posture, limb position, or blood flow restrictive conditions.

As the COVID-19 pandemic transitions to endemic, seasonal boosters are a plausible reality across the globe. We hypothesize that intranasal vaccines can provide better protection against asymptomatic infections and more transmissible variants of SARS-CoV-2. To formulate a protective intranasal vaccine, we utilized a VLP-based platform. Hepatitis B surface antigen- based virus like particles (VLP) linked with receptor binding domain (RBD) antigen were paired with the TLR4-based agonist adjuvant, BECC 470. K18-hACE2 mice were primed and boosted at four-week intervals with either VLP-RBD-BECC or mRNA-1273. Both VLP-RBD-BECC and mRNA-1273 vaccination resulted in production of RBD-specific IgA antibodies in serum. RBD- specific IgA was also detected in the nasal wash and lung supernatants and were highest in VLP-RBD-BECC vaccinated mice. Interestingly, VLP-RBD-BECC vaccinated mice showed slightly lower levels of pre-challenge IgG responses, decreased RBD-ACE2 binding inhibition, and lower neutralizing activityin vitrothan mRNA-1273 vaccinated mice. Both VLP-RBD-BECC and mRNA-1273 vaccinated mice were protected against challenge with a lethal dose of Delta variant SARS-CoV-2. Both vaccines limited viral replication and viral RNA burden in the lungs of mice. CXCL10 is a biomarker of severe SARS-CoV-2 infection and we observed both vaccines limited expression of serum and lung CXCL10. Strikingly, VLP-RBD-BECC when administered intranasally, limited lung inflammation at early timepoints that mRNA-1273 vaccination did not. VLP-RBD-BECC immunization elicited antibodies that do recognize SARS-CoV-2 Omicron variant. However, VLP-RBD-BECC immunized mice were protected from Omicron challenge with low viral burden. Conversely, mRNA-1273 immunized mice had low to no detectable virus in the lungs at day 2. Together, these data suggest that VLP-based vaccines paired with BECC adjuvant can be used to induce protective mucosal and systemic responses against SARS- CoV-2.

There is not yet consensus on the precise differences between non-glabrous and facial skin characteristics. Our lab identified similar responses to local heat stress in forearm and facial skin, while others identified differing responses to autonomic stressors within facial regions. Anatomical differences, such as the thinner nature of facial skin and specifically its thinner stratum corneum, may also impact facial autonomic responses. Considering this layer is a protective barrier, facial skin may be more sensitive to perturbations like drug administration. While non-glabrous skin is innervated by spinal nerves, facial skin is innervated by cranial nerves. Because of these anatomical and physiological differences between non-glabrous and facial skin, it is possible that their differing neural and receptor characteristics impact a key autonomic end-organ response: cutaneous blood flow. In this pilot experiment, we investigated possible regional differences between the forehead and forearm in response to adrenergic and cholinergic agonists. We hypothesized that drugs targeting adrenergic (phenylephrine, clonidine, and isoproterenol) and cholinergic (acetylcholine) cutaneous receptors would elicit similar vasomotor effects in both locations. One female subject underwent forearm and forehead iontophoresis of each agonist using adaptations of published protocols, as well as a control protocol using deionized water (vehicle) alone. We recorded blood flow via laser-Doppler flowmetry (Moor Instruments) and beat-by-beat arterial blood pressure via finger photoplethysmography (ADInstruments). We calculated baseline cutaneous vascular conductance (CVC) and plateau 43°C CVC to determine the change in skin blood flow resulting from drug administration. Our results indicate that while phenylephrine administration caused vasodilation, opposing our hypothesis, administration of all other drugs caused responses in agreement with our expectations. Thus, these pilot data suggest that facial and non-glabrous skin may respond similarly to adrenergic or cholinergic agonists. These findings imply a potential use for topical dermatological drug treatments utilized on the trunk/extremities to benefit cutaneous facial diseases.

Iontophoresis utilizes electrical current to non-invasively deliver agents through the skin. This pilot study sought to determine if iontophoresis could be paired with laser Doppler flowmetry (LDF) to administer adrenergic and cholinergic agonists and measure the subsequent changes in cutaneous blood flow. We hypothesized that iontophoresis administration would produce vascular tone changes consistent with those seen during other delivery methods. We iontophoresed phenylephrine, clonidine, isoproterenol, and acetylcholine to the forearm of one generally healthy 44-year-old female using existing or adapted protocols. We also created half-strength protocols with the goal of establishing dose-response relations. We quantified erythrocyte flux via LDF and beat-by-beat arterial blood pressure via finger photoplethysmography. After baseline, each drug was administered using its half and full-strength protocols, separated by a washout period. Finally, we stimulated maximal blood flow at each iontophoresis site via non-noxious local heating to 43°C. Cutaneous vascular conductance (CVC; laser Doppler flux/ mean arterial pressure) was calculated during baseline and following iontophoresis. We administered vehicle (deionized water) alone as a control, using the same protocols and analysis. The drug responses generally matched our predictions with the exception of phenylephrine, which caused vasodilation. Vehicle administration also caused vasodilation. Full-strength application generally led to a more pronounced change in CVC, suggesting that a dose-response relation might be established with additional data. Applications of certain agents led to a higher CVC than “maximal”, possibly raising the need to alter the method for establishing maximal cutaneous blood flow. Overall, our findings indicate that iontophoresis and LDF can be used to effectively administer adrenergic and cholinergic agonists to non-glabrous skin and affect vascular tone. This non-invasive technique could be used to investigate responses to these agents in those whose cutaneous neural receptor characteristics have been altered as a consequence of disease.

Anaysia and Caviar are temperate siphoviruses isolated from soil using Gordonia terrae 3612 and Mycobacterium smegmatis mc 2 155, respectively. Anaysia’s 52,861-bp genome carries 102 genes, while Caviar’s 47,074-bp genome carries 79 genes. Based on gene content similarity, Anaysia and Caviar are assigned to phage clusters A15 and A3, respectively.

Reconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO2) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO2 inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO2 inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO2-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO2 inhalation.

The ongoing COVID-19 pandemic has contributed largely to the global vaccine disparity. Development of protein subunit vaccines can help alleviate shortages of COVID-19 vaccines delivered to low-income countries. Here, we evaluated the efficacy of a three-dose virus-like particle (VLP) vaccine composed of hepatitis B surface antigen (HBsAg) decorated with the receptor binding domain (RBD) from the Wuhan or Beta SARS-CoV-2 strain adjuvanted with either aluminum hydroxide (alum) or squalene in water emulsion (SWE). RBD HBsAg vaccines were compared to the standard two doses of Pfizer mRNA vaccine. Alum-adjuvanted vaccines were composed of either HBsAg conjugated with Beta RBD alone (β RBD HBsAg+Al) or a combination of both Beta RBD HBsAg and Wuhan RBD HBsAg (β/Wu RBD HBsAg+Al). RBD vaccines adjuvanted with SWE were formulated with Beta RBD HBsAg (β RBD HBsAg+SWE) or without HBsAg (β RBD+SWE). Both alum-adjuvanted RBD HBsAg vaccines generated functional RBD IgG against multiple SARS-CoV-2 variants of concern (VOC), decreased viral RNA burden, and lowered inflammation in the lung against Alpha or Beta challenge in K18-hACE2 mice. However, only β/Wu RBD HBsAg+Al was able to afford 100% survival to mice challenged with Alpha or Beta VOC. Furthermore, mice immunized with β RBD HBsAg+SWE induced cross-reactive neutralizing antibodies against major VOC of SARS-CoV-2, lowered viral RNA burden in the lung and brain, and protected mice from Alpha or Beta challenge similarly to mice immunized with Pfizer mRNA. However, RBD+SWE immunization failed to protect mice from VOC challenge. Our findings demonstrate that RBD HBsAg VLP vaccines provided similar protection profiles to the approved Pfizer mRNA vaccines used worldwide and may offer protection against SARS-CoV-2 VOC.

A large body of literature has explored moral decision-making; however, fewer have examined the explicit role of criminal thinking (CT). This study sought to determine whether moral judgment is influenced by CT in the general population and if this relationship further depends on the type of scenario (i.e., immoral vs. illegal) and/or the actor orientation (i.e., self vs. other). Using a sample of 239 U.S. adults and hypothetical case vignettes, results showed that those who endorsed higher levels of CT rated socially deviant behaviors, regardless of the type of scenario, as significantly more morally acceptable than participants who endorsed lower levels of CT. However, this difference was more pronounced for the immoral dilemma compared to the illegal dilemma. Specifically, proactive CT processes led to higher justification for the immoral dilemma. Neither general nor reactive CT were significantly associated with moral reasoning for the illegal dilemma. Among a mostly non-offending sample, this finding makes sense as it appears participants' levels of criminal thinking may have been high enough to rationalize an immoral dilemma but not so high as to allow for rationalization of an illegal dilemma. No significant differences were found concerning actor orientation. This research not only has important implications for better understanding traits associated with moral decision-making in everyday choices, but it may also have practical application in legal contexts. However, further research is needed in these contexts. Findings were also limited by a lack of racial diversity among participants.

SARS-CoV-2 variants of concern (VoC) are impacting responses to the COVID-19 pandemic. Here, we utilized passive immunization using human convalescent plasma (HCP) obtained from a critically ill COVID-19 patient in the early pandemic to study the efficacy of polyclonal antibodies generated to ancestral SARS-CoV-2 against the Alpha, Beta, and Delta VoC in the K18 human angiotensin converting enzyme 2 (hACE2) transgenic mouse model. HCP protected mice from challenge with the original WA-1 SARS-CoV-2 strain; however, only partially protected mice challenged with the Alpha VoC (60% survival) and failed to save Beta challenged mice from succumbing to disease. HCP treatment groups had elevated receptor binding domain (RBD) and nucleocapsid IgG titers in the serum; however, Beta VoC viral RNA burden in the lung and brain was not decreased due to HCP treatment. While mice could be protected from WA-1 or Alpha challenge with a single dose of HCP, six doses of HCP could not decrease mortality of Delta challenged mice. Overall, these data demonstrate that VoC have enhanced immune evasion and this work underscores the need for

Reflecting on one’s solution is widely recognized as an important part of the problem-solving process, though the cognitive processes underlying this action are not well understood. In previous work, we identified certain strategies students used while reflecting on a solution but found that strategies most often used by experts were not often used by students and were often used incorrectly. In this paper, we present the results of a study that more carefully examines why this could be the case. We conducted think-aloud interviews with students from a variety of physics backgrounds and asked them to check the answer to a particular static equilibrium problem (there were two different problems, but each student saw only one). We found that students’ strategy use varied both by problem features and level of experience. We found students’ epistemological framing to be more stable across problem-difficulty but still correlated with experience. We further noticed more frequent shifting of epistemological frames among intermediate students. Altogether, the results point to an epistemological transition from solution reflection as an algorithmic procedure to be performed using whatever strategy is most useful, to a conceptual procedure more aligned with sense-making as students gain more experience with physics. This will be useful for instructors when thinking about the best ways to encourage novice students to engage in meaningful solution reflection or mathematical sense-making more broadly.

The COVID-19 pandemic has been fueled by novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain’s pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta- challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing infected to uninfected mice revealed that Alpha-challenged mice have more total genes differentially activated, conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. Thein vivoandin silicoobservations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.ImportanceThe Delta variant of SARS-CoV-2 is known to be more transmissible and cause severe disease in human hosts due to mutations in its genome that are divergent from previous variants of concern (VOC). Our study evaluates the pathogenesis of Delta in the K18-hACE2 mouse model compared to the Alpha VOC. We observed that relative to Alpha, Delta challenge results in enhanced inflammation and tissue damage with stronger antiviral responses. These observations provide insight into Delta’s unique pathogenesis.

SARS-CoV-2 is a viral respiratory pathogen responsible for the current global pandemic and the disease that causes COVID-19. All current WHO approved COVID-19 vaccines are administered through the muscular route. We have developed a prototype two-dose vaccine (BReC-CoV-2) by combining the Receptor Binding Domain (RBD) antigen, via conjugation to Diphtheria toxoid (EcoCRM®). The vaccine is adjuvanted with Bacterial Enzymatic Combinatorial Chemistry (BECC), BECC470. Intranasal (IN) administration of BreC-CoV-2 in K18-hACE2 mice induced a strong systemic and localized immune response in the respiratory tissues which provided protection against the Washington strain of SARS-CoV-2. Protection provided after IN administration of BReC-CoV-2 was associated with decreased viral RNA copies in the lung, robust RBD IgA titers in the lung and nasal wash, and induction of broadly neutralizing antibodies in the serum. We also observed that BReC-CoV-2 vaccination administered using an intramuscular (IM) prime and IN boost protected mice from a lethal challenge dose of the Delta variant of SARS-CoV-2. IN administration of BReC-CoV-2 provided better protection than IM only administration to mice against lethal challenge dose of SARS-CoV-2. These data suggest that the IN route of vaccination induces localized immune responses that can better protect against SARS-CoV-2 than the IM route in the upper respiratory tract.

The Colorado River is a critical water resource in the southwestern United States, supplying drinking water for 40 million people in the region and water for irrigation of 2.2 million hectares of land. Extended drought in the Upper Colorado River Basin (UCOL) and the prospect of a warmer climate in the future pose water availability challenges for those charged with managing the river. Limited water availability in the future also may negatively affect aquatic ecosystems and wildlife that depend upon them. Water availability components of special importance in the UCOL include streamflow, salinity in groundwater and surface water, groundwater levels and storage, and the role of snow in the UCOL water cycle. This manuscript provides a review of current “state of the science” for these UCOL water availability components with a focus on identifying gaps in data, modeling, and trends in the basin. Trends provide context for evaluations of current conditions and motivation for further investigation and modeling, models allow for investigation of processes and projections of future water availability, and data support both efforts. Information summarized in this manuscript will be valuable in planning integrated assessments of water availability in the UCOL.

Background While previous research has assessed running kinematics for age-related differences that could increase the risk of a running-related injury, none of these studies have included high school aged runners or assessed running kinematics using 2-dimensional video analysis. Purpose The purpose of this study was to compare sagittal plane kinematics during treadmill running in high school cross-country and young adult recreational runners using 2-dimensional motion analysis techniques. Methods Twenty-five high school cross-country runners (13 women, 12 men) and 25 young adult recreational runners (12 women, 13 men) consented to participate in this study. Reflective markers were placed on each lower extremity over multiple anatomical landmarks. After a five-minute acclimation period in which the participants ran on a treadmill at their preferred running speed, video data were recorded at 240 frames per second for all participants while they continued to run on the treadmill. Results There were no significant differences between left and right extremities. The young adult recreational runners exhibited significantly greater vertical excursion of the center of mass (t = 4.64, p = .0001) compared to the high school runners. There was no significant difference between the two age groups regarding the six other sagittal plane variables. Conclusions The young adult recreational runners demonstrated an increased center-of-mass vertical excursion in comparison to high school cross-country runners. In addition, the results obtained in this study for kinematic variables using 2-dimensional motion analysis were similar to previously reported studies using 3-dimensional motion analysis, demonstrating that 2-dimensional motion analysis could be used for analyzing sagittal plane running kinematics in clinical settings. Level of Evidence 4, Controlled laboratory study, This study looks at comparing sagittal plane kinematics during treadmill running in high school cross-country and young adult recreational runners using 2-D video analysis.

Background While previous research has assessed running kinematics for age-related differences that could increase the risk of a running-related injury, none of these studies have included high school aged runners or assessed running kinematics using 2-dimensional video analysis. # Purpose The purpose of this study was to compare sagittal plane kinematics during treadmill running in high school cross-country and young adult recreational runners using 2-dimensional motion analysis techniques. # Methods Twenty-five high school cross-country runners (13 women, 12 men) and 25 young adult recreational runners (12 women, 13 men) consented to participate in this study. Reflective markers were placed on each lower extremity over multiple anatomical landmarks. After a five-minute acclimation period in which the participants ran on a treadmill at their preferred running speed, video data were recorded at 240 frames per second for all participants while they continued to run on the treadmill. # Results There were no significant differences between left and right extremities. The young adult recreational runners exhibited significantly greater vertical excursion of the center of mass (*t* = 4.64, p = .0001) compared to the high school runners. There was no significant difference between the two age groups regarding the six other sagittal plane variables. # Conclusions The young adult recreational runners demonstrated an increased center-of-mass vertical excursion in comparison to high school cross-country runners. In addition, the results obtained in this study for kinematic variables using 2-dimensional motion analysis were similar to previously reported studies using 3-dimensional motion analysis, demonstrating that 2-dimensional motion analysis could be used for analyzing sagittal plane running kinematics in clinical settings. # Level of Evidence 4, Controlled laboratory study

Background Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease in the central nerve system, in which both innate and adaptive immune cells are involved. BBR3378, an aza-anthrapyrazole prevents experimental autoimmune encephalomyelitis (EAE), an inflammatory condition similar to MS, by antagonizing T cell autoimmune responses. Here, we report BBR3378’s regulatory effect on macrophages. Methods EAE was induced in ten-week-old female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptides followed by BBR3378 or sham treatment administered intraperitoneally, and clinical signs were assessed using a 0–5 scoring system. These mice were subjected to serum ELISA for cytokine IFNγ and TNFα levels, RT qPCR analysis of macrophage markers in isolated monocytes, and flow cytometry analysis for macrophage infiltration in the brain. Macrophages derived from primary monocytes and macrophage cell line RAW 264.7 were used to investigate BBR3378’s effect on LPS-stimulated pro-inflammatory cytokine induction. RAW 264.7 cells expressing NF-κB-driven luciferase reporter were treated with LPS with or without BBR3378, and luciferase assays performed to assess the inhibition on NF-κB activation. LPS-induced activation of mitogen-activated protein kinases (MAPKs) with or without the presence of BBR3378 was also investigated by Western blot analysis. Results BBR3378 down-regulated cytokine-induced macrophage differentiation and activation in EAE mice, contributing to protection against macrophage infiltration in the brain and clinical symptoms from EAE. Treating macrophages with BBR3378 counteracted LPS-induced cytokine production via blocking activation of key signal molecules mediating inflammatory responses, such as NF-κB and MAPKs. Conclusions These data suggest that in addition to T cells, BBR3378 can also target macrophages to attenuate the inflammation associated with EAE.

This opening chapter first discusses the prevalence and current state of Internet use in our society with a focus on social media, including data on who is more inclined to use social media and a brief review of extant literature on the relationship between social media and personality. Also reviewed is the use of social media by legal and mental health professionals more broadly. Branching from these disciplines, we then outline the relevance of Internet-based data to forensic mental health assessment and argue for the need to consider the unique aspects associated with the integration of Internet-based data sources in this context. We highlight existing legal and professional standards that have applicability to collateral information obtained from the Internet and introduce newly proposed guidelines specific to this data modality. The chapter ends with an overview of the content and structure of the remaining chapters.

The current study examined viewers' gaze while observing Facebook profiles of strangers varying in gender and physical attractiveness. Fifty-one participants viewed four Facebook profiles, a physically attractive and unattractive individual of each gender. Participants' eye movements were tracked as they viewed each profile for 60 seconds. Results showed that participants paid more attention to the physical appearance (main profile photograph) of female than of male profile owners and to the personal information (likes and interests) of male than to female profile owners. Participants spent more time focusing on information that was irrelevant to forming an impression of the profile owner (advertisements) when viewing the profiles of unattractive than attractive individuals, suggesting that they made a greater effort to learn about these individuals.