Lactobacillus gasseri and Gardnerella vaginalis produce extracellular vesicles that contribute to the function of the vaginal microbiome and modulate host-Trichomonas vaginalis interactions.

Trichomonas vaginalis is an extracellular protozoan parasite of the human urogenital tract, responsible for a prevalent sexually transmitted infection. Trichomoniasis is accompanied by a dysbiotic microbiome that is characterised by the depletion of host-protective commensals such as Lactobacillus gasseri, and the flourishing of a bacterial consortium that is comparable to the one seen for bacterial vaginosis, including the founder species Gardnerella vaginalis. These two vaginal bacteria are known to have opposite effects on T. vaginalis pathogenicity. Studies on extracellular vesicles (EVs) have been focused on the direction of a microbial producer (commensal or pathogen) to a host recipient, and largely in the context of the gut microbiome. Here, taking advantage of the simplicity of the human cervicovaginal microbiome, we determined the molecular cargo of EVs produced by L. gasseri and G. vaginalis and examined how these vesicles modulate the interaction of T. vaginalis and host cells. We show that these EVs carry a specific cargo of proteins, which functions can be attributed to the opposite roles that these bacteria play in the vaginal biome. Furthermore, these bacterial EVs are delivered to host and protozoan cells, modulating host-pathogen interactions in a way that mimics the opposite effects that these bacteria have on T. vaginalis pathogenicity. This is the first study to describe side-by-side the protein composition of EVs produced by two bacteria belonging to the opposite spectrum of a microbiome and to demonstrate that these vesicles modulate the pathogenicity of a protozoan parasite. Such as in trichomoniasis, infections and dysbiosis co-occur frequently resulting in significant co-morbidities. Therefore, studies like this provide the knowledge for the development of antimicrobial therapies that aim to clear the infection while restoring a healthy microbiome.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Luminal Delivery of Pectin-Modified Oxygen Microbubbles Mitigates Rodent Experimental Intestinal Ischemia.

INTRODUCTION: Ischemic gut injury is common in the intensive care unit, impairs gut barrier function, and contributes to multiorgan dysfunction. One novel intervention to mitigate ischemic gut injury is the direct luminal delivery of oxygen microbubbles (OMB). Formulations of OMB can be modified to control the rate of oxygen delivery. This project examined whether luminal delivery of pectin-modified OMB (OMBp5) can reduce ischemic gut injury in a rodent model. METHODS: The OMBp5 formulation was adapted to improve delivery of oxygen along the length of small intestine. Adult Sprague-Dawley rats (n = 24) were randomly allocated to three groups: sham-surgery (SS), intestinal ischemia (II), and intestinal ischemia plus luminal delivery of OMBp5 (II + O). Ischemia-reperfusion injury was induced by superior mesenteric artery occlusion for 45 min followed by reperfusion for 30 min. Outcome data included macroscopic score of mucosal injury, the histological score of gut injury, and plasma biomarkers of intestinal injury. RESULTS: Macroscopic, microscopic data, and intestinal injury biomarker results demonstrated minimal intestinal damage in the SS group and constant damage in the II group. II + O group had a significantly improved macroscopic score throughout the gut mucosa (P = 0.04) than the II. The mean histological score of gut injury for the II + O group was significantly improved on the II group (P ≤ 0.01) in the proximal intestine only, within 30 cm of delivery. No differences were observed in plasma biomarkers of intestinal injury following OMBp5 treatment. CONCLUSIONS: This proof-of-concept study has demonstrated that luminal OMBp5 decreases ischemic injury to the proximal small intestine. There is a need to improve oxygen delivery over the full length of the intestine. These findings support further studies with clinically relevant end points, such as systemic inflammation and vital organ dysfunction.

Electronic origin of negative thermal expansion in samarium hexaboride revealed by X-ray diffraction and total scattering.

Samarium hexaboride, SmB6, is a negative thermal expansion (NTE) material whose structure is similar to other known NTE materials such as the family of Prussian blues. In the Prussian blues, NTE is due to a phonon mechanism, but we recently showed from DFT calculations that this is unlikely in SmB6 (Li et al., Phys. Chem. Chem. Phys. 2023, 25, 10749). We now report experimental X-ray diffraction and pair distribution function analysis of this material in the temperature range 20-300 K. The interatomic distances shown by both methods are consistent with the NTE instead arising from an electronic effect, by which the samarium atoms lose electrons and thus have a smaller ionic radius as the temperature increases.

Dynamics in the ordered and disordered phases of barocaloric adamantane.

High-entropy order-disorder phase transitions can be used for efficient and eco-friendly barocaloric solid-state cooling. Here the barocaloric effect is reported in an archetypal plastic crystal, adamantane. Adamantane has a colossal isothermally reversible entropy change of 106 J K-1 kg-1. Extremely low hysteresis means that this can be accessed at pressure differences less than 200 bar. Configurational entropy can only account for about 40% of the total entropy change; the remainder is due to vibrational effects. Using neutron spectroscopy and supercell lattice dynamics calculations, it is found that this vibrational entropy change is mainly caused by softening in the high-entropy phase of acoustic modes that correspond to molecular rotations. We attribute this difference in the dynamics to the contrast between an 'interlocked' state in the low-entropy phase and sphere-like behaviour in the high-entropy phase. Although adamantane is a simple van der Waals solid with near-spherical molecules, this approach can be leveraged for the design of more complex barocaloric molecular crystals. Moreover, this study shows that supercell lattice dynamics calculations can accurately map the effect of orientational disorder on the phonon spectrum, paving the way for studying the vibrational entropy, thermal conductivity, and other thermodynamic effects in more complex materials.

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine.

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.

The cisterna chyli: a systematic review of definition, prevalence, and anatomy.

The cisterna chyli is a lymphatic structure found at the caudal end of the thoracic duct that receives lymph draining from the abdominal and pelvic viscera and lower limbs. In addition to being an important landmark in retroperitoneal surgery, it is the key gateway for interventional radiology procedures targeting the thoracic duct. A detailed understanding of its anatomy is required to facilitate more accurate intervention, but an exhaustive summary is lacking. A systematic review was conducted, and 49 published human studies met the inclusion criteria. Studies included both healthy volunteers and patients and were not restricted by language or date. The detectability of the cisterna chyli is highly variable, ranging from 1.7 to 98%, depending on the study method and criteria used. Its anatomy is variable in terms of location (vertebral level of T10 to L3), size (ranging 2-32 mm in maximum diameter and 13-80 mm in maximum length), morphology, and tributaries. The size of the cisterna chyli increases in some disease states, though its utility as a marker of disease is uncertain. The anatomy of the cisterna chyli is highly variable, and it appears to increase in size in some disease states. The lack of well-defined criteria for the structure and the wide variation in reported detection rates prevent accurate estimation of its natural prevalence in humans.

Vmeasur: A software package for experimental and clinical measurement of mesenteric lymphatic contractile function over an extended vessel length.

OBJECTIVE: Conventionally, in vivo mesenteric lymphatic contractile function is measured using a high magnification transmission microscope (field of view 0.3-1.5 mm), which precludes visualization of extended lengths of vessels embedded in mesenteric fat. Existing software is not optimized for imaging at a low magnification using a contrast agent. We aimed to develop a simple and clinically transferable method for in situ visualization, image analysis, and quantitative assessment of mesenteric lymphatic contractile function over an extended area. METHODS: Subserosal injection of various blue dyes was taken up by mesenteric lymphatics and visualized under a stereomicroscope (25×), allowing for video recording of 1.4 × 1.1 cm of intact mesentery. A new R package ("vmeasur") that combines multiple high-performance image analyses into a single workflow was developed. The edges of each vessel were determined by applying an automated threshold to each frame (with real-time manual verification). The vessel width at every point in each frame was plotted to provide contractile parameters over time and along the lymphatic vessel length. RESULTS: Contractile parameters and their differences along the length of the vessel were accurately calculated in a rodent model. In a human mesenteric lymphatic, the algorithm was also able to measure changes in diameter over length. CONCLUSION: This software offers a low cost, rapid, and accessible method to measure lymphatic contractile function over a wide area, showing differences in contractility along the length of a vessel. Because the presence of mesenteric fat has less of an impact on imaging, due to the use of an exogenous contrast agent, there is potential for clinical application.

Optimising fluid requirements after initial resuscitation: A pilot study evaluating mini-fluid challenge and passive leg raising test in patients with predicted severe acute pancreatitis.

BACKGROUND: The goals and approaches to fluid therapy vary through different stages of resuscitation. This pilot study was designed to test the safety and feasibility of a fluid therapy protocol for the second or optimisation stage of resuscitation in patients with predicted severe acute pancreatitis (SAP). METHODS: Spontaneously breathing patients with predicted SAP were admitted after initial resuscitation and studied over a 24-h period in a tertiary hospital ward. Objective clinical assessment (OCA; heart rate, mean arterial pressure, urine output, and haematocrit) was done at 0, 4, 8, 12, 18-20, and 24 h. All patients had mini-fluid challenge (MFC; 250 ml intravenous normal saline within 10 min) at 0 h and repeated at 4 and 8 h if OCA score ≥2. Patients who were fluid responsive (>10% change in stroke volume after MFC) received 5-10 ml/kg/h, otherwise 1-3 ml/kg/h until the next time point. Passive leg raising test (PLRT) was done at each time point and compared with OCA for assessing volume status and predicting fluid responsiveness. RESULTS: This fluid therapy protocol based on OCA, MFC, and PLRT and designed for the second stage of resuscitation was safe and feasible in spontaneously breathing predicted SAP patients. The PLRT was superior to OCA (at 0 and 8 h) for predicting fluid responsiveness and guiding fluid therapy. CONCLUSIONS: This pilot study found that a protocol for intravenous fluid therapy specifically for the second stage of resuscitation in patients with predicted SAP was safe, feasible, and warrants further investigation.

High-resolution 3D imaging and topological mapping of the lymph node conduit system.

The conduit network is a hallmark of lymph node microanatomy, but lack of suitable imaging technology has prevented comprehensive investigation of its topology. We employed an extended-volume imaging system to capture the conduit network of an entire murine lymph node (comprising over 280,000 segments). The extensive 3D images provide a comprehensive overview of the regions supplied by conduits, including perivascular sleeves and distinctive "follicular reservoirs" within B cell follicles, surrounding follicular dendritic cells. A 3D topology map of conduits within the T-cell zone showed homogeneous branching, but conduit density was significantly higher in the superficial T-cell zone compared with the deep zone, where distances between segments are sufficient for T cells to lose contact with fibroblastic reticular cells. This topological mapping of the conduit anatomy can now aid modeling of its roles in lymph node function, as we demonstrate by simulating T-cell motility in the different T-cell zones.

Meta-Analysis of the Composition of Human Intestinal Gases.

BACKGROUND: Understanding intestinal gases volume and composition may contribute to diagnosing digestive diseases and the microbiome's status. This meta-analysis aimed to define the composition of human intestinal gases and changes associated with diet. METHODS: Studies were identified by systematic research of the MEDLINE(Ovid), Scopus, and Cochrane databases. Studies that measured the concentration of intestinal gases in healthy adult humans were retrieved. The JBI critical appraisal tool was used to evaluate the risk of bias. The primary outcomes analysed were the concentration of the most prevalent colonic gases. Participants were divided into groups according to dietary fibre content. RESULTS: Eleven studies were included. The following gases were identified in similar concentrations across all studies (mean ± standard deviation): nitrogen (65.1 ± 20.89%), oxygen (2.3 ± 0.98%), carbon dioxide (9.9 ± 1.6%), hydrogen (2.9 ± 0.7%), and methane (14.4 ± 3.7%). Differences according to the dietary fibre were observed, with a positive correlation between fibre and volume of gas produced, particularly in fermented gases (carbon dioxide, hydrogen, and methane). DISCUSSION: The meta-analysis has found defined concentrations of the five most common gases present in human colonic gas. Limitations included heterogenic methodologies, a low number of participants, and few recent studies. These findings may be helpful in diagnostic applications where colonic gas volume and composition are crucial factors, including functional disorders, microbiome analyses, and bowel perforation diagnostics.

Stress Hyperglycemia Is Independently Associated with Persistent Organ Failure in Acute Pancreatitis.

BACKGROUND/AIMS: Stress hyperglycemia is common in critical illness but it has not been clearly studied in patients with acute pancreatitis (AP). This study aimed to investigate the specific blood glucose (BG) level that defines stress hyperglycemia and to determine the impact of stress hyperglycemia on clinical outcomes in AP patients. METHODS: AP patients admitted ≤ 48 h after abdominal pain onset were retrospectively analyzed. Patients were stratified by pre-existing diabetes and stress hyperglycemia was defined using stratified BG levels for non-diabetes and diabetes with clinical outcomes compared. RESULTS: There were 967 non-diabetic and 114 diabetic (10.5%) patients met the inclusion criteria and the clinical outcomes between these two groups were not significantly different. In non-diabetes, the cut-off BG level of ≥ 180 mg/dl was selected to define stress hyperglycemia with an 8.8-fold higher odds ratio for persistent organ failure (POF) (95% CI 5.4-14.3; P < 0.001). For diabetes, ≥ 300 mg/dl was selected with a 7.5-fold higher odds ratio for POF (95% CI 1.7-34.3; P = 0.009). In multivariable logistic regression, stress hyperglycemia was independently associated with POF, acute necrotic collection, major infection and mortality. The combination of BG and systemic inflammatory response syndrome (SIRS) score in predicting POF was better than SIRS or Glasgow score alone. CONCLUSIONS: This study identifies a cut-off BG level of ≥ 180 mg/dl and ≥ 300 mg/dl was optimal to define stress hyperglycemia for non-diabetic and diabetic AP patients, respectively. There was a significant relationship between stress hyperglycemia and adverse clinical outcomes.

The effect of respiration and body position on terminal thoracic duct diameter and the lymphovenous junction: An exploratory ultrasound study.

The thoracic duct (TD) drains most of the body's lymph back to the venous system via its lymphovenous junction (LVJ), playing a pivotal role in fluid homeostasis, fat absorption and the systemic immune response. The respiratory cycle is thought to assist with lymph flow, but the precise mechanism underpinning terminal TD lymph flow into the central veins is not well understood. The aim of this study was to use ultrasonography (US) to explore the relationship between terminal TD lymph flow, the respiratory cycle, and gravity. The left supraclavicular fossa was scanned in healthy non-fasted volunteers using high-resolution (13-5 MHz) US to identify the terminal TD and the presence of a lymphovenous valve (LVV). The TD's internal diameter was measured in relation to respiration (inspiration vs. expiration) and body positioning (supine vs. Trendelenburg). The terminal TD was visualized in 20/33 (61%) healthy volunteers. An LVV was visualized in only 4/20 (20%) cases. The mean terminal TD diameter in the supine position was 1.7 mm (range 0.8-3.1 mm); this increased in full inspiration (mean 1.8 mm, range 0.9-3.2 mm, p < 0.05), and in the Trendelenburg position (mean 1.8 mm, range 1.2-3.1 mm, p < 0.05). The smallest mean terminal TD diameter occurred in full expiration (1.6 mm, range 0.7-3.1 mm, p < 0.05). Respiration and gravity impact the terminal TD diameter. Due to the challenges of visualizing the TD and LVJ, other techniques such as dynamic magnetic resonance imaging will be required to fully understand the factors governing TD lymph flow.

The complex, bidirectional role of extracellular vesicles in infection.

Cells from all domains of life release extracellular vesicles (EVs), packages that carry a cargo of molecules that participate in communication, co-ordination of population behaviours, virulence and immune response mechanisms. Mammalian EVs play an increasingly recognised role to fight infection, yet may also be commandeered to disseminate pathogens and enhance infection. EVs released by bacterial pathogens may deliver toxins to host cells, signalling molecules and new DNA to other bacteria, and act as decoys, protecting infecting bacteria from immune killing. In this review, we explore the role of EVs in infection from the perspective of both the pathogen and host, and highlight their importance in the host/pathogen relationship. We highlight proposed strategies for EVs in therapeutics, and call attention to areas where existing knowledge and evidence is lacking.

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala.

BACKGROUND: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Research Priorities in Lymphatic Interventions: Recommendations from a Multidisciplinary Research Consensus Panel.

Recognizing the increasing importance of lymphatic interventions, the Society of Interventional Radiology Foundation brought together a multidisciplinary group of key opinion leaders in lymphatic medicine to define the priorities in lymphatic research. On February 21, 2020, SIRF convened a multidisciplinary Research Consensus Panel (RCP) of experts in the lymphatic field. During the meeting, the panel and audience discussed potential future research priorities. The panelists ranked the discussed research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were prioritized by RCP: lymphatic decompression in patients with congestive heart failure, detoxification of thoracic duct lymph in acute illness, development of newer agents for lymphatic imaging, characterization of organ-based lymph composition, and development of lymphatic interventions to treat ascites in liver cirrhosis. The RCP priorities underscored that the lymphatic system plays an important role not only in the intrinsic lymphatic diseases but in conditions that traditionally are not considered to be lymphatic such as congestive heart failure, liver cirrhosis, and critical illness. The advancement of the research in these areas will lead the field of lymphatic interventions to the next level.

Characterisation of an ischemia reperfusion model for the formation of a stage I pressure ulcer in mouse skin.

Pairs of magnets were applied to the loose skin on the backs of mice in order to cause ischemia for periods of 1.5, 2, 2.5 and 3 h followed by reperfusion. We found 1.5 h of ischemia resulted in the most reliable outcome of blanched skin but no redness or skin breakdown. Histological analysis at 4 h of reperfusion showed, in the centre of the insult, condensed nuclei in the epidermis and sebaceous glands with a build up of neutrophils in the blood vessels, and a reduction in the number of fibroblasts. At 24 h, spongiosis was seen in the epidermis and pockets of neutrophils began to accumulate under it, as well as being scatted through the dermis. In the centre of the insult there was a loss of sebaceous gland nuclei and fibroblasts. Four days after the insult, spongiosis was reduced in the epidermis at the edge of the insult but enhanced in the centre and in hair follicles. Leukocytes were seen throughout the central dermis. At 8 days, spongiosis and epidermal thickness had reduced and fibroblasts were reappearing. However, blood vessels still had leukocytes lining the lumen. The gap junction protein connexin 43 was significantly elevated in the epidermis at 4 h and 24 h reperfusion. Ischemia of 1.5 h generates a sterile inflammatory reaction causing the loss of some cell types but leaving the epidermis intact reminiscent of a stage I pressure ulcer.

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction.

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine.SIGNIFICANCE STATEMENT Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associated with greater risk of relapse and treatment failure in substance use disorder. Understanding factors that enhance preference for risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

Anatomy of the lymphovenous valve of the thoracic duct in humans.

The majority of lymph generated in the body is returned to the blood circulation via the lymphovenous junction (LVJ) of the thoracic duct (TD). A lymphovenous valve (LVV) is thought to guard this junction by regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system. Despite these important functions, the morphology and mechanism of this valve remains unclear. The aim of this study was to investigate the anatomy of the LVV of the TD. To do this, the TD and the great veins of the left side of the neck were harvested from 16 human cadavers. The LVJs from 12 cadavers were successfully identified and examined macroscopically, microscopically, and using microcomputed tomography. In many specimens, the TD branched before entering the veins. Thus, from 12 cadavers, 21 LVJs were examined. Valves were present at 71% of LVJs (15/21) and were absent in the remainder. The LVV, when present, was typically a bicuspid semilunar valve, although the relative size and position of its cusps were variable. Microscopically, the valve cusps comprised luminal extensions of endothelium with a thin core of collagenous extracellular matrix. This study clearly demonstrated the morphology of the human LVV. This valve may prevent blood from entering the lymphatic system, but its variability and frequent absence calls into question its utility. Further structural and functional studies are required to better define the role of the LVV in health and disease.

Colossal Pressure-Induced Softening in Scandium Fluoride.

The counterintuitive phenomenon of pressure-induced softening in materials is likely to be caused by the same dynamical behavior that produces negative thermal expansion. Through a combination of molecular dynamics simulation on an idealized model and neutron diffraction at variable temperature and pressure, we show the existence of extraordinary and unprecedented pressure-induced softening in the negative thermal expansion material scandium fluoride ScF_{3}. The pressure derivative of the bulk modulus B, B^{'}=(∂B/∂P)_{P=0}, reaches values as low as -220±30 at 50 K, and is constant at -50 between 150 and 250 K.