Automated slice-specific z-shimming for functional magnetic resonance imaging of the human spinal cord.

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.

Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes.

Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.

A snapshot of public finance research from immediately prior to the pandemic: IIPF 2020.

As the COVID-19 pandemic has shaped public policies and government finances, it has also influenced the topics that public finance economists are researching. Because the 2020 International Institute of Public Finance Congress featured papers that were submitted prior to the start of the pandemic, the Congress allows us to reflect on the state of research prior to the pandemic's shock to both fiscal policies and our worldview. In this article, the Editors of International Tax and Public Finance reflect on interesting papers that were presented at this internationally representative conference in public economics. The exercise provides insight on where the field of public economics was heading prior to the pandemic and will provide a yardstick to see how the field evolves in the coming years afterward.

The impact of taxes on the extensive and intensive margins of FDI.

It is well documented that foreign investment inflows are deterred by host taxes. What is less clear, however, is the degree to which these aggregate changes are driven by firm choices at the extensive (whether to invest) or intensive (how much to invest) margins. Further, there is little evidence on the way in which these two margins are affected by firm and home-country characteristics. We contribute by examining firm-level cross-border investments during 2007-2015 into Europe from a broad group of home countries at both investment margins. Similar to the existing single-country studies, we find that taxes operate primarily on the extensive margin. Building on those results, we delve further and find significant variation across firms with small investors from high-tax home countries especially sensitive to host taxation.

Manipulations of sensory experiences during development reveal mechanisms underlying vocal learning biases in zebra finches.

Biological predispositions in learning can bias and constrain the cultural evolution of social and communicative behaviors (e.g., speech and birdsong), and lead to the emergence of behavioral and cultural "universals." For example, surveys of laboratory and wild populations of zebra finches (Taeniopygia guttata) document consistent patterning of vocal elements ("syllables") with respect to their acoustic properties (e.g., duration, mean frequency). Furthermore, such universal patterns are also produced by birds that are experimentally tutored with songs containing randomly sequenced syllables ("tutored birds"). Despite extensive demonstrations of learning biases, much remains to be uncovered about the nature of biological predispositions that bias song learning and production in songbirds. Here, we examined the degree to which "innate" auditory templates and/or biases in vocal motor production contribute to vocal learning biases and production in zebra finches. Such contributions can be revealed by examining acoustic patterns in the songs of birds raised without sensory exposure to song ("untutored birds") or of birds that are unable to hear from early in development ("early-deafened birds"). We observed that untutored zebra finches and early-deafened zebra finches produce songs with positional variation in some acoustic features (e.g., mean frequency) that resemble universal patterns observed in tutored birds. Similar to tutored birds, early-deafened birds also produced song motifs with alternation in acoustic features across adjacent syllables. That universal acoustic patterns are observed in the songs of both untutored and early-deafened birds highlights the contribution motor production biases to the emergence of universals in culturally transmitted behaviors.

Fecal microbiota and metabolites are distinct in a pilot study of pediatric Crohn's disease patients with higher levels of perceived stress.

Stress is associated with increased Crohn's Disease (CD) activity. This pilot study tested whether pediatric patients with CD reporting higher levels of perceived stress exhibited differences in the fecal microbiome and metabolome. The perceived stress scale (PSS) questionnaire was administered within 2 days of collecting a stool sample for microbiome (using 16S rRNA gene sequencing) and metabolome (using NMR metabolomics) analyses. Higher levels of perceived stress were correlated with increased disease activity on the short Pediatric Crohn's Disease Activity Index (sPCDAI). Patients with High PSS scores vs. Low PSS scores based on a median split had significantly lower relative abundances of Firmicutes and Anaerostipes, as well as higher relative abundances of Parabacteroides. Fecal alanine and nicotinate were also significantly different in patients with High vs. Low PSS Scores. This pilot study suggests that the fecal microbiome and metabolome differs in pediatric patients with CD and high perceived stress.

Dietary Oligosaccharides Attenuate Stress-Induced Disruptions in Immune Reactivity and Microbial B-Vitamin Metabolism.

Background: Exposure to stressful stimuli dysregulates inflammatory processes and alters the gut microbiota. Prebiotics, including long-chain fermentable fibers and milk oligosaccharides, have the potential to limit inflammation through modulation of the gut microbiota. To determine whether prebiotics attenuate stress-induced inflammation and microbiota perturbations, mice were fed either a control diet or a diet supplemented with galactooligosaccharides, polydextrose and sialyllactose (GOS+PDX+SL) or sialyllactose (SL) for 2 weeks prior to and during a 6-day exposure to a social disruption stressor. Spleens were collected for immunoreactivity assays. Colon contents were examined for stressor- and diet- induced changes in the gut microbiome and metabolome through 16S rRNA gene sequencing, shotgun metagenomic sequencing and UPLC-MS/MS. Results: Stress increased circulating IL-6 and enhanced splenocyte immunoreactivity to an ex vivo LPS challenge. Diets containing GOS+PDX+SL or SL alone attenuated these responses. Stress exposure resulted in large changes to the gut metabolome, including robust shifts in amino acids, peptides, nucleotides/nucleosides, tryptophan metabolites, and B vitamins. Multiple B vitamins were inversely associated with IL-6 and were augmented in mice fed either GOS+PDX+SL or SL diets. Stressed mice exhibited distinct microbial communities with lower abundances of Lactobacillus spp. and higher abundances of Bacteroides spp. Diet supplementation with GOS+PDX+SL, but not SL alone, orthogonally altered the microbiome and enhanced the growth of Bifidobacterium spp. Metagenome-assembled genomes (MAGs) from mice fed the GOS+PDX+SL diet unveiled genes in a Bifidobacterium MAG for de novo B vitamin synthesis. B vitamers directly attenuated the stressor-induced exacerbation of cytokine production in LPS-stimulated splenocytes. Conclusions: Overall, these data indicate that colonic metabolites, including B vitamins, are responsive to psychosocial stress. Dietary prebiotics reestablish colonic B vitamins and limit stress-induced inflammation.

Identification of tick periviscerokinin, the first neurohormone of Ixodidae: single cell analysis by means of MALDI-TOF/TOF mass spectrometry.

The first peptidergic neurohormone from the ticks Ixodes ricinus and Boophilus microplus has been identified by using a combination of immunocytochemistry and mass spectrometric analysis of single cells. The novel peptide (Ixori-PVK, PALIPFPRV-NH2) shows a high sequence homology with members of the insect periviscerokinin/CAP2b peptides that in insects are involved in the regulation of water balance. The function of this peptide in ticks is still unknown, but these pests consume large amounts of blood in a single blood meal which is a challenge for the regulation of diuretic processes. Thus, the novel peptide may be involved in one of the key physiological processes in ticks. High energy collision-induced dissociation was successfully used to distinguish between Leu/Ile ambiguities in single cell preparations. This is the first successful de novo sequencing of a peptide from single cell preparations of arthropods.

Standardized protocols for photocarcinogenesis safety testing.

Solar ultraviolet radiation (UVR) is recognized as a major cause of non-melanoma skin cancer in man. Skin cancer occurs most frequently in the most heavily exposed areas and correlates with degree of outdoor exposure. The incidence of skin cancer is also increased by contact with photosensitizing drugs and chemicals such as psoralens, coal tars and petroleum stocks. Other substances which do not act as photosensitizers, such as immunosuppressants taken by organ transplant recipients, also increase the risk of skin cancer. The U.S. Food and Drug Administration requests, on a case-by-case basis, that risk of enhanced photocarcinogenesis is assessed for many classes of drugs. Health Canada's Therapeutic Products Programme has issued a Notice of Intent to regulate pharmaceutical products which may enhance carcinogenicity of the skin induced by ultraviolet radiation. Other national regulatory agencies review such data when they exist, but their own requirements emphasize batteries of short-term in vitro and in vivo tests. While they may support drug development strategies, short-term tests have yet to be validated as predictors of the ability of drugs or chemicals to enhance photocarcinogenesis. Published protocols now describe study designs and procedures capable of determining whether test agents enhance the rate of formation of UVR-induced skin tumors.

Photocarcinogenesis: measuring the reproducibility of a biologic response to ultraviolet radiation exposure in mice.

New drugs undergo safety evaluations of many types. For some drugs, a photocarcinogenesis study forms one of the elements in the overall toxicology package. Photocarcinogenesis studies are designed to evaluate a drug's ability to modify the growth and development of ultraviolet radiation (UVR)-induced skin tumors in albino hairless mice. "Exposure control" groups in such studies receive the UVR, either alone, or in combination with the "vehicle" or carrier associated with each study. This report presents skin tumor data from control groups compiled from nine consecutive studies conducted at this testing facility. The endpoints evaluated included median tumor onset, mortality-free prevalence and tumor yield. "Historical control data" are considered essential for designing, monitoring, interpreting and evaluating studies of a given type. In addition, a compilation of such control data can illustrate trends or provide measures of reproducibility more reliably than can individual studies. This data set shows how clearly the UVR-induced skin tumor onset time is dependent on UVR dose, how skin tumors develop sooner in female mice than in male mice at a low UVR exposure dose, and that topical administration of certain vehicle formulations can enhance photocarcinogenesis.

Foraging activity of two species of predatory leeches exposed to active and sedentary prey.

The foraging activity of the freshwater leeches Nephelopsis obscura and Erpobdella punctata during acclimation to active or sedentary prey, starvation and refeeding was examined by filming over a 24 h cycle. For both species, the time of activity of individual leeches and the total number of leeches active were significantly correlated. Activity in the dark was significantly higher than in the light with the activity of N. obscura in the dark 16.2 times higher in terms of time and 6.7 times higher in terms of numbers of individuals moving than E. punctata. Large N. obscura were significantly more active than medium or small individuals and encountered more sedentary prey. With lower levels of activity E. punctata encounters and feeds on more active prey, and in lotic ecosystems its lower exposure to fish predation and drift is, at least partially, responsible for its numerical abundance over N. obscura. There were no significant differences in the activity of N. obscura or E. punctata fed on active or sedentary prey during either subsequent starvation of 1 to 10 d, or after refeeding, suggesting that unchanged foraging activity provides the optimun net energy gain during periods of change in prey type and availability.

The evolutionary importance of mechanoreception in three erpobdellid leech species.

The ability of an erpobdellid leech, Erpobdella montezuma, to discriminate between two congeneric amphipod prey (Hyalella montezuma and Hyalella azteca) through mechanoreception was examined. Both E. montezuma and H. montezuma, a pelagic filter feeder, are endemic to the near thermally constant environment of Montezuma Well, Arizona, and form a highly specialized predator-prey relationship. In contrast, H. azteca, a benthic detritivore, is widely distributed throughout North America. Erpobdella montezuma was highly responsive to the prey signals of the endemic H. montezuma and showed only a limited response to H. azteca. An inverse relationship occurred between the frequency of attack and size of the leech. The abilities of Erpobdella punctata and Nephelopsis obscura, neither found in Montezuma Well, to detect the signals of both amphipod prey were also examined. These species with non-specialized diets showed a low response to the signals of both prey species. This study demonstrates that very close predator-prey relationships can develop over evolutionary time in isolated aquatic systems through the use of mechanoreception.

Competition and coexistance between Glossiphonia complanata and Helobdella stagnalis (Glossiphoniidae: Hirudinoidea).

The prey utilization of Glossiphonia complanata and Helobdella stagnalis from Bruce Lake, Alberta, Canada was examined quantitatively using serological techniques. While considerable prey range overlap occurred between the species, niche overlap was low during the winter, peaked in March and declined through the summer. Temporal differences in feeding and intraspecific weight class differences in prey utilization were found in both species but more distinctly in G. complanata. It is suggested that co-existance of G. complanata and H. stagnalis is based on adjustments of weight class food resource partitioning on a temporal basis.