Salmonella enterica (Se) bacteria cause persistent intracellular infections while stimulating a robust interferon-γ-producing CD4+ T (Th1) cell response. We addressed this paradox of concomitant ...infection and immunity by tracking fluorescent Se organisms in mice. Se bacteria persisted in nitric oxide synthase (iNOS)-producing resident and recruited macrophages while inducing genes related to protection from nitric oxide. Se-infected cells occupied iNOS+ splenic granulomas that excluded T cells but were surrounded by mononuclear phagocytes producing the chemokines CXCL9 and CXCL10, and Se epitope-specific Th1 cells expressing CXCR3, the receptor for these chemokines. Blockade of CXCR3 inhibited Th1 occupancy of CXCL9/10-dense regions, reduced activation of the Th1 cells, and led to increased Se growth. Thus, intracellular Se bacteria survive in their hosts by counteracting toxic products of the innate immune response and by residing in T cell-sparse granulomas, away from abundant Th1 cells positioned via CXCR3 in a bordering region that act to limit infection.
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•S. enterica (Se) infection stimulates robust expansion of CXCR3+ Th1 cells•Granulomas bordered by CXCL9/10+ phagocytes form during Se infection•Se bacteria are in granuloma cores while Th1 cells are excluded to the borders•Se bacteria produce enzymes that neutralize the effects of nitric oxide
The pathogen Salmonella enterica (Se) can paradoxically persist in hosts while being controlled by IFN-γ-producing Th1 cells. Goldberg et al. show that the bacteria survive by resisting the effects of toxic host molecules in myeloid cells within granulomas, in areas lacking T cells. Infection is constrained by Th1 cells positioned around the granuloma via the CXCR3-CXCL9/10 chemokine axis.
What are the cortical neural correlates that distinguish goal-directed and non-goal-directed movements? We investigated this question in the monkey frontal eye field (FEF), which is implicated in ...voluntary control of saccades. Here, we compared FEF activity associated with goal-directed (G) saccades and non-goal-directed (nG) saccades made by the monkey. Although the FEF neurons discharged before these nG saccades, there were three major differences in the neural activity: First, the variability in spike rate across trials decreased only for G saccades. Second, the local field potential beta-band power decreased during G saccades but did not change during nG saccades. Third, the time from saccade direction selection to the saccade onset was significantly longer for G saccades compared with nG saccades. Overall, our results reveal unexpected differences in neural signatures for G versus nG saccades in a brain area that has been implicated selectively in voluntary control. Taken together, these data add critical constraints to the way we think about saccade generation in the brain.
The nature and function of perisaccadic receptive field (RF) remapping have been controversial. We use a delayed saccade task to reduce previous confounds and examine the remapping time course in the ...lateral intraparietal area and frontal eye fields. In the delay period, the RF shift direction turns from the initial fixation to the saccade target. In the perisaccadic period, RFs first shift toward the target (convergent remapping), but around the time of saccade onset/offset, the shifts become predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appears to follow attention from the initial fixation to the target. We model the data with attention-modulated and CD-gated connections and show that both sets of connections emerge automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability.
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•Remapping directions in LIP/FEF change from convergent to forward in a delayed saccade task•Unlike convergent remapping, forward remapping can adequately guide perception and saccades•Corollary-discharge-gated and attention-modulated connections explain the remapping•These connections emerge in neural networks trained to perform transsaccadic updating
The nature of perisaccadic receptive field remapping has been controversial. Wang et al. show that remapping directions in the LIP and FEF change with time from attentionally driven convergent remapping to corollary-discharge-driven forward remapping. Simulations suggest that connectivity patterns for both types of remapping interact to enable transsaccadic visual stability.
Underrepresented minority groups (URMs) in surgery are not significantly increasing despite evidence suggesting that diversity in health care providers leads to excellent patient outcomes and care. ...Efforts to increase URM representation in surgical residency programs are essential for addressing disparities and improving health care delivery.
This retrospective study outlines a three-phase strategy implemented at a large academic-affiliated hospital to increase URM representation in its general surgery residency program. The strategy encompassed interview selection with a holistic review and implicit bias training for interviewers, modification of the interview scoring rubric, and post-interview recruitment efforts, including a virtual second look event for URM applicants.
Following the implementation of these strategies, the URM match rate improved from 0 to 33.3% in the first year and was sustained at 33.3% in the subsequent year. Consequently, the representation of URMs in the residency program rose from 6.7% before our intervention to 13.3% afterwards.
This structured approach successfully increased URM representation in a surgical residency program, affirming the success of targeted recruitment strategies. By promoting a diverse and inclusive environment, the program better reflects the community it serves, with aims at improved patient care and patient satisfaction.
Nuclear alterations are a well-known manifestation of cancer. However, little is known about the early, microscopically-undetectable stages of malignant transformation. Based on the phenomenon of ...field cancerization, the tissue in the field of a tumor can be used to identify and study the initiating events of carcinogenesis. Morphological changes in nuclear organization have been implicated in the field of colorectal cancer (CRC), and we hypothesize that characterization of chromatin alterations in the early stages of CRC will provide insight into cancer progression, as well as serve as a biomarker for early detection, risk stratification and prevention.
For this study we used transmission electron microscopy (TEM) images of nuclei harboring pre-neoplastic CRC alterations in two models: a carcinogen-treated animal model of early CRC, and microscopically normal-appearing tissue in the field of human CRC. We quantify the chromatin arrangement using approaches with two levels of complexity: 1) binary, where chromatin is separated into areas of dense heterochromatin and loose euchromatin, and 2) grey-scale, where the statistics of continuous mass-density distribution within the nucleus is quantified by its spatial correlation function.
We established an increase in heterochromatin content and clump size, as well as a loss of its characteristic peripheral positioning in microscopically normal pre-neoplastic cell nuclei. Additionally, the analysis of chromatin density showed that its spatial distribution is altered from a fractal to a stretched exponential.
We characterize quantitatively and qualitatively the nanoscale structural alterations preceding cancer development, which may allow for the establishment of promising new biomarkers for cancer risk stratification and diagnosis. The findings of this study confirm that ultrastructural changes of chromatin in field carcinogenesis represent early neoplastic events leading to the development of well-documented, microscopically detectable hallmarks of cancer.
Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to ...immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.
Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA ...replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than polymerase slippage in replicating progenitor cells. These results echo the recent finding that DNA damage in oocytes is a significant source of de novo single nucleotide variants and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to known hotspots of oocyte mutagenesis, nor are postzygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on de novo mutation (DNM) rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at G/C-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and contradict prior attribution of replication slippage as the primary mechanism of STR mutagenesis.
Stress management programs improve efficacy in aviation, military, and professional sports; however, similar educational strategies have not been adopted in surgical training. We have evaluated the ...effectiveness of a stress management program for surgical residents.
From 2011 to 2016, 137 surgical residents participated in a prospective, blinded study. The intervention group (n = 65) underwent training in self-awareness, focus, relaxation, positive self-talk, visualization, and team building. All participants subsequently completed a high-stress trauma simulation, requiring diagnosis and management of a life-threatening problem. Study endpoints included measures of procedural efficiency, and physiologic and subjective measurements of anxiety.
Residents with stress training came to an accurate diagnosis 21% faster than controls (mean diagnosis time: 2.2 vs. 2.8 min; p = 0.04), and performed with greater technical accuracy (mean OSAT scores: 9.4 vs. 8.9; p = 0.03). Both cohorts exhibited similar physiologic and subjective anxiety metrics after simulation.
Stress management education may enhance technical performance in surgical trainees during simulation. This underscores the need for early, comprehensive stress training in surgical residency.
•This is a prospective trial of 137 surgical residents who took part in a stress training program.•Participants and controls subsequently took part in a high-stress surgical simulation.•Residents who completed stress training performed more accurately and quickly.•Both cohorts exhibited similar measures of physiologic and subjective anxiety.
Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple ...cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.
WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays.
Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals.
These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.
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