Distribution of dendritic spines and inhibitory inputs on layer 2 and layer 3 pyramidal neurons of the anterior cingulate cortex

The anterior cingulate cortex (ACC) plays an important role in reward-based decision-making, linking higher-order thinking and emotions. Because of this area's dense connectivity it is important to study the properties of the excitatory and inhibitory network that governs ACC output. The aim of this study was to characterize the morphology of dendritic excitatory postsynaptic sites and inhibitory inputs on layer 2 and layer 3 ACC pyramidal neurons, the principal intracortical projection neurons of the cortex. Using biocytin-filling and high-resolution confocal imaging, we quantified the distribution of dendritic spines, the major sites of excitatory input, on pyramidal cells. We visualized inhibitory inputs apposed to specific pyramidal cell compartments, including the axon initial segment, soma, dendrites, and dendritic spines, through immunohistochemical labeling of vesicular γ-aminobutyric acid transporter. Layer 2 and layer 3 cells had similar spine densities on their apical and basal dendritic compartments, with a maximum spine density occurring in their middle apical and middle basal compartments. Axon initial segments of layer 3 cells had a higher density of inhibitory input compared to the layer 2 cells (0.84 vs 0.66 apps/μm). The apical dendritic shaft had a higher apposition density than the basal dendritic shaft in an individual layer (layer 2, 0.50 vs 0.32; layer 3, 0.50 vs 0.28 apps/μm) with the majority of the innervation occurring on the proximal compartments of both apical and basal segments. Although located in different laminae, these cells showed similar inhibitory input distributions, with higher amounts of inhibition proximally. Finally, these inhibitory inputs also occurred on dendritic spines, with the highest density on thin spines. However, proportionally, mushroom spines had the highest level of innervation, with up to 44% of these spines receiving inhibitory input. These findings add to the understanding of how inhibition at the cellular level can affect the output of the ACC and begin to uncover important relationships between cellular structure and function in this brain region

Trying to Make Sense of Sexual Harassment Law after \u3ci\u3eOncale\u3c/i\u3e, \u3ci\u3eHolman\u3c/i\u3e, and \u3ci\u3eRene\u3c/i\u3e

The state of the law governing sexual harassment, which was far from clear, was rendered more turbid by a 1998 U.S. Supreme Court holding that offered examples of specific situations under which such harassment might be actionable. The Court’s ruling in a case of same-sex harassment has muddied the waters by opening the issue of the alleged harasser’s motivation. This provides a defense for harassers who may rebut the accusation that their actions are motivated by sexual interests. In addition to making same-sex harassment difficult to prove, this holding makes it nearly impossible for an individual to make a case of sexual harassment when that harassment is not specifically directed at that person even though the conduct at issue is severe or pervasive. Employers seeking to promote fair play and to prevent claims of sexual harassment must maintain strict no-harassment policies and educate their staffs on the reasons for such policies

Phase i study of \u27dose-dense\u27 pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

BACKGROUND: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). METHODS: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles. RESULTS: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. CONCLUSIONS: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC

Ex vivo innate immune cytokine signature of enhanced risk of relapsing brucellosis.

BackgroundBrucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5-40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis.Methodology/principal findingsBlood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM.Conclusions/significanceThis work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may allow for better follow-up care of brucellosis patients through improved identification of patients at risk for relapse

A Hybrid Sequencing Approach Completes the Genome Sequence of Thermoanaerobacter ethanolicus JW 200

Thermoanaerobacter ethanolicus JW 200 has been identified as a potential sustainable biofuel producer due to its ability to readily ferment carbohydrates to ethanol. A hybrid sequencing approach, combining Oxford Nanopore and Illumina DNA sequence reads, was applied to produce a single contiguous genome sequence of 2,911,280 bp

Open and Equitable Scholarly Communications: Creating a More Inclusive Future

For many years, the academic and research library workforce has worked to accelerate the transition to more open and equitable systems of scholarship. While significant progress has been made, barriers remain. The Association of College and Research Libraries (ACRL) seeks to stimulate further advances through this action- oriented research agenda, which is designed to provide practical, actionable information for academic librarians; include the perspectives of historically underrepresented communities in order to expand the profession’s understanding of research environments and scholarly communication systems; and point librarians and other scholars toward important research questions to investigate. This report represents a yearlong process of reviewing the scholarly and practice-based literature to take into account established investigation coupled with extensive public consultation to identify the major problems facing the academic library community. Through interviews, focus groups, workshops, and an online survey, over 1,000 members of the ACRL community offered their thoughts and expertise to shape this research agenda. Incorporating guidance and input from ACRL’s Research and Scholarly Environment Committee and an advisory panel, this document recommends ways to make the scholarly communications and research environment more open, inclusive, and equitable

A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children\u27s Oncology Group Study ANBL0931

Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade \u3e/= 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 +/- 4.8% and 79.1 +/- 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNgamma, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032

Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma

<p>Abstract</p> <p>Background</p> <p>This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m². Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m², but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m²) q3 weeks × 2 -3 cycles.</p> <p>Results</p> <p>Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.</p> <p>Conclusions</p> <p>Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m²with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00330044">NCT00330044</a></p