A Hierarchical Cascade of Second Messengers Regulates Pseudomonas aeruginosa Surface Behaviors

Biofilms are surface-attached multicellular communities. Using single-cell tracking microscopy, we showed that apilY1 mutant of Pseudomonas aeruginosa is defective in early biofilm formation. We leveraged the observation that PilY1 pro- tein levels increase on a surface to perform a genetic screen to identify mutants altered in surface-grown expression of this pro- tein. Based on our genetic studies, we found that soon after initiating surface growth, cyclic AMP (cAMP) levels increase, depen- dent on PilJ, a chemoreceptor-like protein of the Pil-Chp complex, and the type IV pilus (TFP). cAMP and its receptor protein Vfr, together with the FimS-AlgR two-component system (TCS), upregulate the expression of PilY1 upon surface growth. FimS and PilJ interact, suggesting a mechanism by which Pil-Chp can regulate FimS function. The subsequent secretion of PilY1 is dependent on the TFP assembly system; thus, PilY1 is not deployed until the pilus is assembled, allowing an ordered signaling cascade. Cell surface-associated PilY1 in turn signals through the TFP alignment complex PilMNOP and the diguanylate cyclase SadC to activate downstream cyclic di-GMP (c-di-GMP) production, thereby repressing swarming motility. Overall, our data support a model whereby P. aeruginosa senses the surface through the Pil-Chp chemotaxis-like complex, TFP, and PilY1 to reg- ulate cAMP and c-di-GMP production, thereby employing a hierarchical regulatory cascade of second messengers to coordinate its program of surface behaviors

Tomonaga-Luttinger parameters for quantum wires

The low-energy properties of a homogeneous one-dimensional electron system are completely specified by two Tomonaga-Luttinger parameters $K_{\rho}$ and $v_{\sigma}$. In this paper we discuss microscopic estimates of the values of these parameters in semiconductor quantum wires that exploit their relationship to thermodynamic properties. Motivated by the recognized similarity between correlations in the ground state of a one-dimensional electron liquid and correlations in a Wigner crystal, we evaluate these thermodynamic quantities in a self-consistent Hartree-Fock approximation. According to our calculations, the Hartree-Fock approximation ground state is a Wigner crystal at all electron densities and has antiferromagnetic order that gradually evolves from spin-density-wave to localized in character as the density is lowered. Our results for $K_{\rho}$ are in good agreement with weak-coupling perturbative estimates $K_{\rho}^{pert}$ at high densities, but deviate strongly at low densities, especially when the electron-electron interaction is screened at long distances. $K_{\rho}^{pert}\sim n^{1/2}$ vanishes at small carrier density $n$ whereas we conjecture that $K_{\rho}\to 1/2$ when $n\to 0$, implying that $K_{\rho}$ should pass through a minimum at an intermediate density. Observation of such a non-monotonic dependence on particle density would allow to measure the range of the microscopic interaction. In the spin sector we find that the spin velocity decreases with increasing interaction strength or decreasing $n$. Strong correlation effects make it difficult to obtain fully consistent estimates of $v_{\sigma}$ from Hartree-Fock calculations. We conjecture that v_{\sigma}/\vf\propto n/V_0 in the limit $n\to 0$ where $V_0$ is the interaction strength.Comment: RevTeX, 23 pages, 8 figures include

Evidence Map of Pancreatic Surgery–A living systematic review with meta-analyses by the International Study Group of Pancreatic Surgery (ISGPS)

Background: Pancreatic surgery is associated with considerable morbidity and, consequently, offers a large and complex field for research. To prioritize relevant future scientific projects, it is of utmost importance to identify existing evidence and uncover research gaps. Thus, the aim of this project was to create a systematic and living Evidence Map of Pancreatic Surgery. Methods: PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched for all randomized controlled trials and systematic reviews on pancreatic surgery. Outcomes from every existing randomized controlled trial were extracted, and trial quality was assessed. Systematic reviews were used to identify an absence of randomized controlled trials. Randomized controlled trials and systematic reviews on identical subjects were grouped according to research topics. A web-based evidence map modeled after a mind map was created to visualize existing evidence. Meta-analyses of specific outcomes of pancreatic surgery were performed for all research topics with more than 3 randomized controlled trials. For partial pancreatoduodenectomy and distal pancreatectomy, pooled benchmarks for outcomes were calculated with a 99% confidence interval. The evidence map undergoes regular updates. Results: Out of 30, 860 articles reviewed, 328 randomized controlled trials on 35, 600 patients and 332 systematic reviews were included and grouped into 76 research topics. Most randomized controlled trials were from Europe (46%) and most systematic reviews were from Asia (51%). A living meta-analysis of 21 out of 76 research topics (28%) was performed and included in the web-based evidence map. Evidence gaps were identified in 11 out of 76 research topics (14%). The benchmark for mortality was 2% (99% confidence interval: 1%–2%) for partial pancreatoduodenectomy and <1% (99% confidence interval: 0%–1%) for distal pancreatectomy. The benchmark for overall complications was 53% (99%confidence interval: 46%–61%) for partial pancreatoduodenectomy and 59% (99% confidence interval: 44%–80%) for distal pancreatectomy. Conclusion: The International Study Group of Pancreatic Surgery Evidence Map of Pancreatic Surgery, which is freely accessible via www.evidencemap.surgery and as a mobile phone app, provides a regularly updated overview of the available literature displayed in an intuitive fashion. Clinical decision making and evidence-based patient information are supported by the primary data provided, as well as by living meta-analyses. Researchers can use the systematic literature search and processed data for their own projects, and funding bodies can base their research priorities on evidence gaps that the map uncovers. © 2021 The Author

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Locally advanced pancreatic cancer: Work-up, staging, and local intervention strategies

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4–6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30–35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

A Video Watermarking Procedure Based on XML Documents

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The Prognostic Impact of Determining Resection Margin Status for Multiple Colorectal Metastases According to the Margin of the Largest Lesion

Background: Although the prognostic role of surgical margin status after resection of colorectal liver metastasis (CRLM) has been previously examined, controversy still surrounds the importance of surgical margin status in patients with multiple tumors. Methods: Patients who underwent curative-intent surgery for CRLM from 2000 to 2015 and who presented with multiple tumors were identified. Patients with R1 resection status determined by the closest resection margin of the non-largest tumor were classified as R1-Type 1; patients with R1 status determined by the resection margin of the largest tumor were defined as R1-Type 2. Data regarding surgical margin status, size of tumors, and overall survival (OS) were collected and assessed. Results: A total of 251 patients met inclusion criteria; 156 patients (62.2%) had a negative margin (R0), 50 had an R1-type 1 (19.9%), and 45 had an R1-type 2 (17.9%) margin. Median and 5-year OS in the entire cohort was 56.4 months and 48.0%, respectively. When all R1 (Type 1 + Type 2) patients were compared with R0 patients, an R1 was not associated with worse prognosis (P = 0.05). In contrast, when R1-type 2 patients were compared with R0 patients, an R1 was strongly associated with worse OS (P = 0.009). On multivariate analysis, although the prognostic impact of all R1 was not associated with OS (hazard ratio [HR] 1.56; P = 0.08), R1-Type 2 margin status independently predicted a poor outcome (HR 1.93; P = 0.03). Conclusions: The impact of margin status varied according to the size of the tumor assessed. While R1 margin status defined according to the non-largest tumor was not associated with OS, R1 margin status relative to the largest index lesion was associated with prognosis. © 2017, Society of Surgical Oncology