Approximating Mexican highways with slime mould

Plasmodium of Physarum polycephalum is a single cell visible by unaided eye. During its foraging behavior the cell spans spatially distributed sources of nutrients with a protoplasmic network. Geometrical structure of the protoplasmic networks allows the plasmodium to optimize transport of nutrients between remote parts of its body. Assuming major Mexican cities are sources of nutrients how much structure of Physarum protoplasmic network correspond to structure of Mexican Federal highway network? To find an answer undertook a series of laboratory experiments with living Physarum polycephalum. We represent geographical locations of major cities by oat flakes, place a piece of plasmodium in Mexico city area, record the plasmodium's foraging behavior and extract topology of nutrient transport networks. Results of our experiments show that the protoplasmic network formed by Physarum is isomorphic, subject to limitations imposed, to a network of principle highways. Ideas and results of the paper may contribute towards future developments in bio-inspired road planning

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Characterization of different FAD-dependent glucose dehydrogenases for possible use in glucose-based biosensors and biofuel cells

In this study, different flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenases (FADGDHs) were characterized electrochemically after “wiring” them with an osmium redox polymer [Os(4,4′-dimethyl-2,2′-bipyridine)2(PVI)10Cl]+ on graphite electrodes. One tested FADGDH was that recently discovered in Glomerella cingulata (GcGDH), another was the recombinant form expressed in Pichia pastoris (rGcGDH), and the third was a commercially available glycosylated enzyme from Aspergillus sp. (AspGDH). The performance of the Os-polymer “wired” GDHs on graphite electrodes was tested with glucose as the substrate. Optimal operational conditions and analytical characteristics like sensitivity, linear ranges and current density of the different FADGDHs were determined. The performance of all three types of FADGDHs was studied at physiological conditions (pH 7.4). The current densities measured at a 20 mM glucose concentration were 494 ± 17, 370 ± 24, and 389 ± 19 μA cm−2 for GcGDH, rGcGDH, and AspGDH, respectively. The sensitivities towards glucose were 2.16, 1.90, and 1.42 μA mM−1 for GcGDH, rGcGDH, and AspGDH, respectively. Additionally, deglycosylated rGcGDH (dgrGcGDH) was investigated to see whether the reduced glycosylation would have an effect, e.g., a higher current density, which was indeed found. GcGDH/Os-polymer modified electrodes were also used and investigated for their selectivity for a number of different sugars

Advanced abuse modelling of Li-ion Cells – A novel description of cell pressurisation and simmering reactions

Thermal runaway (TR) is a significant safety concern for Li-ion batteries (LIBs), which, through computational modelling can be better understood. However, TR models for LIBs lack a proper representation of the build-up of pressure inside a cell under abuse, which is integral to predicting cell venting. Here, an advanced abuse model (AAM) is developed and compared to a classical TR model, considering a lithium iron phosphate (LFP) cell case study. The AAM accounts for two additional features: 1) venting, with a novel description of the internal cell pressure governed by the bubble point of the electrolyte/decomposition-gas mixture, and 2) simmering reactions. The novel bubble pressure assumption is validated against experimental data, and we show that the AAM significantly improves the predictions of time to TR and of temperatures after TR. Further, it is shown that there is significant uncertainty in the parameters defining the decomposition reactions for LFP cells. Importantly, cell pressurisation is most dependent on the gases released by the solid electrolyte interphase reaction, and venting is dependent on cell burst pressure and reaction activation energies. The AAM is essential for accurate abuse modelling, due to its improved temperature predictions, and considerably enhances the LIB TR field of study

Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 μg l−1 at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients

Nodes of Ranvier and Paranodes in Chronic Acquired Neuropathies

Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70±4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis

Assessing anti-rabies baiting – what happens on the ground?

BACKGROUND: Rabies is one of the most hazardous zoonoses in the world. Oral mass vaccination has developed into the most effective management method to control fox rabies. The future need to control the disease in large countries (i.e. Eastern Europe and the Americas) forces cost-benefit discussions. The 'Increase bait density' option refers to the usual management assumption that more baits per km(2 )could compensate for high fox abundance and override the imperfect supply of bait pieces to the individual fox. METHODS: We use a spatial simulation, which combines explicitly fox space use (tessellation polygons) and aeroplane flight lines (straight lines). The number of baits actually falling into each polygon is measured. The manager's strategic options are converted into changes of the resulting bait distribution on the ground. The comparison enables the rating of the options with respect to the management aim (i.e. accessibility of baits). RESULTS: Above 5% (approx. 10%) of all fox groups without any bait (at most 5 baits) relate to the baiting strategy applied in the field (1 km spaced parallel flight lines, 20 baits per km(2 )distributed) under habitat conditions comparable to middle and western Europe (fox group home-range 1 km(2), 2.5 adults; reference strategy). Increasing the bait density on the same flight-line pattern neither reduces the number of under-baited fox group home-ranges, nor improves the management outcome and hence wastes resources. However, reducing the flight line distance provides a more even bait distribution and thus compensates for missed fox groups or extra high fox density. The reference strategy's bait density can be reduced when accounting for the missed fox groups. The management result with the proper strategy is likely the same but with reduced costs. CONCLUSION: There is no overall optimal strategy for the bait distribution in large areas. For major parts of the landscape, the reference strategy will be more competitive. In situations where set backs are attributed to non-homogeneous bait accessibility the distribution scheme has to be refined zone-based (i.e. increase of the flight line length per unit area). However, increase in bait density above the reference strategy appears inappropriate at least for non-urban abundance conditions of the red fox

A systematic review of tests of empathy in medicine

Abstract Background Empathy is frequently cited as an important attribute in physicians and some groups have expressed a desire to measure empathy either at selection for medical school or during medical (or postgraduate) training. In order to do this, a reliable and valid test of empathy is required. The purpose of this systematic review is to determine the reliability and validity of existing tests for the assessment of medical empathy. Methods A systematic review of research papers relating to the reliability and validity of tests of empathy in medical students and doctors. Journal databases (Medline, EMBASE, and PsycINFO) were searched for English-language articles relating to the assessment of empathy and related constructs in applicants to medical school, medical students, and doctors. Results From 1147 citations, we identified 50 relevant papers describing 36 different instruments of empathy measurement. As some papers assessed more than one instrument, there were 59 instrument assessments. 20 of these involved only medical students, 30 involved only practising clinicians, and three involved only medical school applicants. Four assessments involved both medical students and practising clinicians, and two studies involved both medical school applicants and students. Eight instruments demonstrated evidence of reliability, internal consistency, and validity. Of these, six were self-rated measures, one was a patient-rated measure, and one was an observer-rated measure. Conclusion A number of empathy measures available have been psychometrically assessed for research use among medical students and practising medical doctors. No empathy measures were found with sufficient evidence of predictive validity for use as selection measures for medical school. However, measures with a sufficient evidential base to support their use as tools for investigating the role of empathy in medical training and clinical care are available.</p

Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases

\ua9 The Author(s) 2025.Background: Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing. Methods: Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by &gt; 50% of Mendelian disease genes and &gt; 80% of known mitochondrial disease genes in clinically relevant sample types, including peripheral blood mononuclear cells (PBMCs). In total we profiled &gt; 90 individuals including undiagnosed individuals suspected of mitochondrial disease and a supporting cohort of disease controls harbouring pathogenic variants in nuclear and mitochondrial genes. Proteomics data were benchmarked against pathology accredited respiratory chain enzymology to assess the performance of proteomics as a functional test. Proteomics testing was subsequently applied to individuals with suspected mitochondrial disease, including a critically ill infant with a view toward rapid interpretation of variants identified in ultra-rapid genome sequencing. Results: Proteomics testing provided evidence to support variant pathogenicity in 83% of individuals in a cohort with confirmed mitochondrial disease, outperforming clinical respiratory chain enzymology. Freely available bioinformatic tools and criteria developed for this study (https://rdms.app/) allow mitochondrial dysfunction to be identified in proteomics data with high confidence. Application of proteomics to undiagnosed individuals led to 6 additional diagnoses, including a mitochondrial phenocopy disorder, highlighting the disease agnostic nature of proteomics. Use of PBMCs as a sample type allowed rapid return of proteomics data supporting pathogenicity of novel variants identified through ultra-rapid genome sequencing in as little as 54 h. Conclusions: This study provides a framework to support the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of mitochondrial and potentially other rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants