An EPTAS for Scheduling on Unrelated Machines of Few Different Types

In the classical problem of scheduling on unrelated parallel machines, a set of jobs has to be assigned to a set of machines. The jobs have a processing time depending on the machine and the goal is to minimize the makespan, that is the maximum machine load. It is well known that this problem is NP-hard and does not allow polynomial time approximation algorithms with approximation guarantees smaller than $1.5$ unless P$=$NP. We consider the case that there are only a constant number $K$ of machine types. Two machines have the same type if all jobs have the same processing time for them. This variant of the problem is strongly NP-hard already for $K=1$. We present an efficient polynomial time approximation scheme (EPTAS) for the problem, that is, for any $\varepsilon > 0$ an assignment with makespan of length at most $(1+\varepsilon)$ times the optimum can be found in polynomial time in the input length and the exponent is independent of $1/\varepsilon$. In particular we achieve a running time of $2^{\mathcal{O}(K\log(K) \frac{1}{\varepsilon}\log^4 \frac{1}{\varepsilon})}+\mathrm{poly}(|I|)$, where $|I|$ denotes the input length. Furthermore, we study three other problem variants and present an EPTAS for each of them: The Santa Claus problem, where the minimum machine load has to be maximized; the case of scheduling on unrelated parallel machines with a constant number of uniform types, where machines of the same type behave like uniformly related machines; and the multidimensional vector scheduling variant of the problem where both the dimension and the number of machine types are constant. For the Santa Claus problem we achieve the same running time. The results are achieved, using mixed integer linear programming and rounding techniques

Polynomial Kernels for Weighted Problems

Kernelization is a formalization of efficient preprocessing for NP-hard problems using the framework of parameterized complexity. Among open problems in kernelization it has been asked many times whether there are deterministic polynomial kernelizations for Subset Sum and Knapsack when parameterized by the number $n$ of items. We answer both questions affirmatively by using an algorithm for compressing numbers due to Frank and Tardos (Combinatorica 1987). This result had been first used by Marx and V\'egh (ICALP 2013) in the context of kernelization. We further illustrate its applicability by giving polynomial kernels also for weighted versions of several well-studied parameterized problems. Furthermore, when parameterized by the different item sizes we obtain a polynomial kernelization for Subset Sum and an exponential kernelization for Knapsack. Finally, we also obtain kernelization results for polynomial integer programs

Selection of heavy ion reaction channels via particle K X-ray coincidences

To identify the residual nuclei in very asymmetric heavy-ion reactions heavy-ion K X-ray coincidences have been measured. The usefulness and limitations of this method are discussed, and its feasibility is demonstrated in a study of the 14N+197Au reaction at 140 MeV

Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two-and-a-half-day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti-inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti-inflammatory effects of such compounds in a minimally invasive manner

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers

Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies. Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 10 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate. Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1β, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells. Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies

Macrophages inhibit human osteosarcoma cell growth after activation with the bacterial cell wall derivative liposomal muramyl tripeptide in combination with interferon-γ

Drug Delivery Technolog

How Firms Adapt and Interact in Open Source Ecosystems: Analyzing Stakeholder Influence and Collaboration Patterns

[Context and motivation] Ecosystems developed as Open Source Software (OSS) are considered to be highly innovative and reactive to new market trends due to their openness and wide-ranging contributor base. Participation in OSS often implies opening up of the software development process and exposure towards new stakeholders. [Question/Problem] Firms considering to engage in such an environment should carefully consider potential opportunities and challenges upfront. The openness may lead to higher innovation potential but also to frictional losses for engaged firms. Further, as an ecosystem progresses, power structures and influence on feature selection may fluctuate accordingly. [Principal ideas/results] We analyze the Apache Hadoop ecosystem in a quantitative longitudinal case study to investigate changing stakeholder influence and collaboration patterns. Further, we investigate how its innovation and time-to-market evolve at the same time. [Contribution] Findings show collaborations between and influence shifting among rivaling and non-competing firms. Network analysis proves valuable on how an awareness of past, present and emerging stakeholders, in regards to power structure and collaborations may be created. Furthermore, the ecosystem’s innovation and time-to-market show strong variations among the release history. Indications were also found that these characteristics are influenced by the way how stakeholders collaborate with each other

Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumour deposits in colorectal cancer

Both lymph node metastases (LNMs) and tumour deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aimed to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Spatially resolved transcriptomic analysis using digital spatial profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumour cells and tumour microenvironment. Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analysed, and spatial deconvolution was performed. Image-based consensus molecular subtype (imCMS) analysis was performed on all TDs and LNMs included in the study. Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumour and tumour microenvironment segment, with upregulation of matrix remodelling, cell adhesion/motility, and epithelial-mesenchymal transition (EMT) in TDs (all p < 0.05). Spatial deconvolution showed a significantly increased abundance of fibroblasts, macrophages, and regulatory T-cells (p < 0.05) in TDs. Consistent with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p < 0.05). Compared to LNMs, TDs have a more invasive state involving a distinct tumour microenvironment and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasise the heterogeneity of locoregional spread and the fact that TDs should merit more attention both in future research and during staging. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Gait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study

BACKGROUND: The association between unexplained falls and cardiovascular causes is increasingly recognized. Neurally mediated cardiovascular disorders and hypotensive syndromes are found in almost 20 percent of the patients with unexplained falls. However, the approach to these patients remains unclear. Gait assessment might be an interesting approach to these patients as clinical observations suggests that those with cardiovascular or hypotensive causes may not manifest obvious gait alterations. Our primary objective is to analyze the association between gait disorders and a non-cardiovascular cause of falls in patients with unexplained falls. A second objective is to test the sensitivity and specificity of a gait assessment approach for detecting non-cardiovascular causes when compared with intrinsic-extrinsic classification. METHODS: Cross-sectional study performed in a falls clinic at a university hospital in 41 ambulatory elderly participants with unexplained falls. Neurally mediated cardiovascular conditions, neurological diseases, gait and balance problems were assessed. Gait disorder was defined as a gait velocity < 0.8 m/s or Tinetti Gait Score <9. An attributable etiology of the fall was determined in each participant. Comparisons between the gait assessment approach and the attributable etiology regarding a neurally mediated cardiovascular cause were performed. Fisher exact test was used to test the association hypothesis. Sensitivity and specificity of gait assessment approach and intrinsic-extrinsic classification to detect a non-cardiovascular mediated fall was calculated with 95% confidence intervals (CI95%). RESULTS: A cardiovascular etiology (orthostatic and postprandial hypotension, vasovagal syndrome and carotid sinus hypersensitivity) was identified in 14% of participants (6/41). Of 35 patients with a gait disorder, 34 had a non-cardiovascular etiology of fall; whereas in 5 out of 6 patients without a gait disorder, a cardiovascular diagnosis was identified (p < 0.001). Sensitivity and specificity of the presence of gait disorder for identifying a non-cardiovascular mediated cause was 97.1% (CI95% = 85–99) and 83% (CI95% = 36–99), respectively. CONCLUSION: In community dwelling older persons with unexplained falls, gait disorders were associated with non-cardiovascular diagnosis of falls. Gait assessment was a useful approach for the detection of a non-cardiovascular mediated cause of falls, providing additional value to this assessment

Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia

We describe a 15-year-old patient with X-linked agammaglobulinemia who developed malabsorption and bacteremia due to infection of Helicobacter pylori and Campylobacter jejuni. The Campylobacter bacteremia was only recognized after subculturing of blood culture bottles that failed to signal in the automated system. After 2 weeks of treatment with meropenem and erythromycin for 4 weeks, the patient developed a relapse of bacteremia 10 months later with a high level erythromycin resistant C. jejuni. Sequencing revealed an A2058C mutation in the 23 S rRNA gene associated with this resistance. Treatment with doxycycline for 4 weeks finally resulted in complete eradication. This case report illustrates the importance for physicians to use adapted culture methods and adequate prolonged therapy in patients with an immunodeficiency. A summary of published case reports and series of patients with hypogammaglobulinemia or agammaglobulinemia with Campylobacter or Helicobacter bacteremia is given