Site-saturation mutagenesis of 500 human protein domains.

Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins.

The sarcoma ring trial: a case-based analysis of inter-center agreement across 21 German-speaking sarcoma centers.

Purpose: The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers.

MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis, and allostery from deep mutational scanning data.

We present MoCHI, a tool to fit interpretable models using deep mutational scanning data. MoCHI infers free energy changes, as well as interaction terms (energetic couplings) for specified biophysical models, including from multimodal phenotypic data. When a user-specified model is unavailable, global nonlinearities (epistasis) can be estimated from the data.

Pain After Lower Limb Amputations: Insights from the Heidelberg Amputation Registry.

: The experience of unpleasant sensory phenomena after lower limb amputations (LLAs), including phantom limb pain (PLP), phantom limb sensation (PLS), and residual limb pain (RLP), impacts global healthcare and adversely affects outcomes post-amputation. This study aimed to describe the distribution of PLP, PLS, and RLP among patients with LLAs registered in the Heidelberg Amputation Registry. The primary objective was to determine the prevalence of sensory abnormalities across different amputation levels and causes.

Targeting Bone Tumours with 45S5 Bioactive Glass.

Despite advances in treatment modalities, bone tumour therapies still face significant challenges. Severe side effects of conventional approaches, such as chemo- and radiation therapy, result in poor survival rates and high tumour recurrence rates, which are the most common issues that need to be improved upon. The aim of this study was to evaluate the therapeutic properties of 45S5 bioactive glass (BG) for targeting bone tumours.

The genetic architecture of protein interaction affinity and specificity.

The encoding and evolution of specificity and affinity in protein-protein interactions is poorly understood. Here, we address this question by quantifying how all mutations in one protein, JUN, alter binding to all other members of a protein family, the 54 human basic leucine zipper transcription factors. We fit a global thermodynamic model to the data to reveal that most affinity changing mutations equally affect JUN's affinity to all its interaction partners.

Evaluating the suitability of large-scale datasets to estimate nitrogen loads and yields across different spatial scales.

Decision makers are often confronted with inadequate information to predict nutrient loads and yields in freshwater ecosystems at large spatial scales. We evaluate the potential of using data mapped at large spatial scales (regional to global) and often coarse resolution to predict nitrogen yields at varying smaller scales (e.g.

The Global Dam Watch database of river barrier and reservoir information for large-scale applications.

There are millions of river barriers worldwide, ranging from wooden locks to concrete dams, many of which form associated impoundments to store water in small ponds or large reservoirs. Besides their benefits, there is growing recognition of important environmental and social trade-offs related to these artificial structures. However, global datasets describing their characteristics and geographical distribution are often biased towards particular regions or specific applications, such as hydropower dams affecting fish migration, and are thus not globally consistent.

The genetic architecture of protein stability.

There are more ways to synthesize a 100-amino acid (aa) protein (20) than there are atoms in the universe. Only a very small fraction of such a vast sequence space can ever be experimentally or computationally surveyed. Deep neural networks are increasingly being used to navigate high-dimensional sequence spaces.

Differences in Success Rate of Two-Stage Revision for Periprosthetic Joint Infection of the Knee Depending on the Applied Definition.

Background: Success rates of two-stage exchange arthroplasty are subject to substantial variance in the literature. An explanation is the lack of a universally accepted definition of what constitutes treatment success for periprosthetic joint infection. Therefore, the main objective of this study was to assess success rates, applying four definitions to identify the one definition that best captures "true" success from both a clinical and patient-centered perspective.

Massively parallel genetic perturbation reveals the energetic architecture of an amyloid beta nucleation reaction.

Amyloid protein aggregates are pathological hallmarks of more than fifty human diseases but how soluble proteins nucleate to form amyloids is poorly understood. Here we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid beta (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we quantify the nucleation rates of >140,000 variants of Aβ42.

Massive experimental quantification of amyloid nucleation allows interpretable deep learning of protein aggregation.

Protein aggregation is a pathological hallmark of more than fifty human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the amyloid nucleation of >100,000 protein sequences.

From Benign Lipoma to G3 Liposarcoma: Contrast-Enhanced Ultrasound Reveals Tumor Microperfusion and Indicates Malignancy.

Objective: Lipomatous soft tissue tumors (STT), ranging from benign lipomas to malignant liposarcomas, require accurate differentiation for timely treatment. Complementary to MRI, Contrast-enhanced ultrasound (CEUS) is emerging as a promising tool, providing insight into tumor microperfusion in real-time. This study aims to explore the potential of preoperative CEUS in differentiating benign lipomatous tumors from malignant liposarcoma subtypes.

Hypofractionated proton and carbon ion beam radiotherapy for sacrococcygeal chordoma (ISAC): An open label, randomized, stratified, phase II trial.

Introduction: Sacrococcygeal chordomas have high recurrence rates and are challenging to treat.

Methods: In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3-5 NCI-CTC-AE toxicity.

An extension of the Walsh-Hadamard transform to calculate and model epistasis in genetic landscapes of arbitrary shape and complexity.

Accurate models describing the relationship between genotype and phenotype are necessary in order to understand and predict how mutations to biological sequences affect the fitness and evolution of living organisms. The apparent abundance of epistasis (genetic interactions), both between and within genes, complicates this task and how to build mechanistic models that incorporate epistatic coefficients (genetic interaction terms) is an open question. The Walsh-Hadamard transform represents a rigorous computational framework for calculating and modeling epistatic interactions at the level of individual genotypic values (known as genetical, biological or physiological epistasis), and can therefore be used to address fundamental questions related to sequence-to-function encodings.

Intranasal dexmedetomidine for sedation in ABR testing in children: No pain, big gain!

Objectives: Obtaining perfect immobility or sleep in children undergoing ABR auditory brainstem response) testing can be challenging. We examined the effectiveness and safety of intranasal dexmedetomidine for sedation of children undergoing ABR testing.

Material And Methods: We included prospectively all patients aged from 1 to 15 years for whom sedation for ABR testing was required, between July 2018 and November 2021.

A complete map of specificity encoding for a partially fuzzy protein interaction.

Thousands of human proteins function by binding short linear motifs embedded in intrinsically disordered regions. How affinity and specificity are encoded in these binding domains and the motifs themselves is not well understood. The evolvability of binding specificity - how rapidly and extensively it can change upon mutation - is also largely unexplored, as is the contribution of 'fuzzy' dynamic residues to affinity and specificity in protein-protein interactions.

Guidelines for releasing a variant effect predictor.

Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released to date, and there is tremendous variability in their underlying algorithms and outputs, and in the ways in which the methodologies and predictions are shared. This leads to considerable challenges for end users in knowing which VEPs to use and how to use them.

Static spacers play a crucial role in the treatment of complex periprosthetic joint infections of the knee.

Purpose: To determine the superior spacer design, a growing number of studies are comparing treatment results between patients having been treated with articulating and static knee spacers in the setting of two-stage revision for periprosthetic joint infection (PJI). In contrast, the primary objective of this study was to compare preoperative characteristics between patients from both spacer groups and examine whether significant differences were present prior to spacer implantation.

Methods: This retrospective, single-centre, cohort study examined the preoperative situation of 80 consecutive knee PJIs between 2017 and 2020.

Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts.

The energy park of the future: Modelling the combination of wave-, wind- and solar energy in offshore multi-source parks.

To mitigate the effects of climate change, a significant percentage of future energy generation is set to come from renewable energy sources. This has led to a substantial increase of installed offshore wind in the North Sea in the last years (28 GW in 2021) and is projected to further accelerate to an installed capacity of 212 GW by 2050. Increasing the renewable energy grid penetration brings challenges, including 1) limitations in space availability and 2) the reliability of renewable energy systems in terms of grid balancing.

The Warburg Trap: A Novel Therapeutic Approach for Targeting Osteosarcoma.

Although urgently needed, no significant improvements in osteosarcoma (OS) therapy have been achieved within the last decades. Here, we present a new therapeutic approach based on drug combinations consisting of mitochondrial complex I (MCI) inhibitors and ionophores that induce cancer cell-specific cell death based on a modulation of cellular energy metabolism and intracellular pH (pHi) named the Warburg Trap (WT). The effects of several drug combinations on intracellular pH, cell viability, colony-forming capacity and expression of WNT-target genes were analysed using OS cell lines and primary human osteoblasts (HOB).

The energetic and allosteric landscape for KRAS inhibition.

Thousands of proteins have been validated genetically as therapeutic targets for human diseases. However, very few have been successfully targeted, and many are considered 'undruggable'. This is particularly true for proteins that function via protein-protein interactions-direct inhibition of binding interfaces is difficult and requires the identification of allosteric sites.