Explaining Accurate Predictions of Multitarget Compounds with Machine Learning Models Derived for Individual Targets

In drug discovery, compounds with well-defined activity against multiple targets (multitarget compounds, MT-CPDs) provide the basis for polypharmacology and are thus of high interest. Typically, MT-CPDs for polypharmacology have been discovered serendipitously. Therefore, over the past decade, computational approaches have also been adapted for the design of MT-CPDs or their identification via computational screening. Such approaches continue to be under development and are far from being routine. Recently, different machine learning (ML) models have been derived to distinguish between MT-CPDs and corresponding compounds with activity against the individual targets (single-target compounds, ST-CPDs). When evaluating alternative models for predicting MT-CPDs, we discovered that MT-CPDs could also be accurately predicted with models derived for corresponding ST-CPDs; this was an unexpected finding that we further investigated using explainable ML. The analysis revealed that accurate predictions of ST-CPDs were determined by subsets of structural features of MT-CPDs required for their prediction. These findings provided a chemically intuitive rationale for the successful prediction of MT-CPDs using different ML models and uncovered general-feature subset relationships between MT- and ST-CPDs with activities against different targets

Defining the role of CD4+ T cells during human metapneumovirus infection

Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in pediatric, elderly, and immunocompromised populations. Clearance of respiratory viruses like HMPV rely primarily on the destruction of infected cells by cytotoxic CD8+ T cells. However, signals provided by CD4+ helper T cells significantly impact the magnitude and effectiveness of CD8+ T cells. Despite HMPV being an important human pathogen, the role of CD4+ helper T cells in the immune response to HMPV is largely unknown. Using a C57BL/6 mouse model of acute infection, we identified an immunodominant CD4+ T cell epitope in the viral nucleoprotein and constructed the first MHC-II tetramer for HMPV. Analysis of pulmonary T cells revealed that virus-specific cells were most abundant on day 10 post-infection and were TH1-skewed. Additionally, virus-specific CD4+ T cells displayed phenotypic and functional markers of impairment, including inhibitory receptor co-expression and prolonged PD-1 upregulation. To determine the contribution of CD4+ T cells to the CD8+ T cell response, CD4+ T cells were antibody-depleted prior to HMPV infection. Depletion of CD4+ T cells led to delayed viral clearance and enhanced PD-1 expression on virus-specific CD8+ T cells. We also investigated the importance of CD40/CD40L signaling as a mechanism of CD4+ T cell help and demonstrate that either enhancing or blocking this pathway is detrimental in the context of HMPV infection. Further characterization of virus-specific CD4+ helper T cells, their regulation by PD-1, and their role in CD8+ T cell impairment will provide new insights that aid in the design of effective vaccines for HMPV

Veiledning med reflekterende team. Erfaringer fra helsepersonell i spesialisthelsetjenesten

Bakgrunn: Helse- og omsorgstjenesten blir stadig stilt overfor ulike krav til kvalitet. For å imøtekomme dette har det gjennom ulike veiledere, utarbeidet av Sosial- og helsedirektoratet (2005, 2006, 2007), og Melding til Stortinget nr, 13 (2012), blitt fokusert på betydningen av kvalitet- og kompetanseheving i praksisfeltet. Det blir fremhevet at veiledning er en måte å øke dette på. Problemstilling: Hvilke erfaringer har helsepersonell i spesialisthelsetjenesten med bruk av reflekterende team i veiledning. Teori: Funnene blir drøftet ved hjelp av tre teorier; systemteori, kommunikasjonsteori og sosialkonstruksjonisme. Metode: Datamateriale er basert på svarene fra fire kvalitative intervjuer. Etter intervjuene ble det gjennomført en kategoribasert analyse. Resultat: Etter analysen av svarene fra informantene var det tre hovedkategorier som skilte seg ut som viktige funn; organisatoriske forhold, erfaringer med reflekterende team og reflekterende prosesser. Konklusjon: Reflekterende team som veiledningsmetode er en god måte å ha veiledning på. For å øke kvaliteten og potensiale til reflekterende team som en veiledningsmetode, viser funnene at det er viktig med klare rammer og struktur. Stikkord: veiledning, reflekterende team, kommunikasjon, sosialkonstruksjonisme, systemteori, organiserin

Pile installation in submerged sandy slopes: Assessing liquefaction-induced instability

Loose, sandy slopes situated or deposited under water may be susceptible to liquefaction-induced failure. In contrast to 'regular' localised slope failures, flow slides are diffuse, large-scale and potentially disastrous. Earthquake-induced ground vibrations currently dominate the liquefaction engineering scene. In reality, however, many liquefaction failures may be attributed to non-seismic sources of cyclic shear loading, albeit often in less dramatic context. Pile or sheet pile installation form an example. The construction of a new sea lock in IJmuiden brings this issue to the forefront and initiates a series of pile installation tests, conducted in several sandy deposits. The results of these tests are analysed and reveal (1) some key differences with seismic sources of vibration; (2) the importance of the duration and frequency of driving in residual excess pore water pressure (EPP) generation; and (3) the magnitude of spatial and temporal scales on which vibrations and EPPs generally act. The observations from the tests also form the basis for the establishment of a cyclic liquefaction model which simulates vibratory pile driving-induced EPP development. The model is validated using data from the IJmuiden pile installation tests. The cyclic liquefaction model is combined with a constitutive modelling approach for flow, or static, liquefaction behaviour. This enables the creation of a comprehensive strength framework, which allows representative strength parameters, based on the onset of flow liquefaction, to be derived for use in slope stability analyses. This strength framework is rooted in critical state soil mechanics and the related state parameter. A slope stability analysis procedure is advocated in which priority is given to pre-pile installation liquefaction analysis. Given a satisfactorily stable slope, pile installation effects are incorporated, where EPP generation and migration of pore water are considered the dominant contributors to failure. The procedure is applied to a fictional reference slope, where results show significant reduction in safety against global failure during driving. Considering three-dimensional drainage effects, however, suggests that pile installation may only have a minor effect on slope stability, depending on the failure mechanism and volume under examination. From the example stability analysis, some recommendations are made with regard to prevention and mitigation of piling-induced slope failures. Finally, in terms of further study, it must be noted that several major simplifications and assumptions underlie the cyclic liquefaction model and the corresponding method for slope stability analysis, which may be improved upon with more rigorous constitutive modelling and numerical analysis

Explaining Accurate Predictions of Multitarget Compounds with Machine Learning Models Derived for Individual Targets

In drug discovery, compounds with well-defined activity against multiple targets (multitarget compounds, MT-CPDs) provide the basis for polypharmacology and are thus of high interest. Typically, MT-CPDs for polypharmacology have been discovered serendipitously. Therefore, over the past decade, computational approaches have also been adapted for the design of MT-CPDs or their identification via computational screening. Such approaches continue to be under development and are far from being routine. Recently, different machine learning (ML) models have been derived to distinguish between MT-CPDs and corresponding compounds with activity against the individual targets (single-target compounds, ST-CPDs). When evaluating alternative models for predicting MT-CPDs, we discovered that MT-CPDs could also be accurately predicted with models derived for corresponding ST-CPDs; this was an unexpected finding that we further investigated using explainable ML. The analysis revealed that accurate predictions of ST-CPDs were determined by subsets of structural features of MT-CPDs required for their prediction. These findings provided a chemically intuitive rationale for the successful prediction of MT-CPDs using different ML models and uncovered general-feature subset relationships between MT- and ST-CPDs with activities against different targets

Pile driving and submarine slope stability: a hybrid engineering approach

During pile installation into a submerged, sandy slope, liquefaction mechanisms including flow and cyclic liquefaction warrant attention. Because of the interconnection of these mechanisms, evaluating slope stability during and as a result of vibration-inducing construction activity is not trivial. This paper presents a practical approach to such an evaluation. The primary focus of any slope stability analysis must lie with flow liquefaction as the form of failure with the most hazardous potential. Given the importance of excess pore water pressure in giving rise to (delayed) slope failures due to cyclic loading events, excess pore pressure (EPP) generation and dissipation is the mechanism of most interest in modelling cyclic liquefaction. Currently, no engineering method exists which is able to capture the interconnected processes. Therefore, a hybrid model, consisting of a numerical tool which computes EPP generation and dissipation in time, is combined with empirical relations to describe the decay of EPPs generated due to pile driving in space and time. The proposed numerical tool predicts the evolution of EPP in a one-dimensional soil column close to a vibratory-driven pile, taking into account sustained static shear stresses, interim drainage, and pre-shearing. Radial EPP dissipation is considered the dominant mode of drainage. This engineering tool fits within a holistic slope stability analysis procedure, which is demonstrated for a submerged slope in the IJmuiden harbour of the Netherlands, where mooring piles and sheet piles are installed through a relatively loose layer of sand.Geo-engineerin