Can nonhuman animals be used for the benefit of humans in a scientifically and morally justified manner and, if yes, how? Based on our own experiences as scholars from various academic backgrounds, we argue that this question can only be answered as an interdisciplinary and international endeavor, considering insights from research ethics and animal ethics as well as scientific and legal aspects. The aim of this article is to contribute to the foundation of the emerging field of animal research ethics. In doing so, we describe the following seven phases of animal research experiments: ethical, legal and social presumptions (phase 0), planning (phase I), review (phase II), conduct of experiments (phase III), publication/dissemination (phase IV), further exploitation of results (phase V), and evaluation (phase VI). In total, 20 key ethical, legal, and practical challenges that an ethical framework for the use of animals in research needs to address are identified and analyzed. Finally, we characterize the following four meta-challenges and opportunities associated with animal research ethics as a field: (1) moral pluralism, (2) the integration of views and positions outside the laboratory, (3) international plurality of conduct, standards, and legal norms, and (4) interdisciplinary education.
View lessMethionine (Met) is a popular nutritional supplement in humans and animals. It is routinely supplemented to pigs as L-Met, DL-Met, or DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA). Methods: We investigated the effect of these Met supplements on jejunal amino acid (AA) transport in male castrated Piétrain × Danbred pigs, also including a non-supplemented group. The mucosal-to-serosal flux of ten [14C]-labeled AAs (L-glutamine, glycine, L-leucine, L-lysine, L-Met, L-serine, L-threonine, L-tryptophan, L-tyrosine and L-valine) was investigated at two concentrations (50 µM and 5 mM). Inhibition of apical uptake by mucosal L-Met was also measured for these AAs. The intestinal expression of apical AA transporters, angiotensin-converting enzyme II and inflammation-related genes were compared with those of a previous study. Results: Except for tryptophan and lysine at 5 mM, all AA fluxes were Na+-dependent (p ≤ 0.05), and the uptake of most AAs, except glycine and lysine, was inhibited by L-Met (p < 0.001). A correlation network existed between Na+-dependent fluxes of most AAs (except tryptophan and partly glycine). We observed the upregulation of B0AT1 (SLC6A19) (p < 0.001), the downregulation of ATB0,+ (SLC6A14) (p < 0.001) and a lower expression of CASP1, IL1β, IL8, TGFβ and TNFα in the present vs. the previous study (p < 0.001). Conclusions: The correlating AAs likely share the same Na+-dependent transporter(s). A varying effect of the Met supplement type on AA transport in the two studies might be related to a different level of supplementation or a different inflammatory status of the small intestine.
View lessMissing data and class imbalance hinder the accurate prediction of rare events such as dairy mastitis. Resampling and imputation are employed to handle these problems. These methods are often used arbitrarily, despite their profound impact on prediction due to changes caused to the data structure. We hypothesize that their use affects the performance of ML models fitted to automated milking systems (AMSs) data for mastitis prediction. We compare three imputations—simple imputer (SI), multiple imputer (MICE) and linear interpolation (LI)—and three resampling techniques: Synthetic Minority Oversampling Technique (SMOTE), Support Vector Machine SMOTE (SVMSMOTE) and SMOTE with Edited Nearest Neighbors (SMOTEEN). The classifiers were logistic regression (LR), multilayer perceptron (MLP), decision tree (DT) and random forest (RF). We evaluated them with various metrics and compared models with the kappa score. A complete case analysis fitted the RF (0.78) better than other models, for which SI performed best. The DT, RF, and MLP performed better with SVMSMOTE. The RF, DT and MLP had the overall best performance, contributed by imputation or resampling (SMOTE and SVMSMOTE). We recommend carefully selecting resampling and imputation techniques and comparing them with complete cases before deciding on the preprocessing approach used to test AMS data with ML models.
View lessUrbanization is a growing phenomenon affecting soils worldwide. Urban centers have been highlighted as hotspots for global change factors due to heightened anthropogenic activity. However, few studies have investigated the multifaceted impacts of global change factors (GCFs) acting in concert with urban soils. Thus, the objective of this study was to add GCFs in different combinations (0, 1, 2, 5, and 8 simultaneously) in three high-urbanity and three low-urbanity soils in Berlin and to evaluate their effects on soil parameters and functions. We hypothesized four potential outcomes of soil process responses to GCF exposure, Site-Specific Resistance, General Susceptibility, Low-Urbanity Resistance, and High-Urbanity Resistance. We provide evidence for the negative impacts of individual and multiple GCF application on litter decomposition, water repellency, and water-stable aggregates. Additionally, we highlight the General Susceptibility of litter decomposition to GCF exposure regardless of urbanity, as well as the Low-Urbanity Resistance of water repellency and High-Urbanity Resistance of water-stable aggregates under increased exposure to GCFs. This study expands on evidence of the growing threat of global change factors in urban settings and highlights some potential consequences regarding soil function.
View lessPigs (and minipigs) are often restrained with a maxillary sling for blood collection. They mainly produce strong vocalisations and show resistance to the procedure, which subjectively appears to be stressful for the animals. The present study investigated whether minipigs can be trained to tolerate aversive stimuli and whether training can reduce stress during blood collection. Blood was taken from 12 Ellegaard minipigs with fixation; thereafter, the animals were trained for 3 weeks using clicker training. Then, blood was taken again, but without fixation. Before and after each blood sample, saliva samples were taken. The cortisol concentration was determined using ELISAs. Serum cortisol was not significantly different before and after training (paired-sample t-test, t (9) = 2.052, p = 0.07). However, salivary cortisol was significantly lower after training (ANOVA (analysis of variance), p-value < 0.001, F-value 6.181). In addition, trained minipigs showed a significantly lower heart rate after blood sampling (paired-sample t-test, t (11) = 4.678, p = 0.001) as well as significantly lower heart rate variability (t (11) = 3.704, p = 0.003) compared to before training. The minipigs could be trained to tolerate aversive stimuli. This contributed to stress reduction when taking blood samples.
View lessThis study explores the relationship between women’s representation in political power and school closures during the coronavirus pandemic (COVID-19). Using a cross-country dataset in Europe, we document a striking negative relationship between the share of female members in national governments and school closures. We show that a one-standard deviation increase in female members of national governments is associated with a significant reduction in the likelihood of school lockdowns by 24% relative to the average share of school closures. This result is robust to an extensive set of sensitivity checks. We attribute this pattern to a higher awareness of female politicians about the potential costs that school closures imply for families, in particular working mothers with young children.
View lessMagnon band structures in altermagnets are characterized by an energy splitting of modes with opposite chirality, even in the absence of applied external fields and relativistic effects, because of an anisotropy in the Heisenberg exchange interactions. We perform quantitative atomistic spin dynamics simulations based on ab initio electronic structure calculations on rutile RuO2, a prototypical “d-wave” altermagnet, to study magnon currents generated by thermal gradients. We report substantial spin Seebeck and spin Nernst effects, i.e., longitudinal or transverse spin currents, depending on the propagation direction of the magnons with respect to the crystal, together with a finite spin accumulation associated with nonlinearities in the temperature profile. Our findings are consistent with the altermagnetic spin-group symmetry, as well as predictions from linear spin-wave theory and semiclassical Boltzmann transport theory.
View lessThe present study is an extension of the work done by Peddle, Haut, and Wingate [SIAM J. Sci. Comput., 41 (2019), pp. A3476–A3497] and Haut and Wingate [SIAM J. Sci. Comput., 36 (2014), pp. A693–A713], where a two-level Parareal method with mapping and averaging is examined. The method proposed in this paper is a multilevel Parareal method with arbitrarily many levels, which is not restricted to the two-level case. We give an asymptotic error estimate which reduces to the two-level estimate for the case when only two levels are considered. Introducing more than two levels has important consequences for the averaging procedure, as we choose separate averaging windows for each of the different levels, which is an additional new feature of the present study. The different averaging windows make the proposed method especially appropriate for nonlinear multiscale problems, because we can introduce a level for each intrinsic scale of the problem and adapt the averaging procedure such that we reproduce the behavior of the model on the particular scale resolved by the level. The method is applied to nonlinear differential equations. The nonlinearities can generate a range of frequencies in the problem. The computational cost of the new method is investigated and studied on several examples.
View lessThe efficiency of motor skill acquisition is age-dependent, making it increasingly challenging to learn complex manoeuvres later in life. Zebra finches, for instance, acquire a complex vocal motor programme during a developmental critical period after which the learned song is essentially impervious to modification. Although inhibitory interneurons are implicated in critical period closure, it is unclear whether manipulating them can reopen heightened motor plasticity windows. Using pharmacology and a cell-type specific optogenetic approach, we manipulated inhibitory neuron activity in a premotor area of adult zebra finches beyond their critical period. When exposed to auditory stimulation in the form of novel songs, manipulated birds added new vocal syllables to their stable song sequence. By lifting inhibition in a premotor area during sensory experience, we reintroduced vocal plasticity, promoting an expansion of the syllable repertoire without compromising pre-existing song production. Our findings provide insights into motor skill learning capacities, offer potential for motor recovery after injury, and suggest avenues for treating neurodevelopmental disorders involving inhibitory dysfunctions.
View lessThe coupling of circularly polarized light to local band structure extrema ("valleys”) in two dimensional semiconductors promises a new electronics based on the valley degree of freedom. Such pulses, however, couple only to valley charge and not to the valley current, precluding lightwave manipulation of this second vital element of valleytronic devices. Contradicting this established wisdom, we show that the few cycle limit of circularly polarized light is imbued with an emergent vectorial character that allows direct coupling to the valley current. The underlying physical mechanism involves the emergence of a momentum space valley dipole, the orientation and magnitude of which allows complete control over the direction and magnitude of the valley current. We demonstrate this effect via minimal tight-binding models both for the visible spectrum gaps of the transition metal dichalcogenides (generation time ~ 1 fs) as well as the infrared gaps of biased bilayer graphene ( ~ 14 fs); we further verify our findings with state-of-the-art time-dependent density functional theory incorporating transient excitonic effects. Our findings both mark a striking example of emergent physics in the ultrafast limit of light-matter coupling, as well as allowing the creation of valley currents on time scales that challenge quantum decoherence in matter.
View lessDie COVID-19-Krise verdeutlichte die Schlüsselrolle des Öffentlichen Gesundheitsdienstes (ÖGD) mit den rund 375 kommunalen Gesundheitsämtern in der Pandemiebekämpfung. Dabei stellte neben fehlenden personellen Ressourcen auch die unzureichende digitale Reife vieler Gesundheitsämter eine Hürde für die effektive und skalierbare Infektionsmeldung und Kontaktnachverfolgung dar. In diesem Artikel stellen wir das Reifegradmodell (RGM) für die Digitalisierung von Gesundheitsämtern vor, dessen Erarbeitung im Zeitraum Januar 2021 bis Februar 2022 stattfand und durch das Bundesministerium für Gesundheit gefördert wurde. Es findet seit Anfang 2022 Anwendung mit dem Ziel der Stärkung der Digitalisierung des ÖGD. Das RGM zielt darauf ab, Gesundheitsämter Schritt für Schritt anzuleiten, ihre digitale Reife zu erhöhen, um so für zukünftige Herausforderungen gerüstet zu sein. Entwickelt und evaluiert wurde das RGM anhand qualitativer Interviews mit Mitarbeitenden der Gesundheitsämter und weiteren Expert*innen des ÖGD sowie in Workshops und im Rahmen einer quantitativen Umfrage. Das RGM erlaubt die Messung der digitalen Reife in 8 Dimensionen, welche jeweils in 2–5 Subdimensionen untergliedert sind. Innerhalb der Subdimensionen erfolgt eine Einstufung auf 5 verschiedenen Reifegradstufen. Derzeit dient das RGM neben der Erfassung der digitalen Reife der einzelnen Gesundheitsämter auch als Management-Tool für die Planung von Digitalisierungsprojekten. Ziel ist es, auf Basis des RGM eine zielgerichtete Kommunikation zwischen den Gesundheitsämtern zu fördern, um Best Practices für die einzelnen Dimensionen auszutauschen.
View lessRequests for a coordinated response during the COVID-19 pandemic revealed the limitations of locally-operating public health agencies (PHAs) and have resulted in a growing interest in their digitalization. However, digitalizing PHAs – i.e., transforming them technically and organizationally – toward the needs of both employees and citizens is challenging, especially in federally-managed local government settings. This paper reports on a project that develops and evaluates a continuous (vs. a staged) maturity model, the PHAMM, for digitalizing PHAs as a cornerstone of a digitally resilient public health system in the future. The model supports a coordinated approach to formulating a vision and structuring the steps toward it, engaging employees along the transformation journey necessary for a federally-managed field. Further, it is now being used to allocate substantial national funds to foster digitalization. By developing the model in a coordinated approach and using it for distributing federal resources, this work expands the potential usage cases for maturity models. The authors conclude with lessons learned and discuss how the model can incentivize local digitalization in federal fields.
View lessThe Aralkum is a new desert created by the desiccation of the Aral Sea and is an efficient source of dust aerosol which perturbs the regional Central Asian radiation balance. COSMO–MUSCAT model simulations are used to quantify the direct radiative effects (DREs) of Aralkum dust, and investigate the associated perturbations to the atmospheric environment. Considering scenarios of “Past” (end of 20th century) and “Present” (beginning of 21st century) defined by differences in surface water coverage, it is found that in the Present scenario the simulated yearly mean net surface DRE across the Aralkum is -1.34Wm-2with a standard deviation ( ±) of 6.19 Wm-2, of which -0.15±1.19 Wm-2comes from dust emitted by the Aralkum. In the atmosphere the yearly mean DRE is -0.62±2.91 Wm-2, of which -0.05±0.51 Wm-2is from Aralkum dust: on the yearly timescale, Aralkum dust is cooling both at the surface and in the atmosphere, due to its optically scattering properties. The daytime surface cooling effect (solar zenith angle ≲70–80°) outweighs the nighttime heating effect and the atmospheric daytime (solar zenith angle ≲60–70°) heating and nighttime cooling effects. Instantaneous Aralkum dust DREs contribute up to -116Wm-2of surface cooling and +54Wm-2of atmospheric heating. Aralkum dust perturbs the surface pressure in the vicinity of the Aralkum by up to +0.76Pa on the monthly timescale, implying a strengthening of the Siberian High in winter and a weakening of the Central Asian heat low in summer. These results highlight the impacts of anthropogenic lakebed dust on regional atmospheric environments.
View lessAim
A substantial gap between young people's need for mental health care services and their actual access to such services led worldwide organizations (e.g., the WHO) to recommend the implementation of early intervention programs and youth mental health services. Some countries around the world have established structures to meet this recommendation. In this paper, we describe soulspace as the first integrated youth mental health service for young people aged between 15 and 35 years in Berlin, Germany.
Methods
We introduce soulspace as easily accessible mental health care for young people, and we characterize soulspace along the lines of the internationally established eight key principles of integrated youth mental health services (Killackey, et al., 2020, World Economic Forum). Soulspace is a cooperation between clinical outpatient units of psychiatric clinics for adolescents and young adults as well as a community-based counselling service. It provides initial contact, counselling, diagnostics, and treatment.
Results
Our analyses of the pathways to soulspace and the characteristics of the soulspace users suggest that the low threshold is a facilitator to help finding for young people in comparison to more conventional early intervention models. That is, having transferred the early intervention center in a youth-facing counselling service as was done in soulspace seems to have reduced the threshold to seek help for families and for young people in need for support.
Conclusions
In summary, with soulspace, an easily accessible mental health care service was established that integrates counselling and specialized psychiatric treatment if needed.
View lessAn older wild female chimpanzee ( Pan troglodytes ) was found dead with a large calcium oxalate stone in the renal pelvis. Histopathological changes included glomerulosclerosis, interstitial nephritis and fibrosis, focal mineralization, and medial hypertrophy. Urinary albumin‐creatinine‐ratio showed increased values from 15 months before death. Causes of the kidney disease remain unconfirmed.
Vaccination rates for mumps, measles, and rubella (MMR) and tetanus, diphtheria, pertussis, and polio (Tdap‐IPV) fall short of global targets, highlighting the need for vaccination interventions. This study examines the effectiveness of a city‐wide school‐based educational vaccination intervention as part of an on‐site vaccination program aimed at increasing MMR and Tdap‐IPV vaccination rates versus on‐site vaccination alone among sociodemographically diverse students from Berlin, Germany. The study was a 1:1 two‐arm cluster randomized controlled trial, with schools randomly assigned to either the Educational Class Condition (ECC) or the Low‐Intensity Information Condition (LIIC). Both received an on‐site vaccination program, while students in the ECC received an additional educational unit. Primary outcomes were MMR and Tdap‐IPV vaccination rates. In total, 6512 students from 25 randomly selected urban area secondary schools participated. For students providing their vaccination documents on the day of the intervention (2273, 34.9%), adjusted Poisson mixed models revealed significant between‐group differences in favor of the ECC (MMR: logRR = 0.47, 95%CI [0.01,0.92], RR = 1.59; Tdap‐IPV: logRR = 0.28, 95%CI [0.10,0.47], RR = 1.32). When adjusting for socioeconomic and migration background, between‐group differences became non‐significant for MMR but remained significant for Tdap‐IPV. Findings suggest that educational, school‐based on‐site vaccination appears to be a promising strategy for increasing vaccination uptake in adolescents.
View lessMetabolic dysfunction‐associated steatotic liver disease (MASLD) is hallmarked by hepatic steatosis, cell injury, inflammation, and fibrosis. This study elaborates on a multicellular biochip‐based liver sinusoid model to mimic MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. Mouse liver primary hepatocytes, hepatic stellate cells, Kupffer cells, and endothelial cells are seeded in a dual‐chamber biocompatible liver‐on‐a‐chip (LoC). The LoC is then perfused with circulating immune cells (CICs). Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug‐induced liver injury and MASLD, respectively. As a benchmark for the LoC, multiplex immunofluorescence on livers from APAP‐injected and dietary MASLD‐induced mice reveals characteristic changes on parenchymal and immune cell populations. APAP exposure induces cell death in the LoC, and increased inflammatory cytokine levels in the circulating perfusate. Under FFA stimulation, lipid accumulation, cellular damage, inflammatory secretome, and fibrogenesis are increased in the LoC, reflecting MASLD. Both injury conditions potentiate CIC migration from the perfusate to the LoC cellular layers. Lanifibranor prevents the onset of inflammation, while resmetirom decreases lipid accumulation in hepatocytes and increases the generation of FFA metabolites in the LoC. This study demonstrates the LoC potential for functional and molecular evaluation of liver disease drug candidates.
View lessObjective
The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl−/H+-exchange activity is crucial for the biological role of ClC-6.
Methods
We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6−/− mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6.
Results
We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6−/− mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6−/− brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss.
Interpretation
CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl− transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024;96:608–624
View lessCoherent Raman Scattering Imaging offers quick and surface‐sensitive large‐area scans of specimens including fingerprinting of the substances, combined with low detection limits. By using a multi‐photon process, it offers orders of magnitude stronger surface signal in comparison to spontaneous Raman (SR) and fluorescence signals of the substrate are avoided by the detection principle and the near‐infrared laser wavelength. By exciting at a specific wavelength instead of measuring whole spectra the measurement time is remarkably reduced. Here, detecting organic thin films on glass surfaces is investigated. The detection of those thin films is relevant for production processes where the interfacial layer is influenced by the low surface energy of contaminants, especially polysiloxanes. The samples are manufactured by pipetting diluted polydimethylsiloxane (PDMS) in heptane in various concentrations (1%, 0.1%, 0.01%, and 0.001%) on glass substrates. After evaporation of the solvent, thin films of the silicone remain. The resulting average coverage of the thin films equals 100–0.1 μg cm − 2 . Measurements determine the detectability threshold with SR to 10 μg cm − 2 , while the acquired spectrum is used to determine characteristic peaks for the pump laser. Afterwards the samples are imaged at those wavenumbers with Coherent Raman Scattering (CRS) Imaging techniques providing a chemically‐specific contrast.
View lessEarth abundant metal‐based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost‐effective chemical synthesis. In particular, the development of more practical, and durable iron‐based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe‐single atom catalysts (Fe‐SACs) entrapped in N‐doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe‐SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N‐methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.
View less