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An embedding scheme for constraint-based orbital-optimized excitations in molecular and bulk environments
No full textWe recently presented a novel approach to variationally determine electronically excited states based on constrained density functional theory calculations. The constraint-based orbital-optimized excited state method (COOX) [Kussmann et al., J. Chem. Theory Comput., 2024, 20, 8461–8473] allows the evaluation of arbitrary electronic excitations and has several advantages compared to other methods like ΔSCF. In this work, we present an embedding scheme for COOX where the constraint potential is drawn from a sub-system calculation. This approach enables the accurate evaluation of specific excited states within complex environments that are difficult to obtain with conventional methods. The validity and range of applicability of the presented method are investigated for first exemplary calculations
Upholding hyaluronic acid's multi-functionality for nucleic acid drug delivery to target EMT in breast cancer
No full textSynthetic nanoparticles can stably encapsulate nucleic acids as active pharmaceutical payloads. Recently, mRNA- and siRNA-based medicines have been successfully approved for preventing or treating infectious or orphan diseases. RNA interference is particularly relevant for cancer therapy, as tumors often involve up- or dys-regulated proteins that drive malignancy. This study aimed to develop a nanoparticulate delivery vehicle that targets EMT-phenotypic breast cancer cells, which lack effective treatment options. These “undruggable” tumors may be addressed by nanoparticles that target EMT-specific cell surface receptors. CD44, a transmembrane protein linked to cancer malignancy and EMT, was identified as a promising candidate. This work investigated the use of hyaluronic acid (HA) in HA-modified polyelectrolyte complexes (polyplexes, Px) for its dual roles as a targeting ligand and a stabilizing stealth-molecule. Various strategies for non-covalently immobilizing HA on the particle surfaces were tested. HAPx nanoparticles demonstrated HA : PEI-ratio dependent stability against competing anionic biomolecules, improved colloidal stability in protein-rich environments mimicking in vivo conditions, and enhanced selectivity and efficacy in targeting E/M-hybrids and EMT-positive cells via CD44-HA mediated endocytosis. Finally, our results indicate different internalization kinetics and efficiencies between CD44v and CD44s isotypes, highlighting the need to consider CD44 heterogeneities in the clinical development of HA-based drug delivery systems
Display selection of peptide ligands for helical aromatic foldamers
No full textHelical aromatic oligoamide foldamers with a cluster of five biogenic side chains at their surface were designed and synthesized. Display selection of thioether macrocyclic peptides against these targets generated low micromolar binders that are highly selective for the side-chain arrangement
Acoustic cues to the perception of plosive voicing in Madurese
No full textMadurese, a Malayo-Polynesian language of Indonesia, is described as having a three-way phonation contrast between voiced, voiceless, and aspirated plosives. However, acoustic evidence suggests that the voiceless vs aspirated contrast might be marginal because of small differences in voice onset time (VOT) and large differences in the following vowel height (F1). This raises the question of how these cues are weighted in the perception of the voicing contrast. This paper presents a series of experiments designed to see if Madurese listeners discriminate differences in the positive VOT range, and to what extent they use VOT and F1 to identify plosives. Although listeners were able to discriminate between VOT differences of naturally occurring magnitudes in an AXB task, use of positive VOT when distinguishing voiceless from aspirated plosives in a three alternative forced choices task was highly individually specific, even when F1 was uninformative. Conversely, negative VOT emerged as a more robust cue to the voiced category. These results suggest that the Madurese laryngeal contrast is primarily a two-way contrast signaled through differences in (pre-)voicing but not aspiration. The weak but reliable acoustic covariance between vowel height and aspiration may instead have a diachronic and/or physiological-aerodynamic basis
Cellulosimicrobium cellulans endocarditis: a challenge for detection and treatment in interdisciplinary teams
No full textNeuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia
Get PDFMutations in the gene encoding Tectonic β-propeller repeat-containing repeat protein 2 (TECPR2) cause hereditary sensory and autonomic neuropathy subtype 9 (HSAN9) which is a fatal neurodevelopmental and neurodegenerative disorder involving the sensory and peripheral nervous system. TECPR2 is ubiquitously expressed and linked to trafficking and sorting within the cell, however, its functional role remains poorly defined. Moreover, molecular insights into pathogenic mechanisms underlying HSAN9 are lacking. Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression. Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis. The affected medulla area prominently features swollen axons filled with amorphous protein aggregates, glycogen granules, single and double membrane vesicles as well as aberrant organelles including ER and mitochondria whose proteome is distinctly altered. Despite the locally restricted pathology the neuronal demise is detectable in the cerebrospinal fluid and responded to by damage-associated microglia. However, their capacity to clear neuronal debris seems attenuated. Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing. This was confirmed in TECPR2 knockout cells and linked to TECPR2’s interaction with the homotypic fusion and protein sorting (HOPS)–tethering complex. Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region
Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice impacts adipokine secretion, plasma free fatty acids, and improves cerebrovascular health
Get PDFVisceral white adipose tissue (WAT) dysfunction may contribute to obesity-related brain impairments but causal relationship has not been demonstrated. We herein investigated the impact of visceral epididymal WAT (eWAT) lipectomy on brain health and obesity-associated comorbidities (liver steatosis, atherosclerosis, WAT dysfunction) in obese Ldlr-/-.Leiden mice. High-fat diet (HFD)-fed obese mice underwent sham surgery or partial removal (~70%) of eWAT. A separate group of mice was kept on chow diet (control). Liver disease, atherosclerosis and three WAT depots were examined histologically, and WAT biopsies were also cultured ex vivo. Brain structure and function were monitored longitudinally using cognitive tests and neuroimaging, paralleled by histological analysis of brain pathology and hippocampal RNA-sequencing. In ex vivo WAT culture, the surgically removed eWAT portion secreted many adipokines and pro-inflammatory factors. Histological analyses at the end of the study showed that eWAT-lipectomy did not affect liver disease and atherosclerosis development, but reduced the number of severely hypertrophic adipocytes in the residual-eWAT. This was consistent with reduced secretion of adipokines (e.g., leptin, adiponectin) and pro-inflammatory mediators (e.g., PAI-1, MIP-1α/CCL3, IL-17) from the residual-eWAT in the ex vivo culturing experiments. Importantly, lipectomy alleviated HFD-induced adverse effects on hippocampal vasoreactivity, increased cortico-hippocampal (resting-state) functional connectivity and prevented the development of sedentary behavior. Lipectomy did not significantly affect histological neuroinflammation or circulating cytokines/chemokines, but increased specific free fatty acids (e.g., eicosatrienoic acid and docosahexaenoic acid, known to have anti-inflammatory and vaso-protective properties). Hence, partial eWAT lipectomy in mice with manifest obesity partly prevents hippocampal cerebrovascular disturbances, demonstrating a causal involvement of visceral WAT in obesity-associated brain impairments. The beneficial effects of eWAT lipectomy may, at least partly, be mediated by anti-inflammatory free fatty acids, and possible changes in release of adipokines and inflammatory mediators
Precise quantile function estimation from the characteristic function
Get PDFWe provide theoretical error bounds for the accurate numerical computation of the quantile function given the characteristic function of a continuous random variable. We show theoretically and empirically that the numerical error of the quantile function is typically several orders of magnitude larger than the numerical error of the cumulative distribution function for probabilities close to zero or one. We introduce the COS method for computing the quantile function. This method converges exponentially when the density is smooth and has semi-heavy tails and all parameters necessary to tune the COS method are given explicitly. Finally, we numerically test our theoretical results on the normal-inverse Gaussian and the tempered stable distributions