FitMultiCell: simulating and parameterizing computational models of multi-scale and multi-cellular processes.

MOTIVATION: Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyse and understand the processes determining tissue dynamics. These models usually depend on parameters that need to be inferred from experimental data to achieve a quantitative understanding, to predict the response to perturbations, and to evaluate competing hypotheses. However, even advanced inference approaches such as approximate Bayesian computation (ABC) are difficult to apply due to the computational complexity of the simulation of multi-scale models. Thus, there is a need for a scalable pipeline for modeling, simulating, and parameterizing multi-scale models of multi-cellular processes. RESULTS: Here, we present FitMultiCell, a computationally efficient and user-friendly open-source pipeline that can handle the full workflow of modeling, simulating, and parameterizing for multi-scale models of multi-cellular processes. The pipeline is modular and integrates the modeling and simulation tool Morpheus and the statistical inference tool pyABC. The easy integration of high-performance infrastructure allows to scale to computationally expensive problems. The introduction of a novel standard for the formulation of parameter inference problems for multi-scale models additionally ensures reproducibility and reusability. By applying the pipeline to multiple biological problems, we demonstrate its broad applicability, which will benefit in particular image-based systems biology. AVAILABILITY AND IMPLEMENTATION: FitMultiCell is available open-source at https://gitlab.com/fitmulticell/fit.

Controlling the Activation at NiII-CO2 2- Moieties through Lewis Acid Interactions in the Second Coordination Sphere.

Nickel complexes with a two-electron reduced CO2 ligand (CO2 2-, "carbonite") are investigated with regard to the influence alkali metal (AM) ions have as Lewis acids on the activation of the CO2 entity. For this purpose complexes with NiII(CO2)AM (AM=Li, Na, K) moieties were accessed via deprotonation of nickel-formate compounds with (AM)N(iPr)2. It was found that not only the nature of the AM ions in vicinity to CO2 affect the activation, but also the number and the ligation of a given AM. To this end the effects of added (AM)N(R)2, THF, open and closed polyethers as well as cryptands were systematically studied. In 14 cases the products were characterized by X-ray diffraction and correlations with the situation in solution were made. The more the AM ions get detached from the carbonite ligand, the lower is the degree of aggregation. At the same time the extent of CO2 activation is decreased as indicated by the structural and spectroscopic analysis and reactivity studies. Accompanying DFT studies showed that the coordinating AM Lewis acidic fragment withdraws only a small amount of charge from the carbonite moiety, but it also affects the internal charge equilibration between the LtBuNi and carbonite moieties.

BioSimulators: a central registry of simulation engines and services for recommending specific tools.

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.

A 2,2-Difluoroimidazolidine Derivative for Deoxyfluorination Reactions: Mechanistic Insights by Experimental and Computational Studies.

A N-heterocyclic deoxyfluorinating agent SIMesF2 was synthesized by nucleophilic fluorination of N,N-1,3-dimesityl-2-chloroimidazolidinium chloride (3) at room temperature. SIMesF2 was applied to deoxyfluorinate carboxylic acids and alcohols and convert benzaldehyde into difluorotoluene. Mechanistic studies by NMR spectroscopy suggest reaction pathways of the carboxylic acid to acyl fluoride via outer-sphere fluorinations at an imidazolidinium ion by polyfluoride. DFT studies give further insight by exploring mechanistic details which distinguish the fluorination of aldehydes from that of carboxylic acids. Furthermore, a consecutive reaction sequence for the oxidation of an aldehyde followed by in situ fluorination of the generated carboxylic acid was developed.

Hydrogen Bonding in Platinum Indolylphosphine Polyfluorido and Fluorido Complexes.

The reaction of the Pt complexes cis-[Pt(CH3 )(Ar){Ph2 P(Ind)}2 ] (Ind=2-(3-methyl)indolyl, Ar=4-tBuC6 H4 (1 a), 4-CH3 C6 H4 (1 b), Ph (1 c), 4-FC6 H4 (1 d), 4-ClC6 H4 (1 e), 4-CF3 C6 H4 (1 f)) with HF afforded the polyfluorido complexes trans-[Pt(F(HF)2 )(Ar){Ph2 P(Ind)}2 ] 2 a-f, which can be converted into the fluoride derivatives trans-[Pt(F)(Ar){Ph2 P(Ind)}2 ] (3 a-f) by treatment with CsF. The compounds 2 a-f and 3 a-f were characterised thoroughly by multinuclear NMR spectroscopy. The data reveal hydrogen bonding of the fluorido ligand with HF molecules and the indolylphosphine ligand. Polyfluorido complexes 2 a-f show larger |1 J(F,Pt)|, but lower 1 J(H,F) coupling constants when compared to the fluorido complexes 3 a-f. Decreasing 1 J(P,Pt) coupling constants in 2 a-f and 3 a-f suggest a cis influence of the aryl ligands in the following order: 4-tBuC6 H4 (a) ≈4-CH3 C6 H4 (b)

Competition for Hydride Between Silicon and Boron: Synthesis and Characterization of a Hydroborane-Stabilized Silylium Ion.

Potent main-group Lewis acids are capable of activating element-hydrogen bonds. To probe the rivalry for hydride between silylium- and borenium-ion centers, a neutral precursor with the hydrosilane and hydroborane units in close proximity on a naphthalene-1,8-diyl platform was designed. Abstraction of one hydride leads to a hydroborane-stabilized silylium ion rather than a hydrosilane-coordinated borenium ion paired with [B(C6 F5 )4 ]- or [HCB11 Cl11 ]- as counteranions. Characterization by multinuclear NMR spectroscopy and X-ray diffraction supported by DFT calculations reveals a cationic, unsymmetrical open three-center, two-electron (3c2e) Si-H-B linkage.

Synthesis of Intramolecular P/Al-Based Frustrated Lewis Pairs via Aluminum-Tin-Exchange and their Reactivity toward CO2.

Frustrated Lewis pairs (FLPs) composed of acidic alane and basic phosphane functions, separated by a xanthene linker, can be prepared through the corresponding Me3 Sn derivative and methyl aluminum compounds with elimination of Me4 Sn. This way MeClAl-, Cl2 Al- and (C6 F5 )2 Al- moieties could be introduced and the resulting FLPs are stabilized by a further equivalent of the alane precursors. In contact with the FLPs CO2 is bound via the C atom at the phosphane functions and the two O atoms at the Al centers. The residues at the latter determine the binding strength. Hence, in case of MeClAl CO2 capture occurs at higher pressure and under ambient conditions CO2 is released again, while for Cl2 Al and (C6 F5 )2 Al CO2 binding becomes irreversible. The results of DFT calculations rationalize these findings by the high thermodynamic stabilization in case of more electronegative residues, which concomitantly lead to higher barriers, and in case of (C6 F5 )2 Al further stabilization is achieved through a low reorganization energy.

Synthesis, Reactivity, and Bonding of Gold(I) Fluorido-Phosphine Complexes.

Gold(I) fluorido complexes with phosphine ligands have been synthesized from their respective iodido precursors. The bonding situation in comparison between complexes bearing phosphines and N-heterocyclic carbenes (NHCs) was explored quantum-chemically, obtaining similar results for both. Calculations of the 19F NMR chemical shifts match the experimental values well, including the approximately 40 ppm low-field shifts for the phosphine complexes compared to the NHC complexes, in spite of similar negative charges on fluorine. The reactivity of the highly water-sensitive gold(I) fluorido complexes was studied, resulting in substitution at the metal using trimethylsilyl reagents. The compounds studied were characterized using NMR as well as X-ray diffraction methods.

Multi-center evaluation of the highly sensitive Abbott ARCHITECT and Alinity thyroglobulin chemiluminescent microparticle immunoassay.

BACKGROUND: Thyroglobulin (Tg) is an essential part for the management of patients with differentiated thyroid carcinoma (DTC) after thyroidectomy. Highly sensitive Tg assays are now established in clinical practice as they facilitate follow-up of DTC patients. In this study, we evaluated the recently launched highly sensitive Abbott Tg assay for Alinity and ARCHITECT. METHODS: In this three-center study, Tg values of 447 routine patient samples, characterized for the presence of anti-Tg, were measured with the ARCHITECT Tg assay and compared with the Roche Elecsys TgII assay. In addition, a subset of 154 samples was compared also with the Beckman Tg Access assay and another subset (n = 122) with Abbott Tg on the Alinity i analyzer. RESULTS: LoQ was verified to be less than or equal to 0.1 ng/ml confirming that the Tg assay on ARCHITECT and Alinity is highly sensitive. Correlation of ARCHITECT, Alinity, and Roche was excellent with a slope between 0.9 and 1.1 and a correlation coefficient >0.98. Correlation to Beckmann Tg was also very good, but the differences in absolute values were significant (slope: 1.477). CONCLUSIONS: The Abbott Thyroglobulin assay, which is standardized to CRM-457, demonstrated a high correlation to the Roche and Beckman Tg assays, though good agreement of absolute values was only observed between Abbott and Roche. Strength of correlation and slope were not affected by the presence of anti-Tg indicating that all assays included in the study have a similar susceptibility to anti-Tg.

Caregiver maltreatment history and treatment response following an intensive Emotion Focused Family Therapy workshop.

This single-arm, repeated measures study investigated the impact caregiver trauma history may have on treatment response following an intensive, 2-day Emotion Focused Family Therapy (EFFT) caregiver workshop. Caregivers (n = 243) completed questionnaires regarding their child's emotion regulation and clinical symptoms, as well as their own childhood trauma history (i.e., exposure to various forms of child maltreatment), caregiver self-efficacy and caregiver blocks (e.g., fears) to support their child's treatment and recovery. Questionnaires were administered prior to and immediately following the workshop and again 4, 8 and 12 months later. At baseline, caregivers who reported experiences of childhood maltreatment demonstrated more blocks compared with caregivers who did not (B = 6.35, SE = 2.62, p < 0.05). Results indicated that caregivers with and without maltreatment histories reported similar, significant gains in their child's total difficulties (B = 0.64, SE = 0.41, p = 0.12) and emotional negativity and lability (B = 0.51, SE = 0.48, p = 0.29) at 12-month post-workshop. Caregivers with maltreatment histories reported greater improvements in caregiver blocks (B = 5.15, SE = 1.34, p < 0.001) and child emotion regulation (B = 0.90, SE = 0.18, p < 0.001) than caregivers without maltreatment histories. They also report less, but still significant, improvement in parental self-efficacy (B = -0.68, SE = 0.26, p < 0.01) when compared with caregivers without maltreatment histories. Findings suggest that EFFT workshops may be an acceptable and effective trans-diagnostic intervention for families presenting with complex histories, including caregiver exposure to childhood maltreatment.

Help-Seeking Buffers the Impact of Grief on Quality of Life: A Study of Loss During the COVID-19 Pandemic.

The COVID-19 pandemic has presented a global challenge for anticipating the support and treatment needs of bereaved individuals. However, no studies have examined how mourners have been coping with grief and which strategies may buffer negative mental health consequences. We examined the various coping strategies being used and which strategies best support quality of life. Participants completed self-report measures of demographic and loss-related characteristics, grief symptoms, quality of life (QOL), and coping strategies used. Despite help-seeking being one of the least endorsed coping strategies used, help-seeking was the only coping strategy that buffered the impact of grief on QOL for individuals with high grief severity. Results support predictions that grief may become a global mental health concern requiring increased accessibility and availability of grief therapies and professional supports for bereaved individuals during and in the aftermath of the pandemic.

Platinum Indolylphosphine Fluorido and Polyfluorido Complexes: An Interplay between Cyclometallation, Fluoride Migration, and Hydrogen Bonding.

The reaction of [PtCl2 (COD)] (COD=1,5-cyclooctadiene) with diisopropyl-2-(3-methyl)indolylphosphine (iPr2 P(C9 H8 N)) led to the formation of the platinum(ii) chlorido complexes, cis-[PtCl2 {iPr2 P(C9 H8 N)}2 ] (1) and trans-[PtCl2 {iPr2 P(C9 H8 N)}2 ] (2). The cis-complex 1 reacted with NEt3 yielding the complex cis-[PtCl{κ2 -(P,N)-iPr2 P(C9 H7 N)}{iPr2 P(C9 H8 N)}] (3) bearing a cyclometalated κ2 -(P,N)-phosphine ligand, while the isomer 2 with a trans-configuration did not show any reactivity towards NEt3 . Treatment of 1 or 3 with (CH3 )4 NF (TMAF) resulted in the formation of the twofold cyclometalated complex cis-[Pt{κ2 -(P,N)-iPr2 P(C9 H7 N)}2 ] (4). The molecular structures of the complexes 1-4 were determined by single-crystal X-ray diffraction. The fluorido complex cis-[PtF{κ2 -(P,N)-iPr2 P(C9 H7 N)}{iPr2 P(C9 H8 N)}] ⋅ (HF)4 (5 ⋅ (HF)4 ) was formed when complex 4 was treated with different hydrogen fluoride sources. The Pt(ii) fluorido complex 5 ⋅ (HF)4 exhibits intramolecular hydrogen bonding in its outer coordination sphere between the fluorido ligand and the NH group of the 3-methylindolyl moiety. In contrast to its chlorido analogue 3, complex 5 ⋅ (HF)4 reacted with CO or the ynamide 1-(2-phenylethynyl)-2-pyrrolidinone to yield the complexes trans-[Pt(CO){κ2 -(P,C)-iPr2 P(C9 H7 NCO)}{iPr2 P(C9 H8 N)}][F(HF)4 ] (7) and a complex, which we suggest to be cis-[Pt{C=C(Ph)OCN(C3 H6 )}{κ2 -(P,N)-iPr2 P(C9 H7 N)}{iPr2 P(C9 H8 N)}][F(HF)4 ] (9), respectively. The structure of 9 was assigned on the basis of DFT calculations as well as NMR and IR data. Hydrogen bonding of HF and NH to fluoride was proven to be crucial for the existence of 7 and 9.

Matrix Isolation Spectroscopic and Relativistic Quantum Chemical Study of Molecular Platinum Fluorides PtFn (n=1-6) Reveals Magnetic Bistability of PtF4.

Molecular platinum fluorides PtFn , n=1-6, are prepared by two different routes, photo-initiated fluorine elimination from PtF6 embedded in solid noble-gas matrices, and the reaction of elemental fluorine with laser-ablated platinum atoms. IR spectra of the reaction products isolated in rare-gas matrices under cryogenic conditions provide, for the first time, experimental vibrational frequencies of molecular PtF3 , PtF4 and PtF5 . Photolysis of PtF6 enabled a highly efficient and almost quantitative formation of molecular PtF4 , whereas both PtF5 and PtF3 were formed simultaneously by subsequent UV irradiation of PtF4 . The vibrational spectra of these molecular platinum fluorides were assigned with the help of one- and two-component quasirelativistic DFT computation to account for scalar relativistic and spin-orbit coupling effects. Competing Jahn-Teller and spin-orbit coupling effects result in a magnetic bistability of PtF4 , for which a spin-triplet (3 B2g , D2h ) coexists with an electronic singlet state (1 A1g , D4h ) in solid neon matrices.

Tetryl-Tetrylene Addition to Phenylacetylene.

Phenylacetylene adds [Ar*GeH2 -SnAr'], [Ar*GeH2 -PbAr'] and [Ar'SnH2 -PbAr*] at rt in a regioselective and stereoselective reaction. The highest reactivity was found for the stannylene, which reacts immediately upon addition of one equivalent of alkyne. However, the plumbylenes exhibit addition to the alkyne only in reaction with an excess of phenylacetylene. The product of the germylplumbylene addition reacts with a second equivalent of alkyne and the product of a CH-activation, a dimeric lead acetylide, were isolated. In the case of the stannylplumbylene the trans-addition product was characterized as the kinetically controlled product which isomerizes at rt to yield the cis-addition product, which is stabilized by an intramolecular Sn-H-Pb interaction. NMR chemical shifts of the olefins were investigated using two- and four-component relativistic DFT calculations, as spin-orbit effects can be large. Hydride abstraction was carried out by treating [Ar'SnPhC=CHGeH2 Ar*] with the trityl salt [Ph3 C][Al(OC{CF3 })4 ] to yield a four membered ring cation.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

Place cell firing cannot support navigation without intact septal circuits.

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location-specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA-A agonist; and gabazine, a GABA-A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location-specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location-specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.

HyAsP, a greedy tool for plasmids identification.

MOTIVATION: Plasmids are ubiquituous in bacterial genomes, and have been shown to be involved in important evolutionary processes, in particular the acquisition of antimicrobial resistance. However separating chromosomal contigs from plasmid contigs and assembling the later is a challenging problem. RESULTS: We introduce HyAsP, a tool that identifies, bins and assembles plasmid contigs following a hybrid approach based on a database of known plasmids genes and a greedy assembly algorithm. We test HyAsP on a large sample of bacterial datasets and observe that it generally outperforms other tools. AVAILABILITY AND IMPLEMENTATION: https://github.com/cchauve/HyAsP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

LGBTQ+ based discrimination is associated with ptsd symptoms, dissociation, emotion dysregulation, and attachment insecurity among LGBTQ+ adults who have experienced Trauma.

Objectives: LGBTQ+ based discrimination is a form of insidious trauma and minority stress, and is associated with poor mental health. However, there is a dearth of research on the impact of discrimination on the psychological functioning of LGBTQ+ individuals who have experienced trauma. The current study seeks to remedy this gap. It was hypothesized that: (1) LGBTQ+ adults who perceived their experience of trauma as related to LGBTQ+ based discrimination would have greater attachment insecurity, emotion dysregulation, PTSD symptoms, and dissociative symptoms; (2) experiences of LGBTQ+ based discrimination would be associated with greater attachment insecurity, emotion dysregulation, PTSD symptoms, and dissociative symptoms; (3) transgender congruence (i.e., the extent to which one feels authentic and comfortable with their gender identity and appearance) would be negatively associated with attachment insecurity, emotion dysregulation, PTSD symptoms, and dissociative symptoms. Methods: Participants were 157 LGBTQ+ adults who had experienced trauma, and who completed questionnaires on discrimination and psychological functioning. Results: Compared to participants who did not experience their trauma as related to discrimination, those who did were higher in attachment anxiety, attachment avoidance, emotion dysregulation, PTSD, and dissociative symptoms. Biphobia was positively associated with attachment anxiety, emotion dysregulation, PTSD, and dissociative symptoms. Homophobia was positively associated with emotion dysregulation, PTSD, and dissociative symptoms. Transphobia was positively associated with PTSD and dissociative symptoms. Appearance congruence was negatively associated with emotion dysregulation, PTSD, and dissociative symptoms. Conclusions: When working with LGBTQ+ clients who have experienced trauma, clinicians should be mindful of the effects of discrimination on wellbeing.

A Silylene-Borane Lewis Pair as a Tool for Trapping a Water Molecule: Silanol Formation and Dehydrogenation.

The Lewis acid B(C6 F5 )3 and the cyclic silane (ArN 2 Si)3 (1) (ArN =o-(CH3 )2 NCH2 C6 H4 ) are useful precursors to access the silylene(II)-borane adduct ArN 2 Si-B(C6 F5 )3 (2). Treatment of 2 with water led to coordination and gave the Lewis pair (ArN 2 H2 O)Si-B(C6 F5 )3 (3) that exhibits a hydrogen-bond-stabilized silanol unit. It can be converted into the siloxane [(HArN )2 SiOB(C6 F5 )3 ]2 O (6) by dehydrogenation in the presence of a base. Heteronuclear NMR spectroscopic data to characterize the compounds were supported by quantum-chemical calculations.

Activation of tetrafluoropropenes by rhodium(i) germyl and silyl complexes.

The reaction of the rhodium(i) complexes [Rh(E)(PEt3)3] (E = GePh3 (1), Si(OEt)3 (5)) with HFO-1234yf (2,3,3,3-tetrafluoropropene) afforded [Rh(F)(PEt3)3] (2) and the functionalized olefins Z-CF3CH[double bond, length as m-dash]CH(E) (E = GePh3 (4a), Si(OEt)3 (7)). Conceivable reaction pathways were assessed using DFT calculations. Reactions of [Rh(E)(PEt3)3] with HFO-1234ze (E-1,3,3,3-tetrafluoropropene) yielded the rhodium fluorido complex 2 and [Rh{(E)-CH[double bond, length as m-dash]CH(CF3)}(PEt3)3] (9) via two different reaction pathways. Using complexes 1 and 5 as catalysts, functionalized building blocks were obtained.