Guest selectivity of [Ni2] supramolecular helicates.

Two new paramagnetic supramolecular helicates with the formula (X@[Ni2L3])3+ (X = Cl, or Br; L = a bis-pyrazolylpyridine ligand) have been prepared and are described. Helicates of this metal are very rare with virtually no prior examples of them acting as hosts of anionic species. The persistence of the new assemblies in solution has been demonstrated unambiguously by mass spectrometry and paramagnetic 1H NMR. This has allowed us to establish the preference of the coordination [Ni2] host for Cl- over Br-, in agreement with DFT calculations. These results show the promise of the use of metallohelicates as suitable systems for the selective encapsulation of specific anions in solution.

Engineered π⋯π interactions favour supramolecular dimers X@[FeL3]2 (X = Cl, Br, I): solid state and solution structure.

Ditopic bis-pyrazolylpyridine ligands usually react with divalent metal ions (M2+) to produce dinuclear triple-stranded helicates [M2L3]4+ or, via π⋯π interactions, dimers of monoatomic complexes ([ML3]2)4+. The introduction of an additional benzene ring at each end of ligand L increases the number of aromatic contacts within the supramolecular aggregate by 40%, driving the self-recognition process in an irreversible manner. Consequently, the mixing of new bis-pyrazolylquinoline L2 with FeX2 salts leads to crystallization of the tripartite high-spin assemblies (X@[Fe(L2)3]2)3+ (X = Cl, Br or I). The aggregates exhibit exceptional stability, as confirmed by a combination of paramagnetic 1H NMR techniques, demonstrating their persistence in solution. Our investigations further reveal that the guests Br- and I- are retained inside the associate in solution but Cl- is immediately released, resulting in the formation of the empty supramolecular dimer ([Fe(L2)3]2)4+.

Modulated spin dynamics of [Co2] coordination helicates via differential strand composition.

Coordination supramolecular chemistry provides a versatile entry into materials with functionalities of technological relevance at the nanoscale. Here, we describe how two different bis-pyrazolylpyridine ligands (L1 and L2) assemble with Co(II) ions into dinuclear triple-stranded helicates, in turn, encapsulating different anionic guests. These constructs are described as (Cl@[Co2(L1)3])3+, (SiF6@[Co2(L1)(L2)3])2+ and (ClO4@[Co2(L2)3])3+, as established by single-crystal X-ray diffraction. Extensive magnetic and calorimetric measurements, numerical treatments and theoretical calculations reveal that the individual Co(II) centers of these supramolecular entities exhibit field-induced slow relaxation of magnetization, dominated by direct and Raman mechanisms. While the small variations in the spin dynamics are not easily correlated with the evident structural differences among the three species, the specific heat measurements suggest two vibronic pathways of magnetic relaxation: one that would be associated with the host lattice and another linked with the guest.

A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin.

Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean "AND" logic. In the absence of H2O2 (trigger T1), e.g. in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H2O2), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both in vitro and in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.

Efficient Radial-Shell Model for 3D Tumor Spheroid Dynamics with Radiotherapy.

Understanding the complex dynamics of tumor growth to develop more efficient therapeutic strategies is one of the most challenging problems in biomedicine. Three-dimensional (3D) tumor spheroids, reflecting avascular microregions within a tumor, are an advanced in vitro model system to assess the curative effect of combinatorial radio(chemo)therapy. Tumor spheroids exhibit particular crucial pathophysiological characteristics such as a radial oxygen gradient that critically affect the sensitivity of the malignant cell population to treatment. However, spheroid experiments remain laborious, and determining long-term radio(chemo)therapy outcomes is challenging. Mathematical models of spheroid dynamics have the potential to enhance the informative value of experimental data, and can support study design; however, they typically face one of two limitations: while non-spatial models are computationally cheap, they lack the spatial resolution to predict oxygen-dependent radioresponse, whereas models that describe spatial cell dynamics are computationally expensive and often heavily parameterized, impeding the required calibration to experimental data. Here, we present an effectively one-dimensional mathematical model based on the cell dynamics within and across radial spheres which fully incorporates the 3D dynamics of tumor spheroids by exploiting their approximate rotational symmetry. We demonstrate that this radial-shell (RS) model reproduces experimental spheroid growth curves of several cell lines with and without radiotherapy, showing equal or better performance than published models such as 3D agent-based models. Notably, the RS model is sufficiently efficient to enable multi-parametric optimization within previously reported and/or physiologically reasonable ranges based on experimental data. Analysis of the model reveals that the characteristic change of dynamics observed in experiments at small spheroid volume originates from the spatial scale of cell interactions. Based on the calibrated parameters, we predict the spheroid volumes at which this behavior should be observable. Finally, we demonstrate how the generic parameterization of the model allows direct parameter transfer to 3D agent-based models.

Classification of Atretic Small Antral Follicles in the Human Ovary.

The reproductive lifespan in humans is regulated by a delicate cyclical balance between follicular recruitment and atresia in the ovary. The majority of the small antral follicles present in the ovary are progressively lost through atresia without reaching dominance, but this process remains largely underexplored. In our study, we investigated the characteristics of atretic small antral follicles and proposed a classification system based on molecular changes observed in granulosa cells, theca cells, and extracellular matrix deposition. Our findings revealed that atresia spreads in the follicle with wave-like dynamics, initiating away from the cumulus granulosa cells. We also observed an enrichment of CD68+ macrophages in the antrum during the progression of follicular atresia. This work not only provides criteria for classifying three stages of follicular atresia in small antral follicles in the human ovary but also serves as a foundation for understanding follicular degeneration and ultimately preventing or treating premature ovarian failure. Understanding follicular remodeling in the ovary could provide a means to increase the number of usable follicles and delay the depletion of the follicular reserve, increasing the reproductive lifespan.

A food interaction network between psittacines and plants in an urban area in the city of São Carlos - SP, southeastern Brazil.

The Psittacidae presents a great diversity of species in the Neotropical region performing fundamental ecological functions for ecosystems. These frugivorous birds can occupy different positions in the antagonistic-mutualistic gradient of food interactions, acting as predators and/or as seed dispersers. Little is known about bird-plant ecological interaction networks focusing on psittacines in urban environments, which may compromise the management of natural areas in anthropic landscapes and hinder the planning of conservation strategies. In this context, the present study aimed to analyze the network of feeding interactions between psittacines and plants that occur in green areas in urban and periurban areas of the municipality of São Carlos, São Paulo State, southeastern Brazil. Starting with an active searching added to the application of the focal animal sampling at 36 systematized sampling points during the years 2019, 2020 and 2021, the plant species consumed by parrots in the study area were observed. Four species of birds of the Psittacidae family were recorded consuming food resources from 46 plant species. The order of relevance of the birds in structuring the ecological network was: Brotogeris chiriri (Vieillot, 1851), Psittacara leucophthalmus (Statius Muller, 1872), Forpus xanthopterygius (Spix, 1843) and Eupsittula aurea (Gmelin, 1788). The most consumed plants were Syagrus romanzoffiana, Salix babylonica, Caesalpinea pluviosa, Mangifera indica and Handroanthus heptaphyllus. The pattern of consumption by birds was significantly different among species, and overall, they had a broad diet and medium niche overlap. Network nesting was low, as was connectance, i.e., the number of interactions or connections observed between pairs of species was considerably less than the total number possible. Network asymmetry was considerably high, with the psittacine group performing interactions with a large number of plant species, while each plant received on average few psittacine species. The results point to a high plasticity in the use of food resources in anthropic landscapes, indicating that the occupation of the urban environment by psittacines has been occurring successfully and may benefit the populations of the species recorded here.

Is there an influence of perceptual or cognitive impairment on complex sentence processing in hearing aid users?

BACKGROUND: Hearing-impaired listeners often have difficulty understanding complex sentences. It is not clear if perceptual or cognitive deficits have more impact on reduced language processing abilities, and how a hearing aid might compensate for that. METHODS: In a prospective study with 5 hearing aid users and 5 normal hearing, age-matched participants, processing of complex sentences was investigated. Audiometric and working memory tests were performed. Subject- and object-initial sentences from the Oldenburg Corpus of Linguistically and audiologically controlled Sentences (OLACS) were presented to the participants during recording of an electroencephalogram (EEG). RESULTS: The perceptual difference between object and subject leading sentences does not lead to processing changes whereas the ambiguity in object leading sentences with feminine or neuter articles evokes a P600 potential. For hearing aid users, this P600 has a longer latency compared to normal hearing subjects. CONCLUSION: The EEG is a suitable method for investigating differences in complex speech processing for hearing aid users. Longer P600 latencies indicate higher cognitive effort for processing complex sentences in hearing aid users.

A supramolecular helicate with two independent Fe(II) switchable centres and a [Fe(anilate)3]3- guest.

A biphenyl-spaced bis-pyrazolylpyridine ligand interacts with ferrous ions to engender a dimetallic helical coordination cage that encapsulates an Fe3+ tris-anilate complex. The host-guest interaction breaks the symmetry of the Fe2+ centers causing a differential spin crossover behavior in them that can be followed in great detail crystallographically.

Atrioventricular nodal reentry tachycardia in pregnancy: 'I have ice for you'.

Background: Pregnancy is a known trigger of novel and pre-existing supraventricular tachyarrhythmias. We present a case of a stable pregnant patient presenting with atrioventricular nodal reentry tachycardia (AVNRT) and application of the 'facial ice immersion technique'. Case summary: A 37-year-old pregnant woman presented with recurrent AVNRT. Due to unsuccessful attempts of conventional vagal manoeuvres (VMs) and refusal of pharmacological agents, we successfully performed a non-conventional VM with the 'facial ice immersion technique'. This technique was applied successfully at repeated clinical presentation. Discussion: The role of non-pharmacological interventions remains pivotal and may lead to desired therapeutical effects without the use of any costly pharmacological agents with possible adverse events. However, non-conventional VMs such as the 'facial ice immersion technique' are less commonly known but appear to be easy and a safe option for both mother and foetus in the management of AVNRT during pregnancy. Clinical awareness and understanding of treatment options are imperative in contemporary patient care.

Distributive Nd-to-Yb Energy Transfer within Pure [YbNdYb] Heterometallic Molecules.

Facile access to site-selective hetero-lanthanide molecules will open new avenues in the search of novel photophysical phenomena based on Ln-to-Ln' energy transfer (ET). This challenge demands strategies to segregate efficiently different Ln metal ions among different positions in a molecule. We report here the one-step synthesis and structure of a pure [YbNdYb] (1) coordination complex featuring short Yb···Nd distances, ideal to investigate a potential distributive (i.e., from one donor to two acceptors) intramolecular ET from one Nd3+ ion to two Yb3+ centers within a well-characterized molecule. The difference in ionic radius is the mechanism allowing to allocate selectively both types of metal ion within the molecular structure, exploited with the simultaneous use of two ß-diketone-type ligands. To assist the photophysical investigation of this heterometallic species, the analogues [YbLaYb] (2) and [LuNdLu] (3) have also been prepared. Sensitization of Yb3+ and Nd3+ in the last two complexes, respectively, was observed, with remarkably long decay times, facilitating the determination of the Nd-to-Yb ET within the [YbNdYb] composite. This ET was demonstrated by comparing the emission of iso-absorbant solutions of 1, 2, and 3 and through lifetime determinations in solution and solid state. The comparatively high efficiency of this process corroborates the facilitating effect of having two acceptors for the nonradiative decay of Nd3+ created within the [YbNdYb] molecule.

The template effect of a SiF62- guest drives the formation of a heteroleptic Fe(II) coordination helicate.

The anion SiF62- exerts a strong template effect, driving the exclusive assembly of two different bispyridylpyrazolyl ligands into a triple stranded Fe(II) dinuclear heteroleptic helicate, engendering a new class within the large family of coordination helicates.

Dynamic in vitro culture of cryopreserved-thawed human ovarian cortical tissue using a microfluidics platform does not improve early folliculogenesis.

Current strategies for fertility preservation include the cryopreservation of embryos, mature oocytes or ovarian cortical tissue for autologous transplantation. However, not all patients that could benefit from fertility preservation can use the currently available technology. In this regard, obtaining functional mature oocytes from ovarian cortical tissue in vitro would represent a major breakthrough in fertility preservation as well as in human medically assisted reproduction. In this study, we have used a microfluidics platform to culture cryopreserved-thawed human cortical tissue for a period of 8 days and evaluated the effect of two different flow rates in follicular activation and growth. The results showed that this dynamic system supported follicular development up to the secondary stage within 8 days, albeit with low efficiency. Surprisingly, the stromal cells in the ovarian cortical tissue were highly sensitive to flow and showed high levels of apoptosis when cultured under high flow rate. Moreover, after 8 days in culture, the stromal compartment showed increase levels of collagen deposition, in particular in static culture. Although microfluidics dynamic platforms have great potential to simulate tissue-level physiology, this system still needs optimization to meet the requirements for an efficient in vitro early follicular growth.

Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair.

Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing.

Unparalleled selectivity and electronic structure of heterometallic [LnLn'Ln] molecules as 3-qubit quantum gates.

Heterometallic lanthanide [LnLn'] coordination complexes that are accessible thermodynamically are very scarce because the metals of this series have very similar chemical behaviour. Trinuclear systems of this category have not been reported. A coordination chemistry scaffold has been shown to produce molecules of type [LnLn'Ln] of high purity, i.e. exhibiting high metal distribution ability, based on their differences in ionic radius. Through a detailed analysis of density functional theory (DFT) based calculations, we discern the energy contributions that lead to the unparalleled chemical selectivity of this molecular system. Some of the previously reported examples are compared here with the newly prepared member of this exotic list, [Er2Pr(LA)2(LB)2(py)(H2O)2](NO3) (1) (H2LA and H2LB are two ß-diketone ligands). A magnetic analysis extracted from magnetization and calorimetry determinations identifies the necessary attributes for it to act as an addressable, conditional multiqubit spin-based quantum gate. Complementary ab initio calculations confirm the feasibility of these complexes as composite quantum gates, since they present well-isolated ground states with highly anisotropic and distinct g-tensors. The electronic structure of 1 has also been analyzed by EPR. Pulsed experiments have allowed the establishment of the quantum coherence of the transitions within the relevant spin states, as well as the feasibility of a coherent control of these states via nutation experiments.

A ferric guest inside a spin crossover ferrous helicate.

A designed dimetallic Fe(II) helicate made with biphenylene-bridged bispyrazolylpyridine ligands and exhibiting a process of spin crossover at temperatures above ambient is shown to encapsulate an S = 5/2 tris-oxalato Fe(III) ion. The spin relaxation dynamics of this guest are strongly reduced upon encapsulation.

Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma.

Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.

Impact of distant peptide substrate residues on enzymatic activity of SlyD.

Peptidyl-prolyl isomerases (PPIases) catalyze intrinsically slow and often rate-limiting isomerization of prolyl-peptide bonds in unfolded or partially folded proteins, thereby speeding up the folding process and preventing misfolding. They often possess binding and chaperone domains in addition to the domain carrying the isomerization activity. Although generally, their substrates display no identity in their amino acid sequence upstream and downstream of the proline with 20 possibilities for each residue, PPIases are efficient enzymes. SlyD is a highly efficient PPIase consisting of an isomerase domain and an additional chaperone domain. The binding of peptide substrates to SlyD and its enzymatic activity depend to some extend on the proline-proximal residues, however, the impact of proline-distant residues has not been investigated so far. Here, we introduce a label-free NMR-based method to measure SlyD activity on different peptide substrates and analysed the data in the context of obtained binding affinities and several co-crystal structures. We show that especially charged and aromatic residues up to eight positions downstream and three positions upstream of the proline and outside the canonical region of similar conformations affect the activity and binding, although they rarely display distinct conformations in our crystal structures. We hypothesize that these positions primarily influence the association reaction. In the absence of the chaperone domain the isomerase activity strongly correlates with substrate affinity, whereas additional factors play a role in its presence. The mutual orientation of isomerase and chaperone domains depends on the presence of substrates in both binding sites, implying allosteric regulation of enzymatic activity.

Previous caesarean section is associated with lower subsequent in vitro fertilization live birth rates.

This retrospective cohort study examines the association between previous mode of delivery and subsequent live birth rate in women who become pregnant after in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI) after their first delivery. The study included 112 women with a previous caesarean section and 418 women with a previous vaginal delivery, and a total of 1588 embryo transfers between January 2005 and June 2016 (Leiden University Medical Centre, the Netherlands). The mean age was 35 years and mean number of embryos transferred per attempt, 1.18. The study population included a total of 429 pregnancies resulting in 296 live births. The crude odds ratio for a subsequent live birth per embryo transfer was 0.60 (CI; 0.44 to 0.83, p = 0.002) in women with a previous caesarean section compared to women with a previous vaginal delivery. After adjustment for age, fresh/frozen-thawed embryo transfer and quality of the embryo, the odds ratio was 0.64 (CI; 0.46 to 0.89, p = 0.01). It was concluded that in subfertile women trying to achieve a subsequent pregnancy with IVF or ICSI, a history of caesarean section was associated with a reduced live birth rate per embryo transfer compared to women with a history of one previous vaginal delivery.

Unravelling of a [High Spin-Low Spin] ↔ [Low Spin-High Spin] Equilibrium in Spin-Crossover Iron(II) Dinuclear Helicates Using Paramagnetic NMR Spectroscopy.

Spin-crossover between high-spin (HS) and low-spin (LS) states of selected transition metal ions in polynuclear and polymeric compounds is behind their use as multistep switchable materials in breakthrough electronic and spintronic devices. We report the first successful attempt to observe the dynamics of a rarely found broken-symmetry spin state in binuclear complexes, which mixes the states [HS-LS] and [LS-HS] on a millisecond timescale. The slow exchange between these two states, which was identified by paramagnetic NMR spectroscopy in solutions of two spin-crossover iron(II) binuclear helicates that are amenable to molecular design, opens a path to double quantum dot cellular automata for information storage and processing.