Multi-Stimuli-Responsive Network of Multicatalytic Reactions using a Single Palladium/Platinum Catalyst.

Given her unrivalled proficiency in the synthesis of all molecules of life, nature has been an endless source of inspiration for developing new strategies in organic chemistry and catalysis. However, one feature that remains beyond chemists' grasp is her unique ability to adapt the productivity of metabolic processes in response to triggers that indicate the temporary need for specific metabolites. To demonstrate the remarkable potential of such stimuli-responsive systems, we present a metabolism-inspired network of multicatalytic processes capable of selectively synthesising a range of products from simple starting materials. Specifically, the network is built of four classes of distinct catalytic reactions - cross-couplings, substitutions, additions, and reductions, involving three organic starting materials - terminal alkyne, aryl iodide, and hydrosilane. All starting materials are either introduced sequentially or added to the system at the same time, with no continuous influx of reagents or efflux of products. All processes in the system are catalysed by a multifunctional heteronuclear PdII/PtII complex, whose performance can be controlled by specific additives and external stimuli. The reaction network exhibits a substantial degree of orthogonality between different pathways, enabling the controllable synthesis of ten distinct products with high efficiency and selectivity through simultaneous triggering and suppression mechanisms.

Infrared Thermography in Assessment of Facial Temperature of Racing Sighthound-Type Dogs in Different Environmental Conditions.

The aim of the study was to assess the usefulness of IRT measurements of selected regions of interest (ROI), i.e., the eyeball and the nose of whippet dogs, before and after coursing competitions taking place in various environmental conditions, thereby enabling the assessment of well-being and the level of heat stress. The research was carried out over two different periods with different thermal humidity indexes (THIs). In the first period, the THI was 59.27 (Run 1), while in the second period, the THI was 63.77 (Run 2). The experimental subjects comprised 111 sighthound-type dogs-whippets-that were photographed with a thermal imaging camera to determine their eye temperature (ET) and nose temperature (NT). The average minimum and maximum eye temperatures were statistically lower after running in both measurements. Increased minimum and maximum nose temperatures were also demonstrated after both runs. The nasal temperature values were statistically higher for Run 2, for which the THI was higher, compared to Run 1. Eyeball temperature may be a marker of thermoregulation ability, regardless of the ambient temperature. The value of ETmax decreased on average by 2.23 °C and 0.4 °C, while NTmax increased uniformly by 2 °C after both runs. A correlation was found between the IRT measurements and physiological indicators.

Insight into age-related changes of the human facial skeleton based on medieval European osteological collection.

Aging changes in the facial skeleton are concentrated mostly in orbits, maxilla and mandible. The aim of this study was to analyze metric traits of the adult viscerocranium in a medieval sample from Cedynia (Poland, Central Europe) and confront the results with literature data for modern populations. It was assumed that diet-related greater biomechanical forces generated during mastication in medieval versus modern times led to slower rate of bone resorption with age. 3D models of the facial skeleton are created for 230 individuals, categorized into young, middle and old adults, and a subgroup of edentulous middle adults is distinguished. Orbits, piriform aperture, maxilla and mandible are measured using Geomagic Studio 12 and analyzed among age categories as well as dentate and edentulous subgroups. The values of the orbital and piriform aperture measurements tend to increase with age and reached statistical significance in males (right orbit height, left orbit width, piriform aperture surface area). In females, maxillary height significantly decrease at right first premolar and first molar, together with height of the right mandibular ramus. In edentulous individuals of both sexes the orbits are wider, and maxillary and mandibular heights are lower than in dentate individuals. This study reveals similar character and direction of the aging process of the facial skeleton in medieval and modern adults, however slower rate of resorptive changes is found in the former sample, which suggests, that diet-related biomechanical forces can influence intensification of the aging processes in the facial skeleton.

Evaluation of Suitability of New Bedding Material Obtained after Straw Biogasification for Dairy Cows.

This study aimed to compare the biomass obtained via the biogasification of straw with the classic bedding material, wheat straw. It was divided into two stages. In the first stage, a laboratory evaluation of the bedding materials was carried out, taking into account dry matter, pH, and water absorption. In the laboratory tests, the bedding obtained after the biogasification of straw (Verbio) showed better sorptive properties, with a value of 439.86% (wheat straw's value was 294.10%), and its pH value was higher than that of wheat straw. In the second stage of the experiment, field tests were carried out on a production farm, wherein the bedding was evaluated for bedding hygiene, animal hygiene, insulation properties, animal productivity, and microbiological properties. A microbiological assessment was also performed. Regarding cleanliness and production parameters and thermographic insulation properties, the two types of bedding did not show statistically significant differences. In terms of microbiological parameters, a higher number of all examined types of bacteria and fungi was observed in the Verbio bedding compared with straw, but these differences were not statistically significant, except in the case of total coliform. The results indicate that straw obtained after gasification is a suitable bedding material, with parameters similar to those of wheat straw.

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients.

BACKGROUND: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. MATERIALS AND METHODS: The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. RESULTS: Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. CONCLUSIONS: The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.

Enhanced catalytic performance derived from coordination-driven structural switching between homometallic complexes and heterometallic polymeric materials.

A bifunctional ligand 4,4-dimethyl-1-(pyridin-4-yl)pentane-1,3-dione (HL) able to provide two distinct coordination sites, i.e. anionic ß-diketonate (after deprotonation) and neutral pyridine, has been used in the synthesis of Ag(I), Pd(II) and Pt(II) complexes that then have been applied as metalloligands for the construction of new heterometallic polymeric materials. The ambidentate nature of L- enables switching between different modes of coordination within mononuclear complexes or their conversion into polymeric species in a fully controllable way. The coordination-driven processes can be triggered by various stimuli, i.e. a metal salt addition or acid-base equilibria, and presents an efficient strategy for the generation of metallosupramolecular materials. As a consequence of self-assembly, new multimetallic coordination aggregates have been synthesized and characterized in depth in solution (1H NMR, ESI-MS) as well as in the solid state (XPS, SEM-EDS, FTIR, pXRD, TGA). Furthermore, the Pd-based assemblies have been found to be efficient catalyst precursors in the Heck cross-coupling reaction, demonstrating a direct impact of compositional and morphological differences on their catalytic activity.

Does Sport Participation Protect Adolescents from Alcohol Consumption? A Scoping Review.

(1) Background: Participation in youth sports is believed to protect against alcohol consumption. Although this concept has been questioned for over 40 years, the review of methodologically reliable evidence data is scarce. This review summarizes the state of knowledge on the association between practicing sports and alcohol consumption among adolescents (10-19 years old) and its moderators. (2) Methods: The review covers only random-sample-based and population research. A systematic search was conducted on Scopus, PubMed, and WoS, for articles published between 2000 and 2021. From the 1944 identified records, 139 advanced to the full-text review, and 32 to the final data extraction and quality review. (3) Results: About two-thirds of the studies, including all the longitudinal ones, showed a positive association between sport participation and alcohol consumption. The most common mediators were gender (males were at higher risk), discipline (odds for team sports were higher, but professionalization could reduce it), and race, which intersected with gender, putting white males at the highest risk. (4) Conclusions: Further longitudinal research based on random samples using standardized indicators, including psychological and social variables, may provide more consistent outcomes and allow for the identification of mediating mechanisms.

Effects of Iron Supplementation on Metabolism in Calves Receiving Whole Milk.

The objective of this study was to determine the effects of feeding a protein-iron complex (PIC) to calves. Specifically, the aim was to understand how it influences productive performance and indicators of iron metabolism, hematology and biochemical and parameters during feeding with whole milk before weaning. The study was carried out on 20 Polish Holstein Friesian calves. The calves were then divided into a control group (CON), fed with full milk (n = 10), and an experimental group (MFe), who received a PIC additive in milk at 16 g/day (n = 10). In order to determine the production parameters, the calves were weighed at the beginning (i.e., on the 7th day of life) and at the end of the experiment (42nd day of life) using an electronic platform scale. Production parameters such as average weight gain (AWG), feed conversion ratio (FCR), and growth rate (GR) were assessed. Blood was collected from an external jugular vein (vena jugularis externa) on the 7th, 14th, 28th, and 42nd days of life. The mean daily gains in body weight (ADG), growth rate (GR), and the feed conversion ratio were highest in the experimental group, MFe. Therefore, it can be concluded that the addition of a protein-iron complex entailed a significant impact on the iron metabolism indicators in the MFe experimental group.

Pd(II) Complexes with Pyridine Ligands: Substituent Effects on the NMR Data, Crystal Structures, and Catalytic Activity.

A wide range of functionalized pyridine ligands have been employed to synthesize a variety of Pd(II) complexes of the general formulas [PdL4](NO3)2 and [PdL2Y2], where L = 4-X-py and Y = Cl- or NO3-. Their structures have been unambiguously established via analytical and spectroscopic methods in solution (NMR spectroscopy and mass spectrometry) as well as in the solid state (X-ray diffraction). This in-depth characterization has shown that the functionalization of ligand molecules with groups of either electron-withdrawing or -donating nature (EWG and EDG) results in significant changes in the physicochemical properties of the desired coordination compounds. Downfield shifts of signals in the 1H NMR spectra were observed upon coordination within and across the complex families, clearly indicating the relationship between NMR chemical shifts and the ligand basicity as estimated from pKa values. A detailed crystallographic study has revealed the operation of a variety of weak interactions, which may be factors explaining aspects of the solution chemistry of the complexes. The Pd(II) complexes have been found to be efficient and versatile precatalysts in Suzuki-Miyaura and Heck cross-coupling reactions within a scope of structurally distinct substrates, and factors have been identified that have contributed to efficiency improvement in both processes.

Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis.

Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype-phenotype correlation. Here, we present a three-generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high-level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low-level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.

Efficacy and safety of sirolimus therapy in familial hypoinsulinemic hypoglycemia caused by AKT2 mutation inherited from the mosaic father.

Activating mutation in the insulin signal-transducing kinase AKT2 results in severe hypoinsulinemic hypoketotic hypoglycemia and a characteristic phenotype of possible overgrowth and, sometimes, acanthosis nigricans. Herein, we describe a metabolic and hormonal profile before and during treatment with sirolimus in two brothers with AKT2 mutation inherited from the mosaic father, who showed low-level mosaicism in sperm. The boys, aged 1 and 14, who had severe non-insulin-dependent hypoketotic hypoglycemia and a typical dysmorphism, were admitted to endocrinology department for the analysis of their metabolic parameters: lipids, lactate, ammonia, glucose, insulin, c-peptide, and hormones (GH, IGF1, IGFBP3, TSH, fT4, cortisol, ACTH) before and during treatment with sirolimus. Previously, they had been treated with high-carbohydrate diet. The brothers were started on sirolimus with subsequent normalization of glycemia and reduced carbohydrate feedings overnight. The lowest fasting glucose levels improved from 20 mg/dl to 45 mg/dl in both sibs. The BMI of both brothers significantly dropped. After 6 months of sirolimus therapy we did not observe any laboratory or clinical side effects of the treatment.

Hydrogen Bonding Directed Self-Assembly of a Binuclear Ag(I) Metallacycle into a 1D Supramolecular Polymer.

An Ag(I) metallacycle obtained unexpectedly during the preparation of Pd(II) complexes of the bifunctional ligand 5-([2,2'-bipyridin]-5-yl)pyrimidine-2-amine (L) has been characterized using X-ray structure determination as a binuclear, metallacyclic species [Ag2L2](SbF6)2, where both the bipyridine and pyrimidine-N donors of L are involved in coordination to the metal. The full coordination environment of the Ag(I) defines a case of highly irregular 4-coordination. In the crystal, the Ag-metallacycles assemble into one-dimensional supramolecular metalladynamers linked together by hydrogen-bonding interactions.

The Role of ER Stress-Related Phenomena in the Biology of Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNST) are rare but one of the most aggressive types of cancer. Currently, there are no effective chemotherapy strategies for these malignancies. The inactivation of the neurofibromatosis type I (NF1) gene, followed by loss of TP53, is an early stage in MPNST carcinogenesis. NF1 is a negative regulator of the Ras proteins family, which are key factors in regulating cell growth, homeostasis and survival. Cell cycle dysregulation induces a stress phenotype, such as proteotoxic stress, metabolic stress, and oxidative stress, which should result in cell death. However, in the case of neoplastic cells, we observe not only the avoidance of apoptosis, but also the impact of stress factors on the treatment effectiveness. This review focuses on the pathomechanisms underlying MPNST cells physiology, and discusses the possible ways to develop a successful treatment based on the molecular background of the disease.

Brain Tissue Low-Level Mosaicism for MTOR Mutation Causes Smith-Kingsmore Phenotype with Recurrent Hypoglycemia-A Novel Phenotype and a Further Proof for Testing of an Affected Tissue.

De novo somatic variants in genes encoding components of the PI3K-AKT3-mTOR pathway, including MTOR, have been linked to hemimegalencephaly or focal cortical dysplasia. Similarly to other malformations of cortical development, this condition presents with developmental delay and intractable epilepsy, often necessitating surgical treatment. We describe a first patient with the Smith-Kingsmore syndrome phenotype with recurrent hypoglycemia caused by low-level mosaic MTOR mutation restricted to the brain. We provide discussion on different aspects of somatic mosaicism. Deep exome sequencing combined with a variant search in multiple tissues and careful phenotyping may constitute a key to the diagnosis of the causes of rare brain anomalies.

A recurrent de novo variant supports KCNC2 involvement in the pathogenesis of developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEE) are a heterogenous group of conditions characterized by the co-occurrence of epilepsy and intellectual/developmental disability. Despite several known DEE-related genes, including these encoding ion channels, still many cases remain without molecular diagnosis. Here, we present a 2-year-old girl with severe DEE in whom whole exome sequencing revealed de novo p.(Val471Leu) variant in the KCNC2 encoding Kv3.2, a voltage-gated potassium channel. To the best of our knowledge, this is the third DEE case due to KCNC2 mutation. Our clinical and molecular findings, particularly the recurrence of p.(Val471Leu) in patient with similar clinical phenotype, further support KCNC2 as a novel DEE-associated gene.

VDR polymorphisms effect on bone mineral density in Polish postmenopausal women.

Purpose: Osteoporosis is the most widespread systemic disease of the skeleton. According to estimated data for Poland, it affects ca. 3 million people. Although the disease is multifactorial, with significant influence of environmental factors on the increase of the risk of its occurrence, genetic factors play an important role in its pathogenesis. The aim of this study was an analysis of the relation of the ApaI, BsmI and TaqI polymorphisms of the VDR gene, with bone mineral density measured in lumbar spine and/or in proximal femur in a group of polish women. Methods: The study included 135 women at the postmenopausal age from the area of central Poland. BMD was measured at the hip and/or at the lumbar spine, using dual-energy X-ray absorptiometry. The influence of the selected VDR genotypes on bone mineral density was studied using the ApaI, the BsmI and the TaqI restriction enzymes. Lifestyle information was obtained via questionnaire. Results: Women with the 'bb' genotype showed lower BMD values of the hip (Total BMD value) comparing to patients with 'BB' or 'Bb' genotypes. We did not observe similar correlation for the lumbar spine. The remaining polymorphisms (ApaI and TaqI) did not demonstrate a significant relation with the differentiation of the mean BMD values obtained from the hip nor from lumbar vertebrae. Conclusion: The present study has demonstrated that the BsmI polymorphism of the vitamin D receptor gene is a factor of bone mineral density changes in postmenopausal women from Poland.

Charge Neutral [Cu2L2] and [Pd2L2] Metallocycles: Self-Assembly, Aggregation, and Catalysis.

A range of morphologically distinct metallosupramolecular Cu(II) and Pd(II) complexes has been constructed, based on the tritopic ligand 1,1',1″-(benzene-1,3,5-triyl)tris(4,4-dimethylpentane-1,3-dione) (H3L). By control of the reaction conditions, it is possible to generate distinct coordination assemblies possessing either macrocyclic or polymeric structures and more importantly distinct activity in catalysis of the Suzuki-Miyaura cross-coupling.

Simultaneous Formation of a Fully Organic Triply Dynamic Combinatorial Library.

Here we report the simultaneous formation of doubly and triply dynamic libraries as a result of exchange reactions between functionalized organic building blocks. A combination of three different reversible covalent linkages involving a boronate ester transesterification along with an imine and disulfide exchange was employed to generate a new type of fully organic triply dynamic molecular assembly.

Intrinsic Effect of Pyridine-N-Position on Structural Properties of Cu-Based Low-Dimensional Coordination Frameworks.

Metal-organic assemblies have received significant attention for catalytic and other applications, including gas and energy storage, due to their porosity and thermal/chemical stability. Here, we report the synthesis and physicochemical characterization of three metallosupramolecular assemblies consisting of isomeric ambidentate pyridyl-ß-diketonate ligands L1-L3 and Cu(II) metal ions. It has been demonstrated that the topology and dimensionality of generated supramolecular aggregates depend on the location of the pyridine nitrogen donor atom in L1-L3. This is seen in characterization of two distinct 2D polymeric assemblies, i.e., [Cu(L1)2]n and [Cu(L2)2]n, in which both ß-diketonate and pyridine groups are coordinated to the Cu(II) center, as well as in characterization of the mononuclear 1D complex Cu(L3)2, in which the central atom is bound only by two ß-diketonate units.

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit.

Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5-14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient's medical management, and families can receive genetic counseling.