Development of Mefloquine-Based Bifunctional Secondary Amine Organocatalysts for Enantioselective Michael and Friedel-Crafts Reactions.

The chiral framework based on 11-aminomefloquine has been utilized for the first time to construct bifunctional organocatalysts. These catalysts demonstrate high enantioselectivity in both Michael additions and Friedel-Crafts reactions across a variety of substrates, achieving up to >99% ee. The distinctive feature is the incorporation of a secondary amine group, offering unique tight hydrogen-bonding capabilities in the protonated state, as supported by DFT computation. The diversity of these organocatalysts suggests their broad applicability across multiple reaction classes.

Millennial processes of population decline, range contraction and near extinction of the European bison.

European bison (Bison bonasus) were widespread throughout Europe during the late Pleistocene. However, the contributions of environmental change and humans to their near extinction have never been resolved. Using process-explicit models, fossils and ancient DNA, we disentangle the combinations of threatening processes that drove population declines and regional extinctions of European bison through space and across time. We show that the population size of European bison declined abruptly at the termination of the Pleistocene in response to rapid environmental change, hunting by humans and their interaction. Human activities prevented populations of European bison from rebounding in the Holocene, despite improved environmental conditions. Hunting caused range loss in the north and east of its distribution, while land use change was responsible for losses in the west and south. Advances in hunting technologies from 1500 CE were needed to simulate low abundances observed in 1870 CE. While our findings show that humans were an important driver of the extinction of the European bison in the wild, vast areas of its range vanished during the Pleistocene-Holocene transition because of post-glacial environmental change. These areas of its former range have been climatically unsuitable for millennia and should not be considered in reintroduction efforts.

Next-generation phylogeography resolves post-glacial colonization patterns in a widespread carnivore, the red fox (Vulpes vulpes), in Europe.

Carnivores tend to exhibit a lack of (or less pronounced) genetic structure at continental scales in both a geographic and temporal sense and this can confound the identification of post-glacial colonization patterns in this group. In this study we used genome-wide data (using genotyping by sequencing [GBS]) to reconstruct the phylogeographic history of a widespread carnivore, the red fox (Vulpes vulpes), by investigating broad-scale patterns of genomic variation, differentiation and admixture amongst contemporary populations in Europe. Using 15,003 single nucleotide polymorphisms (SNPs) from 524 individuals allowed us to identify the importance of refugial regions for the red fox in terms of endemism (e.g., Iberia). In addition, we tested multiple post-glacial recolonization scenarios of previously glaciated regions during the Last Glacial Maximum using an Approximate Bayesian Computation (ABC) approach that were unresolved from previous studies. This allowed us to identify the role of admixture from multiple source population post-Younger Dryas in the case of Scandinavia and ancient land-bridges in the colonization of the British Isles. A natural colonization of Ireland was deemed more likely than an ancient human-mediated introduction as has previously been proposed and potentially points to a larger mammalian community on the island in the early post-glacial period. Using genome-wide data has allowed us to tease apart broad-scale patterns of structure and diversity in a widespread carnivore in Europe that was not evident from using more limited marker sets and provides a foundation for next-generation phylogeographic studies in other non-model species.

Widespread male sex bias in mammal fossil and museum collections.

A recent study of mammoth subfossil remains has demonstrated the potential of using relatively low-coverage high-throughput DNA sequencing to genetically sex specimens, revealing a strong male-biased sex ratio [P. Pecnerová et al., Curr. Biol. 27, 3505-3510.e3 (2017)]. Similar patterns were predicted for steppe bison, based on their analogous female herd-based structure. We genetically sexed subfossil remains of 186 Holarctic bison (Bison spp.), and also 91 brown bears (Ursus arctos), which are not female herd-based, and found that ∼75% of both groups were male, very close to the ratio observed in mammoths (72%). This large deviation from a 1:1 ratio was unexpected, but we found no evidence for sex differences with respect to DNA preservation, sample age, material type, or overall spatial distribution. We further examined ratios of male and female specimens from 4 large museum mammal collections and found a strong male bias, observable in almost all mammalian orders. We suggest that, in mammals at least, 1) wider male geographic ranges can lead to considerably increased chances of detection in fossil studies, and 2) sexual dimorphic behavior or appearance can facilitate a considerable sex bias in fossil and modern collections, on a previously unacknowledged scale. This finding has major implications for a wide range of studies of fossil and museum material.

[Comparison of intra-abdominal pressure, during spine surgeries, among two prone positional apparatuses in the same patient - a case report]. / Porównanie zmiany wartosci cisnienia sródbrzusznego podczas operacji kregoslupa przy zastosowaniu dwóch systemów ulozenia chorego w pozycji na brzuchu ­ opis przypadku.

Spinal surgeries often require prone positioning of the patient. This is associated with increased intra-abdominal pressure, which may increase the risk of intra- and postoperative complications. The described case enables the comparison of two prone positional apparatuses and their influence on changes in intra-abdominal pressure during spine surgeries. A CASE REPORT: A 74-year-old female patient underwent two spine surgeries due to a fracture of the Th12 vertebra and traumatic kyphosis. Both were performed in the prone position. During the first procedure, stabilization of the fracture, positioning was performed by placing the patient on the Allen table, whereas during the second procedure, laminectomy, by placing the patient on gel pads. During both surgeries the patient's intra-abdominal pressure was measured. The values measured while lying on the Allen table were found to be lower (mean 13.8 mmHg ± 0.66 mmHg) than the results obtained during the procedure utilizing gel pads (mean 24 mmHg ± 1.22 mmHg). Both surgeries were completed without complications. In both cases, creatinine, urea, and potassium concentrations as well as daily diuresis were measured to assess postoperative renal function. The results of these analyses did not indicate renal damage. CONCLUSIONS: The way the patient is positioned on the abdomen has a significant impact on intra-abdominal pressure. Compared to gel pads, the Allen table allows for a reduction in abdominal pressure, which corresponds with lower values of intra-abdominal pressure. This may help reduce the risk of complications during surgeries performed in the prone position.

Chiral Vicinal Diamines Derived from Mefloquine.

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino-Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro-11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi-aminoquinine in terms of selectivity.

Efficacy of Selenourea Organocatalysts in Asymmetric Michael Reactions under Standard and Solvent-Free Conditions.

By varying the steric and electronic surroundings of the hydrogen-bonding motif, the novel chiral Cinchona-alkaloid based selenoureas were developed. Acting as bifunctional catalysts, they were applied in the Michael reactions of dithiomalonate and nitrostyrene providing chiral adducts with up to 96% ee. The asymmetric Michael--hemiacetalization reaction of benzylidene pyruvate and dimedone, performed with the assistance of 5 mol% of selenoureas, furnished the product with up to 93% ee and excellent yields. The effectiveness of the new hydrogen-bond donors was also proved in solvent-free reactions under ball mill conditions, supporting the sustainability of the devised catalytic protocol.

[Hypotension - a complication of subarachnoid anesthesia especially dangerous in patients aged]. / Hipotensja ­ powiklanie znieczulenia podpajeczynówkowego szczególnie grozne u chorych w podeszlym wieku.

Demographic data clearly show the progressive aging of societies. Problems and specificity of anaesthesia in the elderly becomes a particularly important issue in this context. Spinal anesthesia is a method often used to anesthetize elderly patients, and hypotension is one of its most common early complications. Untreated or improperly treated hypotension increases the risk of perioperative complications such as myocardial infarction, ischemic stroke or acute renal failure. The prevention of hypotension consists of intravenous fluid therapy and pre-emptive use of vasoconstrictor drugs. Among vasoconstrictors, ephedrine and phenylephrine are commonly used to treat hypotension due to spinal anaesthesia. Both drugs are available in Poland. Issues related to their use in the treatment of hypotension caused by spinal anaesthesia in the elderly, including the features of both drugs, their method of administration and dosage based on the literature and own experience are the subject of this study. It should be noted, however, that most studies in the use of ephedrine and phenylephrine as a targeted treatment for hypotension concern the obstetric patient population while the elderly population is underrepresented and the results are inconclusive.

Adapt or die-Response of large herbivores to environmental changes in Europe during the Holocene.

Climate warming and human landscape transformation during the Holocene resulted in environmental changes for wild animals. The last remnants of the European Pleistocene megafauna that survived into the Holocene were particularly vulnerable to changes in habitat. To track the response of habitat use and foraging of large herbivores to natural and anthropogenic changes in environmental conditions during the Holocene, we investigated carbon (δ13 C) and nitrogen (δ15 N) stable isotope composition in bone collagen of moose (Alces alces), European bison (Bison bonasus) and aurochs (Bos primigenius) in Central and Eastern Europe. We found strong variations in isotope compositions in the studied species throughout the Holocene and diverse responses to changing environmental conditions. All three species showed significant changes in their δ13 C values reflecting a shift of foraging habitats from more open in the Early and pre-Neolithic Holocene to more forest during the Neolithic and Late Holocene. This shift was strongest in European bison, suggesting higher plasticity, more limited in moose, and the least in aurochs. Significant increases of δ15 N values in European bison and moose are evidence of a diet change towards more grazing, but may also reflect increased nitrogen in soils following deglaciation and global temperature increases. Among the factors explaining the observed isotope variations were time (age of samples), longitude and elevation in European bison, and time, longitude and forest cover in aurochs. None of the analysed factors explained isotope variations in moose. Our results demonstrate the strong influence of natural (forest expansion) and anthropogenic (deforestation and human pressure) changes on the foraging ecology of large herbivores, with forests playing a major role as a refugial habitat since the Neolithic, particularly for European bison and aurochs. We propose that high flexibility in foraging strategy was the key for survival of large herbivores in the changing environmental conditions of the Holocene.

The first case of genetically confirmed sparganosis (Spirometra erinaceieuropaei) in European reptiles.

Sparganosis is a zoonosis caused by the spargana (larvae) of Spirometra sp. (Diphyllobothriidae). Reptiles are particularly important vectors for the transmission of this parasite in Asia; however, their role in sparganosis spread in European wildlife is unrecognized. We investigated the infection of reptiles with Spirometra sp. in NE Poland, where several mammalian hosts have been identified recently and in the past. Of the 59 dead reptiles, plerocercoids were found in two grass snakes (Natrix natrix) from the Bialowieza Primeval Forest (BPF). The Spirometra erinaceieuropaei species was genetically confirmed using the evolutionary conserved nuclear 18S rRNA gene, and then compared to GenBank deposits. The sequences were identical to previously investigated Spirometra sp. found in Eurasian badger and wild boar from BPF. Our finding is the first genetically confirmed record of Spirometra sp. in reptiles in Europe. Since reptiles are often a component of mammalian diet, they can be a source of Spirometra tapeworm infection in European wildlife; however, further studies are needed to investigate the prevalence of infection in reptiles and other non-mammalian hosts.

Deciphering the Wisent Demographic and Adaptive Histories from Individual Whole-Genome Sequences.

As the largest European herbivore, the wisent (Bison bonasus) is emblematic of the continent wildlife but has unclear origins. Here, we infer its demographic and adaptive histories from two individual whole-genome sequences via a detailed comparative analysis with bovine genomes. We estimate that the wisent and bovine species diverged from 1.7 × 106 to 850,000 years before present (YBP) through a speciation process involving an extended period of limited gene flow. Our data further support the occurrence of more recent secondary contacts, posterior to the Bos taurus and Bos indicus divergence (∼150,000 YBP), between the wisent and (European) taurine cattle lineages. Although the wisent and bovine population sizes experienced a similar sharp decline since the Last Glacial Maximum, we find that the wisent demography remained more fluctuating during the Pleistocene. This is in agreement with a scenario in which wisents responded to successive glaciations by habitat fragmentation rather than southward and eastward migration as for the bovine ancestors. We finally detect 423 genes under positive selection between the wisent and bovine lineages, which shed a new light on the genome response to different living conditions (temperature, available food resource, and pathogen exposure) and on the key gene functions altered by the domestication process.

Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling.

Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound - acetylenedicarboxylic acid, with Ki∗=42.5nM and logkGSH=-2.14. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates.

Brønsted-base-catalyzed remote cascade reactivity of 2,4-dienones - asymmetric synthesis of tetrahydrothiophenes.

This study demonstrates that the remote cascade functionalization of 2,4-dienones can be realized by employing Brønsted base catalysis. The developed cascade involving 1,6-addition followed by the intramolecular aldol reaction provides a straightforward access to polysubstituted tetrahydrothiophene derivatives of biological and synthetic importance. Target products, bearing three contiguous stereocenters including one quaternary, have been obtained with excellent yields (up to 98%) and with good to high stereocontrol (>20 : 1 dr, up to 97 : 3 er) with the reaction cascade being promoted by a simple and readily available cinchona alkaloid cinchonine.

Click-Dimerized Cinchona Alkaloids.

A series of Cinchona alkaloid-derived dimers were obtained in high yields in copper-catalyzed 1,3-dipolar "click" cycloaddition using bis(TMS)butadiyne and other bivalent alkynes. The products with bitriazole linkers were effective ligands for asymmetric copper-catalyzed Michael addition. It was shown that the presence of such linker was responsible for effective chirality transfer.

Tricyclic Quaternary Ammonium Salts Derived from Cinchona Alkaloids.

Tricyclic systems with quaternary bridgehead nitrogen atoms are rare but an interesting class of compounds. Chiral quinuclidine derivative salts with fused five and six-membered rings (X-ray) were obtained via modification of Cinchona alkaloids. The ease of ring formation was dependent on its size, while even mild activation sufficed to close the five membered ring. On the other hand the systems with fused benzene and a six-membered ring formed atropisomers separated by a barrier of ca. 15 kcal/mol, whose interconversion was studied by DFT and NMR.

Fluorinated sulfoximines: syntheses, properties and applications.

The interest in fluorinated sulfoximines has rapidly increased over the past twenty years. As sulfoximines are analogues of sulfones where one of the two S[double bond, length as m-dash]O units has been replaced by an S[double bond, length as m-dash]N moiety, they can confer new reactivities and properties never observed for the respective sulfones. In this tutorial review, we present the specific properties of fluorinated sulfoximines (including important bioactivities) and describe the syntheses and the applications of fluoromethyl transfer agents such as Johnson's reagent. Furthermore, we highlight the exceptional electronic effects induced by the presence of strongly electron-withdrawing fluoro-bearing sulfonimidoyl moieties, which allowed the development of remarkable super-acidifiers and super-acceptors with relevance in materials sciences.

The influence of habitat structure on genetic differentiation in red fox populations in north-eastern Poland.

The red fox (Vulpes vulpes) has the widest global distribution among terrestrial carnivore species, occupying most of the Northern Hemisphere in its native range. Because it carries diseases that can be transmitted to humans and domestic animals, it is important to gather information about their movements and dispersal in their natural habitat but it is difficult to do so at a broad scale with trapping and telemetry. In this study, we have described the genetic diversity and structure of red fox populations in six areas of north-eastern Poland, based on samples collected from 2002-2003. We tested 22 microsatellite loci isolated from the dog and the red fox genome to select a panel of nine polymorphic loci suitable for this study. Genetic differentiation between the six studied populations was low to moderate and analysis in Structure revealed a panmictic population in the region. Spatial autocorrelation among all individuals showed a pattern of decreasing relatedness with increasing distance and this was not significantly negative until 93 km, indicating a pattern of isolation-by-distance over a large area. However, there was no correlation between genetic distance and either Euclidean distance or least-cost path distance at the population level. There was a significant relationship between genetic distance and the proportion of large forests and water along the Euclidean distances. These types of habitats may influence dispersal paths taken by red foxes, which is useful information in terms of wildlife disease management.

Transfusion-related acute lung injury in a patient diagnosed with hypofibrinogenemia after a cesarean section--case report and review of the literature.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare, but potentially fatal, complication of blood product transfusion, manifesting as acute respiratory distress syndrome. In most cases, TRALI is associated with massive transfusion of fresh frozen plasma and platelets. CASE REPORT: A 38-year-old-woman at 40 weeks gestation was admitted to hospital with spontaneous labor contractions. A cesarean section was performed due to feto-pelvic disproportion and a male infant (Apgar 10) was delivered. After 37 hours low hemoglobin level and growing subfascial hematoma were detected. Urgent relaparotomy was carried out. The blood loss was over 1500 ml and a massive transfusion (6 units of red cell concentrate, 8 units of fresh frozen plasma and 6 units of cryoprecipitate) was necessary. The patient developed symptoms of acute respiratory distress 10 hours after relaparotomy. No pathological findings were shown in echocardiography and ECG. Chest CT revealed pulmonary edema. Low fibrinogen levels were observed in laboratory tests, decreasing in time after transfusion of the blood products to 1.0/L. Oxygen therapy with facial mask was initiated, furosemide was administered and continued for three days until symptom resolution. A series of hematological tests performed after the patient was discharged from hospital confirmed the diagnosis of TRALI and congenital hypofibrinogenemia. CONCLUSION: Congenital hypofibrinogenemia may be responsible for the development of subfascial hematoma, a complication of cesarean section, necessitating relaparotomy. The following massive transfusion of blood products resulted in a potentially fatal complication in a form of TRALI.

[Anesthesia for cesarean section in patients with preexisting neurologic diseases--10 years of practice]. / Znieczulenie do ciecia cesarskiego u pacjentek z choroba neurologiczna--10 lat doswiadczen.

OBJECTIVES: Regional anesthesia is considered a 'gold standard' for cesarean sections. However, it is very often contraindicated in patients with coexistent neurological diseases. This article attempts to review the specific concerns for administration of anesthesia for cesarean section posed by spinal diseases, epilepsy sclerosis multiplex and others. MATERIALS AND METHODS: We present 85 cases of parturients with pre-existing neurological diseases, who received anesthesia for caesarean section at the First Clinic of Anesthesia and Intensive Care in the last 10 years. We compared those cases with the medical literature. RESULTS: We successfully used general as well as regional anesthesia. The decision about the anesthetic technique was based on the neurological state of each patient. CONCLUSION: No guidelines for anesthesiologist concerning the best anesthetic technique for patients with neurological diseases have been designed so far. The choice of the safest method is made individually and depends on a variety of factors.