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One of Earth's most fundamental climate shifts, the greenhouse-icehouse transition 34 million years ago, initiated Antarctic ice sheet buildup, influencing global climate until today. However, the extent of the ice sheet during the Early Oligocene Glacial Maximum (~33.7 to 33.2 million years ago) that immediately followed this transition-a critical knowledge gap for assessing feedbacks between permanently glaciated areas and early Cenozoic global climate reorganization-is uncertain. In this work, we present shallow-marine drilling data constraining earliest Oligocene environmental conditions on West Antarctica's Pacific margin-a key region for understanding Antarctic ice sheet evolution. These data indicate a cool-temperate environment with mild ocean and air temperatures that prevented West Antarctic Ice Sheet formation. Climate-ice sheet modeling corroborates a highly asymmetric Antarctic ice sheet, thereby revealing its differential regional response to past and future climatic change.

Extensive ice coverage largely prevents investigations of Antarctica's unglaciated past. Knowledge about environmental and tectonic development before large-scale glaciation, however, is important for understanding the transition into the modern icehouse world. We report geochronological and sedimentological data from a drill core from the Amundsen Sea shelf, providing insights into tectonic and topographic conditions during the Eocene (~44 to 34 million years ago), shortly before major ice sheet buildup. Our findings reveal the Eocene as a transition period from >40 million years of relative tectonic quiescence toward reactivation of the West Antarctic Rift System, coinciding with incipient volcanism, rise of the Transantarctic Mountains, and renewed sedimentation under temperate climate conditions. The recovered sediments were deposited in a coastal-estuarine swamp environment at the outlet of a >1500-km-long transcontinental river system, draining from the rising Transantarctic Mountains into the Amundsen Sea. Much of West Antarctica hence lied above sea level, but low topographic relief combined with low elevation inhibited widespread ice sheet formation.

Pulmonary and systemic congestion as a consequence of heart failure are clinically recognized as alarm signals for clinical outcome and mortality. Although signs and symptoms of congestion are well detectable in patients, monitoring of congestion in small animals with heart failure lacks adequate noninvasive methodology yet. Here, we developed a novel ultrasonography-based scoring system to assess pulmonary and systemic congestion in experimental heart failure, by using lung ultrasound (LUS) and imaging of the inferior vena cava (Cava), termed CavaLUS. CavaLUS was established and tested in a rat model of supracoronary aortic banding and a mouse model of myocardial infarction, providing high sensitivity and specificity while correlating to numerous parameters of cardiac performance and disease severity. CavaLUS, therefore, provides a novel comprehensive tool for experimental heart failure in small animals to noninvasively assess congestion. NEW & NOTEWORTHY As thorough, noninvasive assessment of congestion is not available in small animals, we developed and validated an ultrasonography-based research tool to evaluate pulmonary and central venous congestion in experimental heart failure models.

Although great strides have been made in the pathophysiological understanding, diagnosis and management of cardiogenic shock (CS), morbidity and mortality in patients presenting with the condition remain high. Acute MI is the commonest cause of CS; consequently, most existing literature concerns MI-associated CS. However, there are many more phenotypes of patients with acute heart failure. Medical treatment and mechanical circulatory support are well-established therapeutic options, but evidence for many current treatment regimens is limited. The issue is further complicated by the fact that implementing adequately powered, randomized controlled trials are challenging for many reasons. In this review, the authors discuss the history, landmark trials, current topics of medical therapy and mechanical circulatory support regimens, and future perspectives of CS management., Competing Interests: Disclosure: SO has received research and study grants from Novartis; EP is proctor and consultant for and has received institutional grants from Abbott, Medtronic, and Abiomed; BO is a consultant for Teleflex and has received research funding from the British Heart Foundation and the National Institute for Health Science Research. All other authors have no conflict of interest to declare., (Copyright © The Author(s), 2022. Published by Radcliffe Group Ltd.)

Background Degenerative aortic valve (AoV) disease and resulting aortic stenosis are major clinical health problems. Murine models of valve disease are rare, resulting in a translational knowledge gap on underlying mechanisms, functional consequences, and potential therapies. Naïve New Zealand obese (NZO) mice were recently found to have a dramatic decline of left ventricular (LV) function at early age. Therefore, we aimed to identify the underlying cause of reduced LV function in NZO mice. Methods and Results Cardiac function and pulmonary hemodynamics of NZO and age-matched C57BL/6J mice were monitored by serial echocardiographic examinations. AoVs in NZO mice demonstrated extensive thickening, asymmetric aortic leaflet formation, and cartilaginous transformation of the valvular stroma. Doppler echocardiography of the aorta revealed increased peak velocity profiles, holodiastolic flow reversal, and dilatation of the ascending aorta, consistent with aortic stenosis and regurgitation. Compensated LV hypertrophy deteriorated to decompensated LV failure and remodeling, as indicated by increased LV mass, interstitial fibrosis, and inflammatory cell infiltration. Elevated LV pressures in NZO mice were associated with lung congestion and cor pulmonale , evident as right ventricular dilatation, decreased right ventricular function, and increased mean right ventricular systolic pressure, indicative for the development of pulmonary hypertension and ultimately right ventricular failure. Conclusions NZO mice demonstrate as a novel murine model to spontaneously develop degenerative AoV disease, aortic stenosis, and the associated end organ damages of both ventricles and the lung. Closely mimicking the clinical scenario of degenerative AoV disease, the model may facilitate a better mechanistic understanding and testing of novel treatment strategies in degenerative AoV disease.

Inhibition of return (IOR) is thought to be a phenomenon that biases orienting toward novel stimuli and/or facilitates foraging search. Although IOR has been explored using both the spatial cueing paradigm and the search paradigm, there is significant disagreement among scholars over whether these paradigms are reflecting the same underlying mechanism. We sought to address this disagreement by exploring whether a manipulation known to impact IOR in search - maintenance versus removal of the scene - might have a similar impact in the spatial cuing paradigm. As has been observed in both the cuing and search paradigms, we obtained a robust gradient of IOR around the cued location. Importantly, as in search tasks, scene removal resulted in the abolishment of IOR. This similarity lends support to the view that the spatial cuing and search paradigms are exploring the same IOR phenomenon.

We describe a new species of small-sized frogs from degraded rainforest patches in the southern central east of Madagascar. Stumpffia miery sp. nov. has a snout-vent length of 13-15 mm and can be distinguished from all other nominal species of Stumpffia by its body size and absence of toe reduction combined with length reduction of fingers I, II and IV in external view. The advertisement call is a single tonal chirping note that ranges in duration between 51-88 ms and is emitted after relatively regular inter-note intervals (duration of 2679-4247 ms, call repetition rate 0.3/sec, frequency range 7700-8300 Hz, dominant frequency 7751-8225 Hz). Its type locality is the Ambolo forest fragment close to Ranomafana village in southeastern Madagascar. Molecular data from DNA sequences of one mitochondrial and one nuclear gene indicate a high divergence from all nominal species of Stumpffia, suggesting that it represents a strongly differentiated independent evolutionary unit. Stumnpffia miery sp. nov. is apparently able to tolerate some degree of habitat degradation and therefore is probably not threatened with extinction.

We describe a new small-sized microhylid frog of the genus Stumpffia and provide a preliminary survey of Stumpffia diversity in northern and northwestern Madagascar based on molecular and morphological data. Analysis of 68 previously published and 142 newly generated DNA sequences of a fragment of the mitochondrial 16S rRNA gene revealed a large genetic diversity within Stumpffia, with numerous strongly differentiated lineages occurring across Madagascar. The anal. ysis confirmed a clade formed exclusively by Stumpffia species occurring in north/northwestern Madagascar and contain. ing almost all species from this area. Based on DNA sequences of the RAG1 gene, we further assess that most of the deep mitochondrial lineages do not share haplotypes in this nuclear marker, even in the few cases of sympatry, which we interpret as confirmation of their status as independent evolutionary lineages. Micro-computed tomography revealed subtle differences in phalangeal formulae among some of these candidate species, providing additional taxonomic characters for future revisions of the genus. The newly described species Stumpffia analamaina sp. nov. occurs 27 km north-west of Antsohihy and is at present the southernmost confirmed Stumpffia of the north/northwestern clade. It is mainly characterized by a snout-vent length of 10-12 mm, advertisement calls consisting of a series of short melodious chirps, manus with four fingers and pes with five toes, with only slight length reduction of first finger and toe. It furthermore does not share haplotypes with any other Stumpffia species in 16S or RAG1, and has relatively longer hands and feet compared with other small-sized Stumpffia of the north/northwestern clade such as S. madagascariensis and S. pygmaea. The new species lives in an area of dry forest where it was found in leaf litter along a small stream bordered by degraded gallery vegetation. Due to the limited distributions of almost all species in the north/northwestern Stumpffia clade, the rareness of appropriate microhabitat around the type locality of S. analamaina sp. nov. and the rampant habitat destruction in this part of Madagascar, we propose a threat status of Critically Endangered for this new species.

Precise NMR structural determination of distinct hydrogen-bonded secondary folds in unnatural peptides is demonstrated by using residual dipolar couplings (RDCs), measured in organic solvent media. The results show that the conventional constraints, (3)J(HH) and NOE-derived distances alone do not allow the accurate structural elucidation even for rigid foldamers and emphasize the need of RDC-based structure validation and refinement for unnatural peptides in particular and small organic molecules in general.

The structure of the extracellular domain of BMP receptor IA was determined in solution by NMR spectroscopy and compared to its structure when bound to its ligand BMP-2. While most parts of the secondary structure are highly conserved between the bound and unbound forms, large conformational rearrangements can be observed in the beta4beta5 loop of BMPR-IA, which is in contact with BMP-2 and harbors the main binding determinants for the BMPR-IA-BMP-2 interaction. In its unbound form, helix alpha1 in BMPR-IA, which is in the center of the binding epitope for BMP-2, is missing. Since BMP-2 also shows conformational changes in the type I receptor epitope upon binding to BMPR-IA, both binding partners pass through an induced fit mechanism to adapt their binding interfaces to a given interaction surface. The inherent flexibility of both partners possibly explains the promiscuous ligand-receptor interaction observed in the BMP protein superfamily.

The main purpose of homonuclear Hartmann-Hahn or TOCSY experiments is the assignment of spin systems based on efficient coherence transfer via scalar couplings. In partially aligned samples, however, magnetization is also transferred via residual dipolar couplings (RDCs) and therefore through space correlations can be observed in COSY and TOCSY experiments that make the unambiguous assignment of covalently bound spins impossible. In this article, we show that the JESTER-1 multiple pulse sequence, originally designed for broadband heteronuclear isotropic Hartmann-Hahn transfer, efficiently suppresses the homonuclear dipolar coupling Hamiltonian. This suppression can be enhanced even further by variation of the supercycling scheme. The application of the resulting element in homonuclear TOCSY periods results in coherence transfer via J-couplings only. As a consequence, the assignment of scalar coupled spin systems is also possible in partially aligned samples. The bandwidth of coherence transfer for the JESTER-1-derived sequences is comparable to existing TOCSY multiple pulse sequences. Results are demonstrated in theory and experiment.

Investigation of the DNA repair process performed by the spore photoproduct (SP) lyase repair enzyme is strongly hampered by the lack of defined substrates needed for detailed enzymatic studies. The problem is particularly severe because the repair enzyme belongs to the class of strongly oxygen-sensitive radical (S)-adenosylmethionine (SAM) enzymes, which are notoriously difficult to handle. We report the synthesis of the spore photoproduct analogues 1 a and 1 b, which have open backbones and are diastereoisomers. In order to solve the problem of stereochemical assignment, two further derivatives 2 a and 2 b with closed backbones were prepared. The key step of the synthesis of 2 a/b is a metathesis-based macrocyclization that strongly increases the conformational rigidity of the synthetic spore photoproduct derivatives. NOESY experiments of the cyclic isomers furnished a clear cross-peak pattern that allowed the unequivocal assignment of the stereochemistry. The results were transferred to the data for isomers 1 a and 1 b, which were subsequently used for enzymatic-repair studies. These studies were performed with the novel spore photoproduct lyase repair enzyme from Geobacillus stearothermophilus. The studies showed an accordance with a recent investigation performed by us with the spore photoproduct lyase from Bacillus subtilis, in that only the S isomer 1 a is recognized and repaired. The ability to prepare a defined functioning substrate now paves the way for detailed enzymatic studies of the SP-lyase lesion recognition and repair process.

New developments concerning alignment media for apolar solvents like chloroform make it possible to measure anisotropic parameters such as residual dipolar couplings (RDCs) at relatively low concentrations and natural isotopic abundance. As RDCs provide structural restraints with respect to an external coordinate system, long-range structural arrangements of the time-averaged structure can be determined with high precision. The method is demonstrated on the well-studied cyclo-undecapeptide Cyclosporin A (CsA), for which crystal and conventionally derived NMR structures are available. Neither crystal nor NMR structure are consistent with heteronuclear D(CH) RDCs measured in a stretched poly(dimethylsiloxane) gel, and refinement by using the anisotropic parameter results in a highly defined structure with a slightly changed backbone conformation. The applied methods and interpretation of the structural model are discussed.

This study examined the relationship between two risk factors for dementia, the apolipoprotein (APOE) epsilon4 allele and poor memory test performance. Participants were from the Canadian Study of Health and Aging, a 4-year longitudinal population-based study. Persons with no cognitive impairment who had an epsilon4 allele but whose memory was average or better were not at increased risk of developing dementia after five years. Risk was increased for those with below average memory and no epsilon4 allele, but was particularly increased for those with below average memory and an epsilon4 allele. While the APOE epsilon4 allele was associated with slightly lower memory test performance for persons without cognitive impairment at baseline, it only increased their risk of developing dementia if their memory was below average.