A DELAY OF GERMINATION 1 (DOG1)-like protein regulates spore germination in the moss Physcomitrium patens.

DELAY OF GERMINATION 1 is a key regulator of dormancy in flowering plants before seed germination. Bryophytes develop haploid spores with an analogous function to seeds. Here, we investigate whether DOG1 function during germination is conserved between bryophytes and flowering plants and analyse the underlying mechanism of DOG1 action in the moss Physcomitrium patens. Phylogenetic and in silico expression analyses were performed to identify and characterise DOG1 domain-containing genes in P. patens. Germination assays were performed to characterise a Ppdog1-like1 mutant, and replacement with AtDOG1 was carried out. Yeast two-hybrid assays were used to test the interaction of the PpDOG1-like protein with DELLA proteins from P. patens and A. thaliana. P. patens possesses nine DOG1 domain-containing genes. The DOG1-like protein PpDOG1-L1 (Pp3c3_9650) interacts with PpDELLAa and PpDELLAb and the A. thaliana DELLA protein AtRGA in yeast. Protein truncations revealed the DOG1 domain as necessary and sufficient for interaction with PpDELLA proteins. Spores of Ppdog1-l1 mutant germinate faster than wild type, but replacement with AtDOG1 reverses this effect. Our data demonstrate a role for the PpDOG1-LIKE1 protein in moss spore germination, possibly alongside PpDELLAs. This suggests a conserved DOG1 domain function in germination, albeit with differential adaptation of regulatory networks in seed and spore germination.

Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis.

In chordates, energy buffering is achieved in part through phosphocreatine, which requires cellular uptake of creatine by the membrane-embedded creatine transporter (CRT1/SLC6A8). Mutations in human slc6a8 lead to creatine transporter deficiency syndrome, for which there is only limited treatment. Here, we used a combined homology modeling, molecular dynamics, and experimental approach to generate a structural model of CRT1. Our observations support the following conclusions: contrary to previous proposals, C144, a key residue in the substrate binding site, is not present in a charged state. Similarly, the side chain D458 must be present in a protonated form to maintain the structural integrity of CRT1. Finally, we identified that the interaction chain Y148-creatine-Na+ is essential to the process of occlusion, which occurs via a "hold-and-pull" mechanism. The model should be useful to study the impact of disease-associated point mutations on the folding of CRT1 and identify approaches which correct folding-deficient mutants.

Cooperative Binding of Substrate and Ions Drives Forward Cycling of the Human Creatine Transporter-1.

Creatine serves as an ATP buffer and is thus an integral component of cellular energy metabolism. Most cells maintain their creatine levels via uptake by the creatine transporter (CRT-1, SLC6A8). The activity of CRT-1, therefore, is a major determinant of cytosolic creatine concentrations. We determined the kinetics of CRT-1 in real time by relying on electrophysiological recordings of transport-associated currents. Our analysis revealed that CRT-1 harvested the concentration gradient of NaCl and the membrane potential but not the potassium gradient to achieve a very high concentrative power. We investigated the mechanistic basis for the ability of CRT-1 to maintain the forward cycling mode in spite of high intracellular concentrations of creatine: this is achieved by cooperative binding of substrate and co-substrate ions, which, under physiological ion conditions, results in a very pronounced (i.e. about 500-fold) drop in the affinity of creatine to the inward-facing state of CRT-1. Kinetic estimates were integrated into a mathematical model of the transport cycle of CRT-1, which faithfully reproduced all experimental data. We interrogated the kinetic model to examine the most plausible mechanistic basis of cooperativity: based on this systematic exploration, we conclude that destabilization of binary rather than ternary complexes is necessary for CRT-1 to maintain the observed cytosolic creatine concentrations. Our model also provides a plausible explanation why neurons, heart and skeletal muscle cells must express a creatine releasing transporter to achieve rapid equilibration of the intracellular creatine pool.

Optimizing the Substrate Uptake Rate of Solute Carriers.

The diversity in solute carriers arose from evolutionary pressure. Here, we surmised that the adaptive search for optimizing the rate of substrate translocation was also shaped by the ambient extracellular and intracellular concentrations of substrate and co-substrate(s). We explored possible solutions by employing kinetic models, which were based on analytical expressions of the substrate uptake rate, that is, as a function of the microscopic rate constants used to parameterize the transport cycle. We obtained the defining terms for five reaction schemes with identical transport stoichiometry (i.e., Na+: substrate = 2:1). We then utilized an optimization algorithm to find the set of numeric values for the microscopic rate constants, which provided the largest value for the substrate uptake rate: The same optimized rate was achieved by different sets of numerical values for the microscopic rate constants. An in-depth analysis of these sets provided the following insights: (i) In the presence of a low extracellular substrate concentration, a transporter can only cycle at a high rate, if it has low values for both, the Michaelis-Menten constant (KM) for substrate and the maximal substrate uptake rate (Vmax). (ii) The opposite is true for a transporter operating at high extracellular substrate concentrations. (iii) Random order of substrate and co-substrate binding is superior to sequential order, if a transporter is to maintain a high rate of substrate uptake in the presence of accumulating intracellular substrate. Our kinetic models provide a framework to understand how and why the transport cycles of closely related transporters differ.

Marine temperatures underestimated for past greenhouse climate.

Understanding the Earth's climate system during past periods of high atmospheric CO2 is crucial for forecasting climate change under anthropogenically-elevated CO2. The Mesozoic Era is believed to have coincided with a long-term Greenhouse climate, and many of our temperature reconstructions come from stable isotopes of marine biotic calcite, in particular from belemnites, an extinct group of molluscs with carbonate hard-parts. Yet, temperatures reconstructed from the oxygen isotope composition of belemnites are consistently colder than those derived from other temperature proxies, leading to large uncertainties around Mesozoic sea temperatures. Here we apply clumped isotope palaeothermometry to two distinct carbonate phases from exceptionally well-preserved belemnites in order to constrain their living habitat, and improve temperature reconstructions based on stable oxygen isotopes. We show that belemnites precipitated both aragonite and calcite in warm, open ocean surface waters, and demonstrate how previous low estimates of belemnite calcification temperatures has led to widespread underestimation of Mesozoic sea temperatures by ca. 12 °C, raising estimates of some of the lowest temperature estimates for the Jurassic period to values which approach modern mid-latitude sea surface temperatures. Our findings enable accurate recalculation of global Mesozoic belemnite temperatures, and will thus improve our understanding of Greenhouse climate dynamics.

#patientstoo - Professional sexual misconduct by healthcare professionals towards patients: a representative study.

AIMS: Sexual border violations are a severe problem in the healthcare system. Studies using non-probability samples indicate a high prevalence of professional sexual misconduct (PSM) towards patients. However, valid prevalence rates are lacking. METHODS: We did a cross-sectional, observational study in Germany from February to April 2020. By different sampling steps, a probability sample of the German population above the age of 14 was generated. The final sample consisted 2503 persons (50.2% female, mean age: 49.5 years). Participants were asked about sexual contacts with and sexual harassment by healthcare professionals. Using descriptive statistics, prevalence rates of PSM were estimated. RESULTS: PSM was reported by 56 (4.5%) female and 17 (1.4%) male participants. In detail, 28 (2.2%) female and 10 (0.8%) male participants reported sexual contacts with healthcare professionals. One third of these sexual contacts took place before the age of 18 and one third against the will of the patients. 40 (3.2%) female and 8 (0.6%) male participants reported unnecessary physical examinations, 31 (2.5%) female and 7 (0.6%) male participants reported sexual harassment. The majority of perpetrators were male. CONCLUSIONS: Our data provide an important first insight into the prevalence of PSM by healthcare professionals towards patients in a representative sample. Results suggest a high prevalence of PSM in the general population of Germany. Preventive measures to increase awareness of PSM and concepts for protection of patients are needed.

Ocean warming affected faunal dynamics of benthic invertebrate assemblages across the Toarcian Oceanic Anoxic Event in the Iberian Basin (Spain).

The Toarcian Oceanic Anoxic Event (TOAE; Early Jurassic, ca. 182 Ma ago) represents one of the major environmental disturbances of the Mesozoic and is associated with global warming, widespread anoxia, and a severe perturbation of the global carbon cycle. Warming-related dysoxia-anoxia has long been considered the main cause of elevated marine extinction rates, although extinctions have been recorded also in environments without evidence for deoxygenation. We addressed the role of warming and disturbance of the carbon cycle in an oxygenated habitat in the Iberian Basin, Spain, by correlating high resolution quantitative faunal occurrences of early Toarcian benthic marine invertebrates with geochemical proxy data (δ18O and δ13C). We find that temperature, as derived from the δ18O record of shells, is significantly correlated with taxonomic and functional diversity and ecological composition, whereas we find no evidence to link carbon cycle variations to the faunal patterns. The local faunal assemblages before and after the TOAE are taxonomically and ecologically distinct. Most ecological change occurred at the onset of the TOAE, synchronous with an increase in water temperatures, and involved declines in multiple diversity metrics, abundance, and biomass. The TOAE interval experienced a complete turnover of brachiopods and a predominance of opportunistic species, which underscores the generality of this pattern recorded elsewhere in the western Tethys Ocean. Ecological instability during the TOAE is indicated by distinct fluctuations in diversity and in the relative abundance of individual modes of life. Local recovery to ecologically stable and diverse post-TOAE faunal assemblages occurred rapidly at the end of the TOAE, synchronous with decreasing water temperatures. Because oxygen-depleted conditions prevailed in many other regions during the TOAE, this study demonstrates that multiple mechanisms can be operating simultaneously with different relative contributions in different parts of the ocean.

The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome.

Creatine provides cells with high-energy phosphates for the rapid reconstitution of hydrolyzed adenosine triphosphate. The eponymous creatine transporter (CRT1/SLC6A8) belongs to a family of solute carrier 6 (SLC6) proteins. The key role of CRT1 is to translocate creatine across tissue barriers and into target cells, such as neurons and myocytes. Individuals harboring mutations in the coding sequence of the human CRT1 gene develop creatine transporter deficiency (CTD), one of the pivotal underlying causes of cerebral creatine deficiency syndrome. CTD encompasses an array of clinical manifestations, including severe intellectual disability, epilepsy, autism, development delay, and motor dysfunction. CTD is characterized by the absence of cerebral creatine, which implies an indispensable role for CRT1 in supplying the brain cells with creatine. CTD-associated variants dramatically reduce or abolish creatine transport activity by CRT1. Many of these are point mutations that are known to trigger folding defects, leading to the retention of encoded CRT1 proteins in the endoplasmic reticulum and precluding their delivery to the cell surface. Misfolding of several related SLC6 transporters also gives rise to detrimental pathologic conditions in people; e.g., mutations in the dopamine transporter induce infantile parkinsonism/dystonia, while mutations in the GABA transporter 1 cause treatment-resistant epilepsy. In some cases, folding defects are amenable to rescue by small molecules, known as pharmacological and chemical chaperones, which restore the cell surface expression and transport activity of the previously non-functional proteins. Insights from the recent molecular, animal and human case studies of CTD add toward our understanding of this complex disorder and reveal the wide-ranging effects elicited upon CRT1 dysfunction. This grants novel therapeutic prospects for the treatment of patients afflicted with CTD, e.g., modifying the creatine molecule to facilitate CRT1-independent entry into brain cells, or correcting folding-deficient and loss-of-function CTD variants using pharmacochaperones and/or allosteric modulators. The latter justifies a search for additional compounds with a capacity to correct mutation-specific defects.

Cold spells in the Nordic Seas during the early Eocene Greenhouse.

The early Eocene (c. 56 - 48 million years ago) experienced some of the highest global temperatures in Earth's history since the Mesozoic, with no polar ice. Reports of contradictory ice-rafted erratics and cold water glendonites in the higher latitudes have been largely dismissed due to ambiguity of the significance of these purported cold-climate indicators. Here we apply clumped isotope paleothermometry to a traditionally qualitative abiotic proxy, glendonite calcite, to generate quantitative temperature estimates for northern mid-latitude bottom waters. Our data show that the glendonites of the Danish Basin formed in waters below 5 °C, at water depths of <300 m. Such near-freezing temperatures have not previously been reconstructed from proxy data for anywhere on the early Eocene Earth, and these data therefore suggest that regionalised cool episodes punctuated the background warmth of the early Eocene, likely linked to eruptive phases of the North Atlantic Igneous Province.

Temperature-related body size change of marine benthic macroinvertebrates across the Early Toarcian Anoxic Event.

The Toarcian Oceanic Anoxic Event (TOAE, Early Jurassic, ~182 Ma ago) was characterised by severe environmental perturbations which led to habitat degradation and extinction of marine species. Warming-induced anoxia is usually identified as main driver, but because marine life was also affected in oxygenated environments the role of raised temperature and its effects on marine life need to be addressed. Body size is a fundamental characteristic of organisms and is expected to decrease as a response to heat stress. We present quantitative size data of bivalves and brachiopods across the TOAE from oxygenated habitats in the Iberian Basin, integrated with geochemical proxy data (δ13C and δ18O), to investigate the relationship between changes in temperature and body size. We find a strong negative correlation between the mean shell size of bivalve communities and isotope-derived temperature estimates, suggesting heat stress as a main cause of body size reduction. While within-species size changes were minor, we identify changes in the abundance of differently sized species as the dominant mechanism of reduced community shell size during the TOAE. Brachiopods experienced a wholesale turnover across the early warming phase and were replaced by a virtually monotypic assemblage of a smaller-sized, opportunistic species.

Orbital pacing and secular evolution of the Early Jurassic carbon cycle.

Global perturbations to the Early Jurassic environment (∼201 to ∼174 Ma), notably during the Triassic-Jurassic transition and Toarcian Oceanic Anoxic Event, are well studied and largely associated with volcanogenic greenhouse gas emissions released by large igneous provinces. The long-term secular evolution, timing, and pacing of changes in the Early Jurassic carbon cycle that provide context for these events are thus far poorly understood due to a lack of continuous high-resolution δ13C data. Here we present a δ13CTOC record for the uppermost Rhaetian (Triassic) to Pliensbachian (Lower Jurassic), derived from a calcareous mudstone succession of the exceptionally expanded Llanbedr (Mochras Farm) borehole, Cardigan Bay Basin, Wales, United Kingdom. Combined with existing δ13CTOC data from the Toarcian, the compilation covers the entire Lower Jurassic. The dataset reproduces large-amplitude δ13CTOC excursions (>3‰) recognized elsewhere, at the Sinemurian-Pliensbachian transition and in the lower Toarcian serpentinum zone, as well as several previously identified medium-amplitude (∼0.5 to 2‰) shifts in the Hettangian to Pliensbachian interval. In addition, multiple hitherto undiscovered isotope shifts of comparable amplitude and stratigraphic extent are recorded, demonstrating that those similar features described earlier from stratigraphically more limited sections are nonunique in a long-term context. These shifts are identified as long-eccentricity (∼405-ky) orbital cycles. Orbital tuning of the δ13CTOC record provides the basis for an astrochronological duration estimate for the Pliensbachian and Sinemurian, giving implications for the duration of the Hettangian Stage. Overall the chemostratigraphy illustrates particular sensitivity of the marine carbon cycle to long-eccentricity orbital forcing.

[Children of mentally ill parents : Also a topic in the context of child protection]. / Kinder psychisch erkrankter Eltern : Auch ein Thema im Rahmen des Kinderschutzes.

BACKGROUND: Severe mental illness in parents increases the risk of neglect, physical and sexual abuse (adverse childhood experiences, ACE) of children. OBJECTIVE: Presentation of the current situation of child protection issues in psychiatric care in Germany and the derivation of needs and potential solution strategies. MATERIAL AND METHODS: Based on a selective literature search, the needs and the current situation in Germany are presented and potential solution strategies are pointed out. The analysis is supplemented by a descriptive evaluation of specific consultation requests to the medical child protection hotline, which were descriptively evaluated and served as a starting point for the selective literature search. RESULTS: Despite the well-known comprehensive influence of mental illnesses of parents on their children, psychiatric patients have not yet been systematically registered regarding whether they have to care for underage children. There is a lack of systematic and comprehensive support for families at risk. Of all calls to the project medical child protection hotline, calls from the field of adult psychiatry and psychosomatics make up by far the highest proportion from the field of adult medicine. CONCLUSION: An increased awareness of child protection issues is necessary in the field of adult psychiatric treatment. Systematic counselling services for acute cases and also networking and structured cooperation with other medical fields, such as child and youth psychiatry, pediatrics and child and youth welfare should be addressed.

Deducing the source and composition of rare earth mineralising fluids in carbonatites: insights from isotopic (C, O, 87Sr/86Sr) data from Kangankunde, Malawi.

Carbonatites host some of the largest and highest grade rare earth element (REE) deposits but the composition and source of their REE-mineralising fluids remains enigmatic. Using C, O and 87Sr/86Sr isotope data together with major and trace element compositions for the REE-rich Kangankunde carbonatite (Malawi), we show that the commonly observed, dark brown, Fe-rich carbonatite that hosts REE minerals in many carbonatites is decoupled from the REE mineral assemblage. REE-rich ferroan dolomite carbonatites, containing 8-15 wt% REE2O3, comprise assemblages of monazite-(Ce), strontianite and baryte forming hexagonal pseudomorphs after probable burbankite. The 87Sr/86Sr values (0.70302-0.70307) affirm a carbonatitic origin for these pseudomorph-forming fluids. Carbon and oxygen isotope ratios of strontianite, representing the REE mineral assemblage, indicate equilibrium between these assemblages and a carbonatite-derived, deuteric fluid between 250 and 400 °C (δ18O + 3 to + 5‰VSMOW and δ13C - 3.5 to - 3.2‰VPDB). In contrast, dolomite in the same samples has similar δ13C values but much higher δ18O, corresponding to increasing degrees of exchange with low-temperature fluids (< 125 °C), causing exsolution of Fe oxides resulting in the dark colour of these rocks. REE-rich quartz rocks, which occur outside of the intrusion, have similar δ18O and 87Sr/86Sr to those of the main complex, indicating both are carbonatite-derived and, locally, REE mineralisation can extend up to 1.5 km away from the intrusion. Early, REE-poor apatite-bearing dolomite carbonatite (beforsite: δ18O + 7.7 to + 10.3‰ and δ13C -5.2 to -6.0‰; 87Sr/86Sr 0.70296-0.70298) is not directly linked with the REE mineralisation.

Fungal decomposition of terrestrial organic matter accelerated Early Jurassic climate warming.

Soils - constituting the largest terrestrial carbon pool - are vulnerable to climatic warming. Currently existing uncertainties regarding carbon fluxes within terrestrial systems can be addressed by studies of past carbon cycle dynamics and related climate change recorded in sedimentary successions. Here we show an example from the Early Jurassic (early Toarcian, c. 183 mya) marginal-marine strata from Poland, tracking the hinterland response to climatic changes through a super-greenhouse event. In contrast to anoxia-related enhanced carbon storage in coeval open marine environments, Total Organic Carbon (TOC) concentrations in the Polish successions are substantially reduced during this event. Increasing temperature favoured fungal-mediated decomposition of plant litter - specifically of normally resistant woody tissues. The associated injection of oxidized organic matter into the atmosphere corresponds to abrupt changes in standing vegetation and may have contributed significantly to the amplified greenhouse climate on Earth. The characteristic Toarcian signature of multiple warm pulses coinciding with rapidly decreasing carbon isotope ratios may in part be the result of a radical reduction of the terrestrial carbon pool as a response to climate change.

Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse.

The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in δ(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE.

Jurassic climate mode governed by ocean gateway.

The Jurassic (∼201-145 Myr ago) was long considered a warm 'greenhouse' period; more recently cool, even 'icehouse' episodes have been postulated. However, the mechanisms governing transition between so-called Warm Modes and Cool Modes are poorly known. Here we present a new large high-quality oxygen-isotope dataset from an interval that includes previously suggested mode transitions. Our results show an especially abrupt earliest Middle Jurassic (∼174 Ma) mid-latitude cooling of seawater by as much as 10 °C in the north-south Laurasian Seaway, a marine passage that connected the equatorial Tethys Ocean to the Boreal Sea. Coincidence in timing with large-scale regional lithospheric updoming of the North Sea region is striking, and we hypothesize that northward oceanic heat transport was impeded by uplift, triggering Cool Mode conditions more widely. This extreme climate-mode transition provides a counter-example to other Mesozoic transitions linked to quantitative change in atmospheric greenhouse gas content.

Coral-based climate records from tropical South Atlantic: 2009/2010 ENSO event in C and O isotopes from Porites corals (Rocas Atoll, Brazil).

Coral skeletons contain records of past environmental conditions due to their long life span and well calibrated geochemical signatures. C and O isotope records of corals are especially interesting, because they can highlight multidecadal variability of local climate conditions beyond the instrumental record, with high fidelity and sub-annual resolution. Although, in order to get an optimal geochemical signal in coral skeleton, sampling strategies must be followed. Here we report one of the first coral-based isotopic record from the Equatorial South Atlantic from two colonies of Porites astreoides from the Rocas Atoll (offshore Brazil), a new location for climate reconstruction. We present time series of isotopic variation from profiles along the corallite valley of one colony and the apex of the corallite fan of the other colony. Significant differences in the isotopic values between the two colonies are observed, yet both record the 2009/2010 El Niño event - a period of widespread coral bleaching - as anomalously negative δ18O values (up to -1 permil). δ13C is found to be measurably affected by the El Niño event in one colony, by more positive values (+0.39 ‰), and together with a bloom of endolithic algae, may indicate physiological alteration of this colony. Our findings indicate that corals from the Rocas Atoll can be used for monitoring climate oscillations in the tropical South Atlantic Ocean.

Threat of hepatitis E virus infection in Somalia during Operation Restore Hope.

In support of Operation Restore Hope, the United States military established a diagnostic laboratory for infectious diseases, the Joint Forward Laboratory, in Mogadishu, Somalia. Because sporadic hepatitis due to unknown causes was a frequent problem, staff members of the Joint Forward Laboratory evaluated 31 Somalis, five displaced Ethiopians, and three Western relief workers who had acute clinical hepatitis. Patients lived in multiple locations in Somalia--Mogadishu, Baidoa, and Merca--and became ill between December 1992 and February 1993. IgM antibody to hepatitis A virus was found in one English relief worker, and IgM antibody to hepatitis E virus was found in 20 (65%) of 31 Somalis, two (40%) of five Ethiopians, and two (67%) of three Western relief workers. No patient had evidence of acute hepatitis B, malaria, yellow fever, or other arbovirus infections. These data indicate that hepatitis E virus--the major cause of enterically transmitted non-A, non-B hepatitis--was a common cause of acute sporadic hepatitis in Somalia during the initial stages of Operation Restore Hope.