Blooming and pruning: learning from mistakes with memristive synapses.

Blooming and pruning is one of the most important developmental mechanisms of the biological brain in the first years of life, enabling it to adapt its network structure to the demands of the environment. The mechanism is thought to be fundamental for the development of cognitive skills. Inspired by this, Chialvo and Bak proposed in 1999 a learning scheme that learns from mistakes by eliminating from the initial surplus of synaptic connections those that lead to an undesirable outcome. Here, this idea is implemented in a neuromorphic circuit scheme using CMOS integrated HfO2-based memristive devices. The implemented two-layer neural network learns in a self-organized manner without positive reinforcement and exploits the inherent variability of the memristive devices. This approach provides hardware, local, and energy-efficient learning. A combined experimental and simulation-based parameter study is presented to find the relevant system and device parameters leading to a compact and robust memristive neuromorphic circuit that can handle association tasks.

Vector Symbolic Finite State Machines in Attractor Neural Networks.

Hopfield attractor networks are robust distributed models of human memory, but they lack a general mechanism for effecting state-dependent attractor transitions in response to input. We propose construction rules such that an attractor network may implement an arbitrary finite state machine (FSM), where states and stimuli are represented by high-dimensional random vectors and all state transitions are enacted by the attractor network's dynamics. Numerical simulations show the capacity of the model, in terms of the maximum size of implementable FSM, to be linear in the size of the attractor network for dense bipolar state vectors and approximately quadratic for sparse binary state vectors. We show that the model is robust to imprecise and noisy weights, and so a prime candidate for implementation with high-density but unreliable devices. By endowing attractor networks with the ability to emulate arbitrary FSMs, we propose a plausible path by which FSMs could exist as a distributed computational primitive in biological neural networks.

Robust land surface temperature record for north China over the past 21,000 years.

Numerous proxy reconstructions have provided general insight into late Quaternary East Asian Monsoon variability. However, challenges persist in precisely assessing absolute temperature impacts on proxy variations. Here, we use two independent paleothermometers, based on bacterial membrane lipids and clumped isotopes of snail shells, in the same section of the western Chinese Loess Plateau to establish a robust land surface temperature record spanning the past approximately 21,000 years. Our independent temperature records consistently reveal (i) similar land surface temperatures between the Last Glacial Maximum and late Holocene and (ii) a gradual cooling Holocene, which contrasts with the climate model predictions. We propose that changes in soil moisture availability over the deglaciation modulates the land surface temperature recorded by the proxies. A land surface energy partitioning model confirms this mechanism, suggesting that effects of soil moisture availability should be properly considered when comparing proxy records with climate model outputs.

Changes in gut microbiota and lactose intolerance symptoms before and after daily lactose supplementation in individuals with the lactase nonpersistent genotype.

BACKGROUND: Approximately 70%-100% of the Asian adult population is lactase nonpersistent (LNP). The literature shows that many individuals with the LNP-genotype can consume ≤12 g of lactose without experiencing gastrointestinal discomfort. Repetitive consumption of lactose may reduce intolerance symptoms via adaptation of the gut microbiota. OBJECTIVE: This study aimed to assess the effects of daily consumption of incremental lactose doses on microbiota composition and function, and intolerance symptoms. METHODS: Twenty-five healthy adults of Asian origin, carrying the LNP-genotype were included in this 12-wk before and after intervention trial. Participants consumed gradually increasing lactose doses from 3 to 6 g to 12 g twice daily, each daily dose of 6 g, 12 g, or 24 g being provided for 4 consecutive weeks. Participants handed-in repeated stool samples and underwent a 25 g lactose challenge hydrogen breath test (HBT) before and after the 12-wk intervention. Daily gastrointestinal symptoms and total symptom scores (TSSs) during the lactose challenge were recorded. RESULTS: A significant increase from 5.5% ± 7.6% to 10.4% ± 9.6% was observed in Bifidobacterium relative abundance after the intervention (P = 0.009), accompanied by a 2-fold increase (570 ± 269 U/g; P < 0.001) in fecal ß-galactosidase activity compared with baseline (272 ± 158 U/g). A 1.5-fold decrease (incremental area under the curve; P = 0.01) in expired hydrogen was observed during the second HBT (38 ± 35 ppm·min), compared with the baseline HBT (57 ± 38 ppm·min). There was a nonsignificant decrease in TSS (10.6 ± 8.3 before compared with 8.1 ± 7.2 after intervention; P = 0.09). Daily consumption of lactose was well tolerated, with mild to no gastrointestinal complaints reported during the intervention. CONCLUSIONS: Increased levels of Bifidobacterium indicate an adaptation of the gut microbiota upon repetitive consumption of incremental doses of lactose, which was well tolerated as demonstrated by reduced expired hydrogen concentrations during the second 25-g lactose HBT. Bifidobacteria metabolize lactose without gas production thereby potentially reducing intestinal gas formation in the gut of individuals with the LNP-genotype. This increased lactose tolerance possibly lifts the necessity to remove nutrient-rich dairy foods completely from the diet. The trial is registered at the International Clinical Trials Registry Platform: NL9516. The effect of dietary lactose in lactase nonpersistent individuals on gut microbiota.

Morphological changes of macular neovascularization during long-term anti-VEGF-therapy in neovascular age-related macular degeneration.

PURPOSE: To analyze the morphological changes of macular neovascularization (MNV) in exudative neovascular age-related macular degeneration under long-term intravitreal anti-vascular endothelial growth factor (VEGF) therapy in a retrospective cohort study. METHODS AND PATIENTS: We evaluated 143 nAMD eyes of 94 patients (31 male, 63 female; initial age 55-97 y, mean age 75.9 ± 7.5 y), who started anti-VEGF therapy (IVAN pro re nata (PRN) protocol) between 2009-2018 and received ongoing therapy until the last recorded visit (mean follow-up 5.3 ± 2.9 y, range 1-14 y). The mean total number of injections was 33.3 ± 19.8 with 7.0 ± 2.3 injections/year. MNV size and, if present, associated complete retinal pigment epithelium (RPE) and outer retina atrophy (cRORA) size were measured on optical coherence tomography (OCT) volume scans at the initial visit and for each year of follow-up. MNV and cRORA were identified on B-scans and their respective borders were manually transposed onto the en-face near infrared image and measured in mm2. RESULTS: MNV enlarged through follow-up, with a mean growth rate of 1.24 mm2 / year. The mean growth in MNV size was independent of initial MNV size, age, gender, MNV subtypes or number of injections per year. Nevertheless, a great interindividual variation in size and growth was observed. cRORA developed in association with increasing MNV size and its incidence increased linearly over follow-up. cRORA lesions also showed continuous growth by a rate of 1.22 mm2 / year. CONCLUSIONS: Despite frequent long-term anti-VEGF therapy, we observed ongoing MNV growth. This is consistent with the concept that the development of MNV may be a physiological biological repair mechanism to preserve RPE and photoreceptor function, provided hyperpermeability and fluid exudation are controlled. Whether recurring low VEGF levels or other factors are responsible for MNV growth remains controversial.

Reconciling Southern Ocean fronts equatorward migration with minor Antarctic ice volume change during Miocene cooling.

Gradual climate cooling and CO2 decline in the Miocene were recently shown not to be associated with major ice volume expansion, challenging a fundamental paradigm in the functioning of the Antarctic cryosphere. Here, we explore Miocene ice-ocean-climate interactions by presenting a multi-proxy reconstruction of subtropical front migration, bottom water temperature and global ice volume change, using dinoflagellate cyst biogeography, benthic foraminiferal clumped isotopes from offshore Tasmania. We report an equatorward frontal migration and strengthening, concurrent with surface and deep ocean cooling but absence of ice volume change in the mid-late-Miocene. To reconcile these counterintuitive findings, we argue based on new ice sheet modelling that the Antarctic ice sheet progressively lowered in height while expanding seawards, to maintain a stable volume. This can be achieved with rigorous intervention in model precipitation regimes on Antarctica and ice-induced ocean cooling and requires rethinking the interactions between ice, ocean and climate.

Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy.

The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.

Assessing the effects of embedding resins on carbonate stable and clumped isotope analyses.

RATIONALE: Embedding resins are widely used to fix carbonates for high-precision sample preparation and high-resolution sampling. However, these embedding materials are difficult to remove after sample preparation and are known to affect the accuracy of carbonate stable isotope analyses. Nevertheless, their impact on clumped isotope analysis, which is particularly sensitive to contamination artifacts, has so far not been tested. The observation that running resin-containing samples decreased the reproducibility of clumped isotope values for internal laboratory carbonate standards and increased the external standard deviation (SD 0.061-0.088‰) compared to the long-term observations (0.034‰), prompted us to set up an experiment to test the influence of resin addition on instrument performance. METHODS: Here we analyzed the stable and clumped isotope composition of a pure calcium carbonate standard (ETH-4) mixed with three types of embedding resins in 2:1 and 1:1 proportions. Our aim was to assess how resin addition affects isotope analyses. RESULTS: We found that none of the stable isotopic values were significantly different. The δ13 C values were -10.22 ± 0.07‰ (mean ± SD) for pure ETH-4, while the δ13 C values of ETH-4 mixed with embedding resins in 2:1 and 1:1 proportions were -10.21 ± 0.06‰ and -10.18 ± 0.06‰, respectively (p > 0.05). The δ18 O values were -18.82 ± 0.11‰ for pure ETH-4 versus -18.81 ± 0.09‰ and -18.82 ± 0.08‰ for 2:1 and 1:1 ETH-4:resin mixtures, respectively (p > 0.05). Given the large uncertainty in our results, we did not find significant differences between different mixtures in the carbonate clumped isotope values (Δ47 ), with 0.458 ± 0.107‰, 0.464 ± 0.086‰, and 0.417 ± 0.089‰ in pure ETH-4 and ETH-4 with 2:1 and 1:1 resin mixtures, respectively (p > 0.05). However, a resin-related bias in the results might be masked by the large uncertainty. The measured ETH-4 values in our study are similar to the InterCarb values (δ13 C = -10.20‰, δ18 O = -18.81‰, Δ47  = 0.450‰, InterCarb-Carbon Dioxide Equilibrium Scale). However, the external SD of Δ47 in sessions measuring ETH-4 with resins is higher than in sessions without deliberate resin addition for the same measuring period. CONCLUSIONS: We find that the potential contamination from the resin addition leads to a larger variability for Δ47 values in sessions measuring ETH-4 including resins. We therefore recommend purification of embedded samples using a contamination trap with Porapak prior to analysis, if possible, or avoiding resins during sample preparation and workup, as well as monitoring the measurement quality during and after sessions with samples containing embedding resins.

North Atlantic surface ocean warming and salinization in response to middle Eocene greenhouse warming.

Quantitative reconstructions of hydrological change during ancient greenhouse warming events provide valuable insight into warmer-than-modern hydrological cycles but are limited by paleoclimate proxy uncertainties. We present sea surface temperature (SST) records and seawater oxygen isotope (δ18Osw) estimates for the Middle Eocene Climatic Optimum (MECO), using coupled carbonate clumped isotope (Δ47) and oxygen isotope (δ18Oc) data of well-preserved planktonic foraminifera from the North Atlantic Newfoundland Drifts. These indicate a transient ~3°C warming across the MECO, with absolute temperatures generally in accordance with trace element (Mg/Ca)-based SSTs but lower than biomarker-based SSTs for the same interval. We find a transient ~0.5‰ shift toward higher δ18Osw, which implies increased salinity in the North Atlantic subtropical gyre and potentially a poleward expansion of its northern boundary in response to greenhouse warming. These observations provide constraints on dynamic ocean response to warming events, which are consistent with theory and model simulations predicting an enhanced hydrological cycle under global warming.

The Architecture of Macular Neovascularizations Predicts Treatment Responses to Anti-VEGF Therapy in Neovascular AMD.

Introduction: Anti-VEGF therapy is an effective option for improving and stabilizing the vision in neovascular age-related macular degeneration (nAMD). However, the response to treatment is markedly heterogeneous. The aim of this study was therefore to analyze the vascular characteristics of type 1,2, and 3 macular neovascularizations (MNV) in order to identify biomarkers that predict treatment response, especially with regard to changes in intraretinal and subretinal fluid. Materials and Methods: Overall, 90 treatment-naive eyes with nAMD confirmed by optic coherence tomography (OCT), fluorescein angiography, and OCT angiography (OCTA) were included in this retrospective study. The MNV detected by OCTA were subjected to quantitative vascular analysis by binarization and skeletonization of the vessel using ImageJ. We determined their area, total vascular length (sumL), fractal dimension (FD), flow density, number of vascular nodes (numN), and average vascular diameter (avgW). The results were correlated with the treatment response to the initial three injections of anti-VEGF and the changes in intraretinal (IRF) and subretinal fluid (SRF) and the occurrence of pigment epithelial detachements (PED). Results: All patients found to have no subretinal or intraretinal fluid following the initial three injections of anti-VEGF showed a significantly smaller MNV area (p < 0.001), a lower sumL (p < 0.0005), and lesser FD (p < 0.005) before treatment than those who still exhibited signs of activity. These parameters also showed a significant influence in the separate analysis of persistent SRF (p < 0.005) and a persistent PED (p < 0.05), whereas we could not detect any influence on changes in IRF. The vascular parameters avgW, numN, and flow density showed no significant influence on SRF/IRF or PED changes. Conclusions: The size, the total vessel length, and the fractal dimension of MNV at baseline are predictors for the treatment response to anti-VEGF therapy. Therefore, particularly regarding the development of new classes of drugs, these parameters could yield new insights into treatment response.

Multilayer redox-based HfOx/Al2O3/TiO2 memristive structures for neuromorphic computing.

Redox-based memristive devices have shown great potential for application in neuromorphic computing systems. However, the demands on the device characteristics depend on the implemented computational scheme and unifying the desired properties in one stable device is still challenging. Understanding how and to what extend the device characteristics can be tuned and stabilized is crucial for developing application specific designs. Here, we present memristive devices with a functional trilayer of HfOx/Al2O3/TiO2 tailored by the stoichiometry of HfOx (x = 1.8, 2) and the operating conditions. The device properties are experimentally analyzed, and a physics-based device model is developed to provide a microscopic interpretation and explain the role of the Al2O3 layer for a stable performance. Our results demonstrate that the resistive switching mechanism can be tuned from area type to filament type in the same device, which is well explained by the model: the Al2O3 layer stabilizes the area-type switching mechanism by controlling the formation of oxygen vacancies at the Al2O3/HfOx interface with an estimated formation energy of ≈ 1.65 ± 0.05 eV. Such stabilized area-type devices combine multi-level analog switching, linear resistance change, and long retention times (≈ 107-108 s) without external current compliance and initial electroforming cycles. This combination is a significant improvement compared to previous bilayer devices and makes the devices potentially interesting for future integration into memristive circuits for neuromorphic applications.

Limited Lateral Transport Bias During Export of Sea Surface Temperature Proxy Carriers in the Mediterranean Sea.

Some lipid-biomarker-based sea surface temperature (SST) proxies applied in the modern Mediterranean Sea exhibit large offsets from expected values, generating uncertainties in climate reconstructions. Lateral transport of proxy carriers along ocean currents prior to burial can contribute to this offset between reconstructed and expected SSTs. We perform virtual particle tracking experiments to simulate transport prior to and during sinking and derive a quantitative estimate of transport bias for alkenones and glycerol dibiphytanyl glycerol tetraethers (GDGTs), which form the basis of the UK' 37 and TEX86 paleothermometers, respectively. We use a simple 30-day surface advection scenario and sinking speeds appropriate for the export of various proxy carriers (6, 12, 25, 50, 100, 250, 500, and 1000 md-1). For the assessed scenarios, lateral transport bias is generally small (always <0.85°C) within the Mediterranean Sea and does not substantially contribute to uncertainties in UK' 37- or TEX86-based SSTs.

Artificial neural network performance based on correlation analysis qualitatively comparable with human performance in behavioral signal detection experiments.

Standard Gaussian signal detection theory (SDT) is a widely used approach to assess the detection performance of living organisms or technical systems without looking at the inner workings of these systems like neural or electronic mechanisms. Nevertheless, a consideration of the inner mechanisms of a system and how they produce observed behaviors should help to better understand the functioning. It might even offer the possibility to demonstrate isolated pattern separation processes directly in the model. To do so, modeling the interaction between the entorhinal cortex (EC) and the hippocampal subnetwork dentate gyrus (DG) via the perforant path reveals the decorrelation network's mode of operation. We show that the ability to do pattern separation is crucial for high-performance pattern recognition, but also for lure discrimination, and depends on the proportionality between input and output network. NEW & NOTEWORTHY We elucidate the interplay of the entorhinal cortex and the hippocampal dentate gyrus during pattern separation tasks by providing a new simulation model. Functional memory formation and processing of similar memory content is illuminated from within the system. For the first time orthogonalized spiking patterns are evaluated with signal detection theory methods, and the results are applied to clinically established and novel tests.

Vascular Analysis of Type 1, 2, and 3 Macular Neovascularization in Age-Related Macular Degeneration Using Swept-Source Optical Coherence Tomography Angiography Shows New Insights into Differences of Pathologic Vasculature and May Lead to a More Personalized Understanding.

Background: The clinical appearance of macular neovascularization (MNV) in age-related macular degeneration (nAMD) varies widely, but so far, this has had no relevance in terms of therapeutic approaches or prognosis. Therefore, our purpose was to investigate if and which differences exist in the vascular architecture of MNV and to quantify them. Methods: In 90 patients with newly diagnosed nAMD, MNV was identified by means of optical coherence tomography angiography (OCTA), and automated quantitative vascular analysis was carried out. The analyzed vascular parameters were area, flow, fractal dimension (FD), total vascular length (sumL), number of vascular nodes (numN), flow, and average vessel caliber (avgW). The current classification of MNVs divides them according to their localization into type 1 (grown from the choroid below the RPE), type 2 (grown from the choroid through RPE), and type 3 (grown from the retina toward the RPE). We compared the analyzed vascular parameters of each of the three MNV types. Kruskal−Wallis test was applied, Dunn test was performed for post hoc analysis, and for pairwise comparison, p-values were adjusted using Bonferroni comparison. Results: Regarding the MNV area, there was no significant difference between types 1 and 2, but type 3 was significantly smaller than types 1 and 2 (p < 0.00001). For FD, types 1 and 2 did not differ significantly, but again, type 3 was lower than type 1 and 2 (p < 0.00001). The numN were significantly higher in types 1 and 3 than in 2 (p < 0.005), but not between types 1 and 3. No significant differences were found between MNV types for flow. As for sumL, types 1 and 2 did not differ significantly, but type 3 was significantly lower than types 1 and 2 (p < 0.00001). For avgW, there was no significant difference between types 1 and 2 or between types 2 and 3, but type 3 was significantly larger than type 1 (p < 0.05). Conclusions OCTA yields detailed information on the vascular morphology of MNV in patients with nAMD and is able to show differences among types 1, 2, and 3. Especially comparing types 1 and 2 with type 3 reveals significant differences in area, FD, sumL, and numN. One explanation could be the similar pathogenesis of types 1 and 2 with their origin in the choroid and their growth towards the retinal pigment epithelium (RPE), whereas type 3 originates in the deep capillary plexus. Between types 1 and 2, however, only the numN differ significantly, which could be due to the fact that type 1 spreads horizontally below the RPE and, thus, display more vascular branching, while type 2 grows more vertically through the RPE and under the neurosensory retina. Detailed information about the pathologic vasculature is important for proper monitoring of the disease and to assess the efficacy of medication, especially with regard to new substances. This should be taken into consideration in future studies.

CRISPRi enables fast growth followed by stable aerobic pyruvate formation in Escherichia coli without auxotrophy.

CRISPR interference (CRISPRi) was applied to enable the aerobic production of pyruvate in Escherichia coli MG1655 under glucose excess conditions by targeting the promoter regions of aceE or pdhR. Knockdown strains were cultivated in aerobic shaking flasks and the influence of inducer concentration and different sgRNA binding sites on the production of pyruvate was measured. Targeting the promoter regions of aceE or pdhR triggered pyruvate production during the exponential phase and reduced expression of aceE. In lab-scale bioreactor fermentations, an aceE silenced strain successfully produced pyruvate under fully aerobic conditions during the exponential phase, but loss of productivity occurred during a subsequent nitrogen-limited phase. Targeting the promoter region of pdhR enabled pyruvate production during the growth phase of cultivations, and a continued low-level accumulation during the nitrogen-limited production phase. Combinatorial targeting of the promoter regions of both aceE and pdhR in E. coli MG1655 pdCas9 psgRNA_aceE_234_pdhR_329 resulted in the stable aerobic production of pyruvate with non-growing cells at YP/S  =  0.36 ± 0.029 gPyruvate/gGlucose in lab-scale bioreactors throughout an extended nitrogen-limited production phase.

Energetics of Floor Gymnastics: Aerobic and Anaerobic Share in Male and Female Sub-elite Gymnasts.

BACKGROUND: Artistic gymnastics is a popular Olympic discipline where female athletes compete in four and male athletes in six events with floor exercise having the longest competition duration in Women's and Men's artistic gymnastics (WAG, MAG). To date no valid information on the energetics of floor gymnastics is available although this may be important for specific conditioning programming. This study evaluated the metabolic profile of a simulated floor competition in sub-elite gymnasts. METHODS: 17 (9 male, 8 female) sub-elite gymnasts aged 22.5 ± 2.6y took part in a floor-training-competition where oxygen uptake was measured during and until 15 min post-exercise. Additionally, resting and peak blood lactate concentration after exercise were obtained. The PCr-LA-O2 method was used to calculate the metabolic energy and the relative aerobic (WAER), anaerobic alactic (WPCr) and anaerobic lactic (WBLC) energy contribution. Further, the athletes completed a 30 s Bosco-jumping test, a countermovement jump and a drop jump. RESULTS: The competition scores were 9.2 (CI:8.9-9.3) in WAG and 10.6 (CI:10.4-10.9) in MAG. The metabolic profile of the floor routine was mainly aerobic (58.9%, CI: 56.0-61.8%) followed by the anaerobic alactic (24.2%, CI: 21.3-27.1%) and anaerobic lactic shares (16.9%, CI:14.9-18.8%). While sex had a significant (p = .010, d = 1.207) large effect on energy contribution, this was not the case for competition duration (p = .728, d = 0.061). Relative energy contribution of WAG and MAG differed in WAER (64.0 ± 4.7% vs. 54.4 ± 6.8%, p = .004, d = 1.739) but not in WPCr (21.3 ± 6.1% vs. 26.7 ± 8.0%, p = .144, d = 0.801) and WBLC (14.7 ± 5.4% vs. 18.9 ± 4.2%, p = .085, d = 0.954). Further no correlation between any energy share and performance was found but between WPCr and training experience (r = .680, p = .044) and WBLC and competition level (r = .668, p = .049). CONCLUSION: The results show a predominant aerobic energy contribution and a considerable anaerobic contribution with no significant difference between anaerobic shares. Consequently, gymnastic specific aerobic training should not be neglected, while a different aerobic share in WAG and MAG strengthens sex-specific conditioning. All in all, the specific metabolic share must secure adequate energy provision, while relative proportions of the two anaerobic pathways seem to depend on training and competition history.

Correlation of retinal alterations with vascular structure of macular neovascularisation in swept-source optical coherence tomography angiography in age-related macular degeneration.

PURPOSE: The aim of this study was to find out whether the vascular architecture of untreated macular neovascularisations (MNV) in neovascular age-related macular degeneration (nAMD) as visualised with optic coherence tomography angiography (OCTA) is associated with functional and known morphological alterations of the retina in optic coherence tomography (SD-OCT). METHODS: The study design was retrospective with consecutive patient inclusion. In 107 patients with newly diagnosed nAMD, MNV were detected by means of OCTA and automated quantitative vascular analysis was performed. The MNV characteristics measured were area, flow density, total vascular length (sumL), density of vascular nodes (numN), fractal dimension (FD) and average vascular width (avgW). These parameters were assessed for associations with vision (BCVA), central retinal thickness (CRT), fluid distribution, the elevation of any pigment epithelial detachment (PED), the occurrence of subretinal haemorrhage and atrophy. RESULTS: BCVA was significantly worse with greater MNV area and sumL. Fluid distribution differed significantly in relation to area (p < 0.005), sumL (p < 0.005) and FD (p = 0.001). Greater PED height was significantly associated with higher numN (p < 0.05) and lower avgW (p < 0.05). Atrophy was present significantly more often in MNV with larger area (p < 0.05), higher sumL (p < 0.05) and higher flow density (p = 0.002). None of the MNV parameters had a significant association with CRT or the occurrence of haemorrhage. CONCLUSION: OCTA is not restricted to evaluation of secondary changes but offers the opportunity to analyse the vascular structure of MNV in detail. Differences in vascular morphology are associated with certain secondary changes in retinal morphology. There are thus grounds for optimism that further research may identify and classify OCTA-based markers to permit more individualised treatment of nAMD.

Temperature Dependence of Clumped Isotopes (∆47) in Aragonite.

Clumped isotope thermometry can independently constrain the formation temperatures of carbonates, but a lack of precisely temperature-controlled calibration samples limits its application on aragonites. To address this issue, we present clumped isotope compositions of aragonitic bivalve shells grown under highly controlled temperatures (1-18°C), which we combine with clumped isotope data from natural and synthetic aragonites from a wide range of temperatures (1-850°C). We observe no discernible offset in clumped isotope values between aragonitic foraminifera, mollusks, and abiogenic aragonites or between aragonites and calcites, eliminating the need for a mineral-specific calibration or acid fractionation factor. However, due to non-linear behavior of the clumped isotope thermometer, including high-temperature (>100°C) datapoints in linear clumped isotope calibrations causes them to underestimate temperatures of cold (1-18°C) carbonates by 2.7 ± 2.0°C (95% confidence level). Therefore, clumped isotope-based paleoclimate reconstructions should be calibrated using samples with well constrained formation temperatures close to those of the samples.