Moderate Changes Research Articles

Effect of potentiated cryopreserved mesenchymal stem cells in intervertebral disc repair

The aim of the study was to investigate the effect of cryopreserved mesenchymal stem cells (CrMSCs) from different tissue (bone marrow, adipose tissue, cartilage) potentiated with some growth and differentiation factors (TGFβ and bFGF) on intervertebral disc (IVD) cartilage repair using compression model of degenerative damage. In the group with self-healing histological changes in IVD cartilage tissue were pronounced. Administration of untreated CrMSCs (regardless of their origin) regenerated IVD structure up to a moderate degree on the 45th day. After therapy with TGFβ-potentiated cells, the histological structure of the disc remained similar to untreated CrMSC influence, which according to the integrated semi-quantitative scale corresponded to moderate degenerative changes. Whereas, the administration of bFGF-potentiated cells contributed to the restoration of the disc structure up to a mild degree of histological damages. In the latter case, there was an increase in cellularity of the fibrous ring, regeneration of cracks and gaps, and restoration of collagen febrile structure in annulus fibrosus on the 45th day after therapy. At the same time, the average cell density of fibrous rings increased by 1.35, 1.50, and 1.39 times and IVD height grew by 1.33, 1.36, and 1.37 times for bone marrow-, adipose- and cartilage-derived CrMSC of potentiated by bFGF respectively compared to untreated analog. Thus, administration of CrMSCs from all studied sources activates regenerative processes in degenerated intervertebral discs of rats, the rate of which increases using of bFGF-potentiated cells.

Climate change and health in Kuwait: temperature and mortality projections under different climatic scenarios

It is uncertain what climate change could bring to populations and countries in the hot desert environment of the Arabian Peninsula. Not only because they are already hot, countries in this region also have unique demographic profiles, with migrant populations potentially more vulnerable and constituting a large share of the population. In Kuwait, two-thirds of the population are migrant workers and record-high temperatures are already common. We quantified the temperature-related mortality burdens in Kuwait in the mid- (2050–2059) and end-century (2090–2099) decades under moderate (SSP2-4.5) and extreme (SSP5-8.5) climate change scenarios. We fitted time series distributed lag non-linear models to estimate the baseline temperature–mortality relationship which was then applied to future daily mean temperatures from the latest available climate models to estimate decadal temperature-mortality burdens under the two scenarios. By mid-century, the average temperature in Kuwait is predicted to increase by 1.80 °C (SSP2-4.5) to 2.57 °C (SSP5-8.5), compared to a 2000–2009 baseline. By the end of the century, we could see an increase of up to 5.54 °C. In a moderate scenario, climate change would increase heat-related mortality by 5.1% (95% empirical confidence intervals: 0.8, 9.3) by end-century, whereas an extreme scenario increases heat-related mortality by 11.7% (2.7, 19.0). Heat-related mortality for non-Kuwaiti migrant workers could increase by 15.1% (4.6, 22.8). For every 100 deaths in Kuwait, 13.6 (−3.6, 25.8) could be attributed to heat driven by climate change by the end of the century. Climate change induced warming, even under more optimistic mitigation scenarios, may markedly increase heat-related mortality in Kuwait. Those who are already vulnerable, like migrant workers, could borne a larger impact from climate change.

Metabolomics profile of 5649 users and nonusers of hormonal intrauterine devices in Finland

Use of hormonal intrauterine devices has grown during the last decades. Although hormonal intrauterine devices act mostly via local effects on the uterus, measurable concentrations of levonorgestrel are absorbed into the systemic circulation. The possible metabolic changes and large-scale biomarker profiles associated with hormonal intrauterine devices have not yet been studied in detail. To examine through the metabolomics approach the metabolic profile of patients using hormonal intrauterine devices and how this metabolic profile is affected by duration and discontinuation of use. The study consisted of cross-sectional analyses of 5 population-based surveys (FINRISK and FinHealth studies), spanning from 1997 to 2017. All fertile-aged participants (18-49 years) in the surveys with available information on hormonal contraceptive use and metabolomics data (n=5649) were included in the study. Altogether, 211 metabolic measures of users of hormonal intrauterine devices (n=1006) were compared with those of nonusers of hormonal contraception (n=4643) via multivariable linear regression models. To allow comparison across multiple measures, association magnitudes were reported in standard deviation units of difference in biomarker concentration compared with the reference group. After adjustment for covariates, levels of 141 metabolites differed in current users of hormonal intrauterine devices compared with nonusers of hormonal contraception (median difference in biomarker concentration, 0.09 standard deviation): lower levels of particle concentration of larger lipoprotein subclasses, triglycerides, cholesterol and derivatives, apolipoproteins A and B, fatty acids, glycoprotein acetyls, and aromatic amino acids. The metabolic pattern of hormonal intrauterine device use did not change according to duration of use. When comparing previous users and never-users of hormonal intrauterine devices, no significant metabolic differences were observed. The use of hormonal intrauterine devices was associated with several moderate metabolic changes previously associated with reduced arterial cardiometabolic risk. The metabolic effects were independent of duration of use of the hormonal intrauterine devices. Moreover, the metabolic profiles were similar after discontinuation of hormonal intrauterine device use and in never-users.

Optimization of rooftop photovoltaic installations to maximize revenue in Finland based on customer class load profiles and simulated generation

The profitability of a rooftop solar photovoltaic (PV) system depends on several factors, such as the retail price of electricity, the load profile of the building, and orientation of the solar PV modules. If there are consumption peaks in the morning, evening, or both, the solar PV modules can be oriented eastward, westward, or east–west, respectively, in order to increase self-consumption. However, the market price of electricity varies, which makes it challenging to evaluate the revenue of a solar PV system in advance.In this study, solar PV module orientation is considered based on profitability. The study uses hourly data of 13 different statistical customer class load profiles, historical electricity market price data for the years 2016–2020, and simulated solar PV yield from southern Finland. A comparison is made between single-azimuth and dual-azimuth systems, the latter of which having the orientation of half of the modules mirrored respective to the north–south axis.A single-azimuth system is usually more profitable when compensation is paid for surplus electricity. The optimal orientations are at azimuth angles of −15°–5° and at tilt angles of 35°–45° with both fixed and dynamic electricity purchase prices. However, if no compensation is paid for surplus electricity, it is usually more profitable to minimize the electricity purchase by orienting the solar PV modules in two azimuths between east and west with tilt angles of 10°–55° depending on the capacity of the solar PV system and the load profile. The revenue is not very sensitive to moderate changes in orientation.

Malabsorption syndrome aggravates calcium homeostasis impairment in chronic kidney disease patients

Abstract. Recent data on the role of digestive pathology in the progression of chronic kidney disease (CKD) remain scarce. Calcium homeostasis plays an important role in the progression of renal pathology, especially in patients with malabsorption syndrome (MAS).
 The research aimed to evaluate calcium homeostasis in CKD patients with MAS.
 Methods. In this cross-sectional observational study, 99 CKD patients with MAS were enrolled. The patients were divided into 4 groups according to the CKD stage and the presence of MAS. Group I included 25 patients with CKD stages 1 and 2 without MAS; Group II consisted of 26 patients with CKD stages 1 and 2, and MAS; Group ІІІ (n = 23) and Group ІV (n = 25) included patients with CKD stage 3 without and with MAS, respectively. According to the morphological study of in vivo biopsies of the small intestinal mucosa, mild and moderate morphological changes were observed among all patients. The levels of calcium, phosphorus, parathyroid hormone, osteocalcin, and calcitonin in the blood, as well as urinary calcium levels, were detected.
 Results. Pathological changes in calcium metabolism were observed among CKD patients with MAS. The severity of calcium homeostasis disorders was more evident among patients with CKD stage 3 compared with stages 1 and 2. Urinary calcium levels were reduced in the patients of Groups III and IV. No changes were detected in phosphorus levels. Changes in parathyroid hormone and osteocalcin are caused primarily by combined renal pathology with impaired renal calcium absorption.
 Conclusion. MAS in CKD patients leads to deep violations of calcium homeostasis resulting in rapid CKD progression and bone tissue violation.

Outcomes of dual kidney transplants from high KDPI kidneys are superior compared to single kidney high KDPI transplants at 1 year.

Dual kidney transplantation (DKT), utilizing two adult kidneys from the same donor for one recipient, has been used as a way to expand the available donor pool. These kidneys often come from high Kidney Donor Profile Index donors (KDPI>85%). Data comparing outcomes between high KDPI DKT and single kidney transplants (SKT) remain limited. We assessed outcomes of 336 high KDPI kidney transplants performed at our center; 11.0% (n=37) were DKT. Recipients of DKT were older (P=.02) and donors had a higher KDPI score (median 96%vs. 91%, P<.0001). DKT operative time was higher compared to SKT (+1.4hours, P<.0001). There were no differences in delayed graft function (54.1%vs. 51.5%, P=.77) and hospital length of stay (median 4.0vs. 3.0 days, P=.21) between DKT and SKT. Grade I Clavien-Dindo complications occurred in 8.1% of DKT and 13.7% of SKT (P=.008). There were no grade IVa, IVb, or V complications in either group. DKT had more glomerulosclerosis (P=.04), interstitial fibrosis (P=.02), tubular atrophy (P=.01), and arterial thickening (P=.03) on 1-year protocol biopsies. Estimated glomerular filtration was higher for DKT at 1- (P=.004) and 2-years post-transplant (P=.01). There were no differences in patient (HR 1.3, 95% CI .5-3.3, P=.58) or graft (HR 1.1, 95% CI .5-2.3, P=.83) survival. Good outcomes can be achieved with DKT using high KDPI kidneys with moderate chronic changes. DKT is a good option to help further utilize high KDPI kidneys and minimize discard.

Renal Lesions in Horses with Oleander (Nerium oleander) Poisoning.

Simple SummaryOleander (Nerium oleander) poisoning is diagnosed postmortem based on gross and microscopic changes in the heart combined with the identification of oleandrin in samples from the affected animals. Several studies in multiple mammalian species have identified microscopic lesions in the kidneys as well, although this has only been briefly mentioned in horses. In this study, we retrospectively reviewed several cases of spontaneous oleander poisoning in horses, described gross and microscopic lesions in the kidneys, and assessed the prevalence of such microscopic lesions compared with other causes of death in order to determine if they can be used as a diagnostic marker of oleander poisoning in horses. Microscopic kidney lesions were detected in horses with oleander poisoning and were similar to the changes documented in other mammalian species, although the frequency and severity were generally lower. Similar renal changes could be detected in horses that died spontaneously due to other causes or that were euthanized. We concluded that microscopic kidney lesions occur in horses with oleander poisoning, but these are not a specific diagnostic marker to differentiate it from other disease processes.A presumptive postmortem diagnosis of oleander (Nerium oleander) poisoning is made based on the histological observation of cardiomyocyte degeneration and necrosis, which is considered to be a reliable diagnostic marker, and can be confirmed via the detection of oleandrin in tissues or fluids. However, cardiac lesions may not be present in every case, and autolysis can often preclude the identification of subtle changes in the cardiomyocytes. Several studies of experimental oleander poisoning have noted the presence of renal lesions in multiple mammalian species, and case studies of accidental exposure have found similar, although more variably severe, renal abnormalities. Kidney pathology in horses with oleander poisoning has been only briefly mentioned. In this study, we reviewed 21 cases of spontaneous oleander poisoning in horses, evaluated the kidneys microscopically, and compared the renal microscopic lesions with those detected in 10 horses that died or were euthanized due to other causes to assess if histological renal changes could serve as an additional diagnostic marker for oleander poisoning in horses. We found that microscopic renal lesions, principally mild to moderate tubular changes such as hyaline cast formation, neutrophilic casts, epithelial attenuation and necrosis, as well as mineralization and congestion, occur in horses with oleander poisoning. Most of these changes match the descriptions of lesions previously noted in other species, although with less frequency and severity. Similar lesions were found in horses that died spontaneously due to different causes or were euthanized. We concluded that microscopic renal lesions may be detected in horses with oleander poisoning but they cannot be used as a diagnostic marker that allows differentiation from other disease processes or causes of death.

Double Moving Average Control Chart for Autocorrelated Data

The assumption of normality and independence is necessary for statistical inference of control charts. Misleading results are obtained if the traditional control chart technique is applied on the auto-correlated data. When data is correlated, a time series model is employed to produce an optimum output. The objective is to create a new control chart methodology that takes the autocorrelation of observations into account. Charts of Moving Average, Exponentially Weighted and Cumulative Sum better perform in the existence of autocorrelation data for small and moderate changes. The proposed methodology is highly skilled and receptive to minor, moderate and major changes in the process. Propsed DMA chart increases efficiency of average run length (ARL) chart for moving average (MA) to detect the small to medium magnitude shifts in the mean. The simulation also demonstrates that the DMA chart with spans of w=10 and 15 generally performs well in terms of average run length (ARL) as compared to clasical MA. This research may be extended to a multivariate autocorrelated statistical process control, but it can also be used to recognise and categorise seven categories of traditional control chart patterns, such as Downward, Upward Shift, Normal Trend, Cyclic, Systematic patterns, Increasing and Decresing Trend. In order to identify and categorize a set of subclasses of abnormal patterns, this model (multivariate autocorrelated statistical process control chart) should employ a multilayer feed forward Artificial Neural Network (ANN) architecture controlled by a back-propagation learning rule.

Evaluation of Brain Functions in Conversion Disorder with PET/MRI

IntroductionSince there is no objective criteria, unique clinical symptom or laboratory test to make the diagnosis of conversion disorder; its diagnosis and treatment is challenging which leads to a poor prognosis.ObjectivesThe aim of this study is to investigate the brain metabolic activity of patients with conversion disorder with PET/MRI.Methods12 conversion disorder patients were included. Somatosensory Amplification Scale, Somatoform Dissociation Scale, Patient Health Questionnaire-15, Toronto Alexithymia Scale were filled in by the participants. Neurological, mental status examinations, Wechsler Adult Intelligence Scale-Revised Form (WAIS-R) and brain F18-FDG-PET/MRI were performed. Structured Clinical Interview for DSM-5, Hamilton Depression and Anxiety Scales were administered.Results83% of the patients were female, the mean age was 33 years and average education period was 10,2 years. WAIS-R total scores were consistent with low avarage intelligence level.Cerebral hypermetabolism was detected in the primary visual cortex. Average regional brain metabolic activity had a tendency to increase in bilateral prefrontal, right sensorimotor (SM),cingulate,right inferior parietal,occipital lateral,right temporal lateral cortices and cerebellum. Each region was metabolically correlated with the homologous contralateral regions. Significant correlations in the same direction was found between frontal and occipital lateral &amp; primary visual cortices; cerebellum and left sensorimotor cortex; anterior cingulate cortex(ACC) and superior parietal cortex &amp; cerebellum. No correlations were found between ACC and left SM cortex.ConclusionsFindings of our study indicate that there are moderate changes in regional brain metabolic activities and inter-regional correlations in patients with conversion disorder. In order to confirm these findings, furter functional neuroimaging studies are needed.DisclosureNo significant relationships.

Reverse Total Shoulder Arthroplasty for Treatment of Massive, Irreparable Rotator Cuff Tear

Massive tears of the rotator cuff can result in severe functional deficits due to loss of the axial force couple and effective fulcrum that the intact cuff normally provides. For massive, irreparable rotator cuff tears, especially in the setting of early to moderate degenerative changes, reverse total shoulder arthroplasty functions to modify the center of joint rotation, allowing the deltoid and intact components of the cuff to carry out shoulder function more effectively. Our preferred technique uses a standard open deltopectoral shoulder approach with a 3-dimensional glenoid baseplate model and a 135° prosthesis in an onlay configuration to reduce the risk of scapular notching and increase lateralization of the humerus.

Oxygen nonstoichiometry effects in spin Seebeck insulating Y3−xPrxFe5O12+ δ materials

Yttrium iron garnet (Y3Fe5O12) and its derivatives are ferrimagnetic spin Seebeck insulating materials crucial for the spin transport based phenomena such as the spin Seebeck effect (SSE) and spin Hall magnetoresistance. Structure–property correlation studies of such materials under different conditions are useful for optimizing the relevant constraint in the existed phenomena. The usage of Y3Fe5O12 type materials over the broad range of temperature conditions (27–450 °C) in SSE is under study. We report here the structure–property correlation in spin Seebeck insulating Y3−xPrxFe5O12+δ oxides as a representative material and introduce the additional degrees of freedom in the crystal system relevant to the spin transport based phenomena under high temperature conditions. The natural tendency of having oxygen nonstoichiometry in an iron garnet family of materials strengthens the Fe–O–Fe superexchange interaction, which, in turn, tends to increase the spin voltage correlated magnetic parameters. The analysis of experimental high temperature neutron diffraction data (over 27–450 °C) reveals the oxide ion nonstoichiometry and excess oxide ion transport pathways at moderate temperature 150 °C in the crystal lattices of studied garnet materials. Oxide ion nonstoichiometry, ionic transport, and electron hopping in crystal lattices cause a tremendous variation of electrical conductivity (10−11–10−2 S cm−1) over a moderate change of temperature (27–450 °C). The occurrence of electrical transport in the required thermal gradient over the garnet material in SSE can evoke the additional degrees of freedom in the usage of such materials at high temperatures. The present work provides a new outlook in terms of structure–property correlation for spin transport based materials.

Pulmonary toxicity and gene expression changes in response to whole-body inhalation exposure to multi-walled carbon nanotubes in rats

Purpose: To investigate the molecular mechanisms underlying the pulmonary toxicity induced by exposure to one form of multi-walled carbon nanotubes (MWCNT-7). Materials and methods: Rats were exposed, by whole-body inhalation, to air or an aerosol containing MWCNT-7 particles at target cumulative doses (concentration x time) ranging from 22.5 to 180 (mg/m3)h over a three-day (6 hours/day) period and toxicity and global gene expression profiles were determined in the lungs. Results: MWCNT-7 particles, associated with alveolar macrophages (AMs), were detected in rat lungs following the exposure. Mild to moderate lung pathological changes consisting of increased cellularity, thickening of the alveolar wall, alveolitis, fibrosis, and granuloma formation were detected. Bronchoalveolar lavage (BAL) toxicity parameters such as lactate dehydrogenase activity, number of AMs and polymorphonuclear leukocytes (PMNs), intracellular oxidant generation by phagocytes, and levels of cytokines were significantly (p < 0.05) increased in response to exposure to MWCNT-7. Global gene expression profiling identified several significantly differentially expressed genes (fold change >1.5 and FDR p value <0.05) in all the MWCNT-7 exposed rats. Bioinformatic analysis of the gene expression data identified significant enrichment of several diseases/biological function categories (for example, cancer, leukocyte migration, inflammatory response, mitosis, and movement of phagocytes) and canonical pathways (for example, kinetochore metaphase signaling pathway, granulocyte and agranulocyte adhesion and diapedesis, acute phase response, and LXR/RXR activation). The alterations in the lung toxicity parameters and gene expression changes exhibited a dose-response to the MWCNT exposure. Conclusions: Taken together, the data provided insights into the molecular mechanisms underlying the pulmonary toxicity induced by inhalation exposure of rats to MWCNT-7.

Chirality sensing employing parity-time-symmetric and other resonant gain-loss optical systems

Molecular chirality detection and enantiomer discrimination are very important issues for many areas of science and technology, prompting intensive investigations via optical methods. However, these methods are hindered by the intrinsically weak nature of chiro-optical signals. Here, we investigate and demonstrate the potential of gain materials and of combined gain-loss media to enhance these signals. Specifically, we show that the proper combination of a thin chiral layer with a gain-loss bilayer can lead to large enhancements of both the circular dichroism (CD) response and the dissymmetry factor $g$ compared with the chiral layer alone. The most pronounced enhancements are obtained in the case of a parity-time ($\mathit{PT}$) symmetric gain-loss bilayer, while deviations from the exact $\mathit{PT}$ symmetry lead to only moderate changes of the CD and $g$ response, demonstrating also the possibility of tuning the system response by tuning the gain layer properties. In the case of $\mathit{PT}$-symmetric gain-loss bilayers, we found that the largest CD enhancement is obtained at the system lasing threshold, while the $g$ enhancements are at the anisotropic transmission resonances of the systems. Our results clearly demonstrate the potential of gain materials in chirality detection. Moreover, our gain-involving approach can be applied in conjunction with most of the nanophotonics/nanostructures-based approaches that have already been proposed for chirality sensing, further enhancing the performance/output of both approaches.

Characterizing changes in mental health-related outcomes for health service psychology graduate students during the first year of the COVID-19 pandemic.

ObjectivesHealth service psychology (HSP) graduate students experienced adverse mental health outcomes during COVID‐19. However, little is known about how mental health outcomes changed in this population after the onset of COVID‐19.Methods N = 496 HSP graduate students reported onset or worsening of mental health outcomes, inability to access mental health care, worry about COVID‐19, and stress at two different timepoints during the first year of the COVID‐19 outbreak (timepoint 1: May 1 to June 25, 2020; timepoint 2: September 2 to October 17, 2020). This study tested whether mental health outcomes improved, worsened, or stayed stable during this timeframe. The study also examined whether rising COVID‐19 case rates in the state where a participant lived moderated changes in mental health outcomes.ResultsOverall, HSP graduate students endorsed adverse mental health outcomes at a higher rate during the first survey relative to the second survey. Even still, 62.68% of students reported worsened mental health symptoms, 49.84% reported worsened sleep, and 23.92% reported increased alcohol and substance use in the 2 months leading up to the second survey.ConclusionHSP programs should monitor graduate students' evolving mental health, provide wellness resources, and adopt flexible approaches to support graduate students navigating training during periods of immense disruption.

Real- and momentum-space description of the excitons in bulk and monolayer chromium tri-halides

Excitons with large binding energies ~2–3 eV in CrX3 have been characterized as being localized (Frenkel) excitons that emerge from the atomic d − d transitions between the Cr-3d-t2g and eg orbitals. The argument has gathered strength in recent years as the excitons in recently made monolayers are found at almost the same energies as the bulk. The Laporte rule, which restricts such parity forbidden atomic transitions, can relax if a symmetry-breaking mechanism is present. While what can be classified as a purely Frenkel exciton is a matter of definition, we show using an advanced first principles parameter-free approach that these excitons in CrX3, in both its bulk and monolayer variants, have band origin and it is the dp hybridization between Cr and X that primarily acts as the symmetry-breaking mechanism that relaxes the Laporte rule. We show that the character of these excitons is mostly determined by the Cr-d orbital manifold, nevertheless, the fractions of the spectral weight shared with the ligand halogen states increases as the dp hybridization enhances. The hybridization enhances as the halogen atom becomes heavier, bringing the X-p states closer to the Cr-d states in the sequence Cl → Br → I, with an attendant increase in exciton intensity and a decrease in binding energy. By applying a range of different kinds of perturbations that qualitatively mimics the effects originating from the missing vertex in self-energy, we show that moderate changes to the two-particle Hamiltonian that essentially modifies the Cr-d-X-p hybridization, can alter both the intensities and positions of the exciton peaks. A detailed analysis of several deep-lying excitons, with and without strain, elucidates the fact that the exciton is most Frenkel-like in CrCl3 and CrBr3 and acquires mixed Frenkel–Wannier character in CrI3, making the excitons in CrI3 most susceptible to environmental screening and spin–orbit coupling.

Modified Photochemical Reflectance Indices as New Tool for Revealing Influence of Drought and Heat on Pea and Wheat Plants.

In environmental conditions, plants can be affected by the action of numerous abiotic stressors. These stressors can induce both damage of physiological processes and adaptive changes including signaling-based changes. Development of optical methods of revealing influence of stressors on plants is an important task for plant investigations. The photochemical reflectance index (PRI) based on plant reflectance at 531 nm (measuring wavelength) and 570 nm (reference wavelength) can be effective tool of revealing plant stress changes (mainly, photosynthetic changes); however, its efficiency is strongly varied at different conditions. Earlier, we proposed series of modified PRIs with moderate shifts of the measuring wavelength and showed that these indices can be effective for revealing photosynthetic changes under fluctuations in light intensity. The current work was devoted to the analysis of sensitivity of these modified PRIs to action of drought and short-term heat stress. Investigation of spatially-fixed leaves of pea plants showed that the modified PRI with the shorter measuring wavelength (515 nm) was increased under response of drought and heat; by contrast, the modified PRI with the longer wavelength (555 nm) was decreased under response to these stressors. Changes of investigated indices could be related to parameters of photosynthetic light reactions; however, these relations were stronger for the modified PRI with the 555 nm measuring wavelength. Investigation of canopy of pea (vegetation room) and wheat (vegetation room and open-ground) supported these results. Thus, moderate changes in the measuring wavelengths of PRI can strongly modify the efficiency of their use for the estimation of plant physiological changes (mainly photosynthetic changes) under action of stressors. It is probable that the modified PRI with the 555 nm measuring wavelength (or similar indices) can be an effective tool for revealing photosynthetic changes induced by stressors.

Moderate DNA methylation changes associated with nitrogen remobilization and leaf senescence in Arabidopsis.

The lifespan of plants is restricted by environmental and genetic components. Following the transition to reproductive growth, leaf senescence ends cellular life in monocarpic plants to remobilize nutrients to storage organs. In Arabidopsis, we initially observed altered leaf to seed ratios, faster senescence progression, altered leaf nitrogen recovery after transient nitrogen removal, and ultimately enhanced nitrogen remobilization from the leaves in two methylation mutants (ros1 and the triple dmr1/2 cmt3 knockout). Analysis of the DNA methylome in wild type Col-0 leaves identified an initial moderate decline of cytosine methylation with progressing leaf senescence, predominantly in the CG context. Late senescence was associated with moderate de novo methylation of cytosines, primarily in the CHH context. Relatively few differentially methylated regions, including one in the ROS1 promoter linked to down-regulation of ROS1, were present, but these were unrelated to known senescence-associated genes. Differential methylation patterns were identified in transcription factor binding sites, such as the W-boxes that are targeted by WRKYs. Methylation in artificial binding sites impaired transcription factor binding in vitro. However, it remains unclear how moderate methylome changes during leaf senescence are linked with up-regulated genes during senescence.

Interaction of Arginine-Rich Cell-Penetrating Peptides with an Artificial Neuronal Membrane.

Arginine-rich cell-penetrating peptides (RRCPPs) exhibit intrinsic neuroprotective effects on neurons injured by acute ischemic stroke. Conformational properties, interaction, and the ability to penetrate the neural membrane are critical for the neuroprotective effects of RRCCPs. In this study, we applied circular dichroism (CD) spectroscopy and coarse-grained molecular dynamics (CG MD) simulations to investigate the interactions of two RRCPPs, Tat(49–57)-NH2 (arginine-rich motif of Tat HIV-1 protein) and PTD4 (a less basic Ala-scan analog of the Tat peptide), with an artificial neuronal membrane (ANM). CD spectra showed that in an aqueous environment, such as phosphate-buffered saline, the peptides mostly adopted a random coil (PTD4) or a polyproline type II helical (Tat(49–57)-NH2) conformation. On the other hand, in the hydrophobic environment of the ANM liposomes, the peptides showed moderate conformational changes, especially around 200 nm, as indicated by CD curves. The changes induced by the liposomes were slightly more significant in the PTD4 peptide. However, the nature of the conformational changes could not be clearly defined. CG MD simulations showed that the peptides are quickly attracted to the neuronal lipid bilayer and bind preferentially to monosialotetrahexosylganglioside (DPG1) molecules. However, the peptides did not penetrate the membrane even at increasing concentrations. This suggests that the energy barrier required to break the strong peptide–lipid electrostatic interactions was not exceeded in the simulated models. The obtained results show a correlation between the potential of mean force parameter and a peptide’s cell membrane-penetrating ability and neuroprotective properties.

Simulated Changes in Seasonal and Low Flows with Climate Change for Irish Catchments

We assess changes in the seasonal mean and annual low flows (Q95) for 37 catchments across the Republic of Ireland. Two hydrological models (SMART and GR4J) are trained and evaluated for their ability to capture key hydrological signatures from observations before being forced with bias corrected outputs from 12 Earth System Models from the CMIP6 ensemble. Projected changes are derived for three shared socio-economic pathways (SSP126, SSP370 and SSP585) for the 2020s, 2050s, and 2080s. The results show a wide range of change in all metrics across the catchment sample. While even the direction of change is highly uncertain in spring and autumn, there is a tendency towards increased flows in winter and reduced flows in summer, together with large reductions in annual low flows. Under SSP370, the median reduction in summer flows across catchments for the 2080s simulated by GR4J is −21.3 percent (90 percent CI: 4.8 to −36.9 percent). For Q95, for the 2080s, GR4J returns a median reduction of −20.9 percent (90 percent CI: −2.5 to −38.2 percent), while SMART suggests a median reduction of −21.2 percent (90 percent CI: −6.0 to −36.9 percent). Such changes would pose significant challenges for water management, requiring significant adaptation. Notably, for low flows in particular, significant reductions in emissions under SSP126 result in more moderate future changes, indicating the importance of both adaptation and mitigation to sustainable water management.

Validity of data extraction in evidence synthesis practice of adverse events: reproducibility study.

ObjectivesTo investigate the validity of data extraction in systematic reviews of adverse events, the effect of data extraction errors on the results, and to develop a classification framework for data extraction errors to support further methodological research.DesignReproducibility study.Data sourcesPubMed was searched for eligible systematic reviews published between 1 January 2015 and 1 January 2020. Metadata from the randomised controlled trials were extracted from the systematic reviews by four authors. The original data sources (eg, full text and ClinicalTrials.gov) were then referred to by the same authors to reproduce the data used in these meta-analyses.Eligibility criteria for selecting studiesSystematic reviews were included when based on randomised controlled trials for healthcare interventions that reported safety as the exclusive outcome, with at least one pair meta-analysis that included five or more randomised controlled trials and with a 2×2 table of data for event counts and sample sizes in intervention and control arms available for each trial in the meta-analysis.Main outcome measuresThe primary outcome was data extraction errors summarised at three levels: study level, meta-analysis level, and systematic review level. The potential effect of such errors on the results was further investigated.Results201 systematic reviews and 829 pairwise meta-analyses involving 10 386 randomised controlled trials were included. Data extraction could not be reproduced in 1762 (17.0%) of 10 386 trials. In 554 (66.8%) of 829 meta-analyses, at least one randomised controlled trial had data extraction errors; 171 (85.1%) of 201 systematic reviews had at least one meta-analysis with data extraction errors. The most common types of data extraction errors were numerical errors (49.2%, 867/1762) and ambiguous errors (29.9%, 526/1762), mainly caused by ambiguous definitions of the outcomes. These categories were followed by three others: zero assumption errors, misidentification, and mismatching errors. The impact of these errors were analysed on 288 meta-analyses. Data extraction errors led to 10 (3.5%) of 288 meta-analyses changing the direction of the effect and 19 (6.6%) of 288 meta-analyses changing the significance of the P value. Meta-analyses that had two or more different types of errors were more susceptible to these changes than those with only one type of error (for moderate changes, 11 (28.2%) of 39 v 26 (10.4%) 249, P=0.002; for large changes, 5 (12.8%) of 39 v 8 (3.2%) of 249, P=0.01).ConclusionSystematic reviews of adverse events potentially have serious issues in terms of the reproducibility of the data extraction, and these errors can mislead the conclusions. Implementation guidelines are urgently required to help authors of future systematic reviews improve the validity of data extraction.