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Abstract Anomalous dark rings found in black cherry (Prunus serotina Ehrh.) sawlogs have been anecdotally related to defoliations from cherry scallop shell moth (CSSM) (Hydria prunivorata Ferguson). Using six timber harvest sites on the Allegheny National Forest and a thinning on the Kane Experimental Forest in northwestern Pennsylvania, we documented the occurrence of dark rings in the 1970s, 1980s, and 1990s, concurrent with historical CSSM defoliations. Thirty cross-sections sampled from six Allegheny National Forest sites showed that dark rings formed on 18 sections in the 1970s, 17 sections in the 1980s, and 5 sections in the 1990s. Fourteen cross-sections had multiple (2–4) dark rings. Anatomical studies show the dark rings formed in these three decades have similar characteristics: darkened and thinner (>50 percent) fiber cell walls than normal-colored fiber cell walls. A long-term Kane Experimental Forest study was thinned in 2011–12, and dark ring frequency on recently cut stumps ranged from 48 percent to 68 percent across three replications. Dark rings in 12 of 20 cross-sections were associated with a ≥50 percent growth reduction in mean ring width during 1982–84. These results show that dark rings are associated with CSSM defoliation and that growth may be significantly reduced by defoliation.

In the folate cycle MTHFD1, encoded by MTHFD1 , is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590–2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [ 14 C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Pharmacological self-management of osteoarthritis (OA) with over the counter (OTC) drugs remains challenging. To compare the safety, tolerability, and efficacy of a finished phytotherapeutic product (FPP; 2-propanolic dry extract from stinging nettle leaves, Hox alpha [HOXA]) with conventional non-steroidal anti-inflammatory drugs (NSAIDs) used as OTC self-medication in OA. Retrospective, longitudinal exploratory analysis of depersonalized data from the German Pain e-Registry. Two propensity score-matched cohorts of 1073 OA patients each, reporting at least 3 months of continuous OTC treatment with HOXA or NSAIDs, were evaluated. The composite primary endpoint was the proportion of patients who did not discontinue due to an adverse drug reaction (ADR) AND achieved a clinically relevant reduction in average 24‑h pain intensity at the end of the evaluation period. Secondary endpoints included improvements in pain intensities, pain‑related disability, and physical/mental quality of life; safety analyses assessed ADR frequency, number of affected patients, and ADR‑related discontinuations. Both treatments were associated with significant relief of OA-related symptoms compared to baseline, with greater improvements observed for HOXA across all evaluated domains (all p < 0.001). The frequency of ADRs (789 vs 152), the proportion of patients with ADRs (46.8 vs 13.1%) and ADR-related discontinuations (25.2 vs 2.1) were all significantly higher with NSAIDs compared to HOXA (all p < 0.001). The composite primary endpoint was achieved by 96.2% (HOXA) vs 73.2% (NSAIDs; p < 0.001; OR 9.23; RR 7.02; effect size 0.319). In this real‑world OTC setting, HOXA use was associated with fewer ADRs and more favorable multidimensional outcomes compared with NSAID. Given the retrospective design, these findings should be interpreted as exploratory and hypothesis‑generating and confirmed in randomized controlled trials. HMA‑EMA Catalogues of real‑world data sources and studies; EU PAS number 1000000564 (encepp.europa.eu).

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

Patent ductus arteriosus is a common complication of prematurity that frequently requires surgical or medical treatment. The benefit of prophylactic treatment by indometacin, a cyclo-oxygenase inhibitor, remains uncertain compared with curative treatment. This benefit could be improved with ibuprofen, another cyclo-oxygenase inhibitor with fewer adverse effects than indometacin on renal, mesenteric, and cerebral perfusion. We aimed to compare prophylactic and curative ibuprofen in the treatment of this abnormality in very premature infants. We did a randomised controlled trial in infants younger than 28 weeks of gestation, who were randomly assigned to receive either three doses of ibuprofen or placebo within 6 h of birth. After day 3, symptomatic patent ductus arteriosus was treated first by open curative ibuprofen, then back-up indometacin, surgery, or both. The primary endpoint was need for surgical ligation. Analysis was per protocol. The study was stopped prematurely after 135 enrolments because of three cases of severe pulmonary hypertension in the prophylactic group. 65 infants received prophylactic ibuprofen, and 66 received placebo. Prophylaxis reduced the need for surgical ligation from six (9%) to zero (p=0·03), and decreased the rate of severe intraventricular haemorrhage from 15 (23%) to seven (11%) (p=0·10). However, survival was not improved (47 [71%] placebo vs 47 [72%] treatment, p=1·00), because of high frequency of adverse respiratory, renal, and digestive events. In premature infants, prophylactic ibuprofen reduces the need for surgical ligation of patent ductus arteriosus, but does not reduce mortality or morbidity. Therefore, it should not be preferred to early curative ibuprofen.

We report three cases of severe hypoxaemia after ibuprofen administration during a randomised controlled trial of prophylactic treatment of patent ductus arteriosus with ibuprofen in premature infants born at less than 28 weeks of gestation. Echocardiography showed severely decreased pulmonary blood flow. Hypoxaemia resolved quickly on inhaled nitric oxide therapy. We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if hypoxaemia occurs after prophylactic administration of ibuprofen.

This study reports the production of cellulose nanofibrils (CNF) from a bleached eucalyptus pulp using a commercial stone grinder. Scanning electronic microscopy and transmission electronic microscopy imaging were used to reveal morphological development of CNF at micro and nano scales, respectively. Two major structures were identified: (1) highly kinked, naturally helical, and untwisted fibrils that serve as backbones of CNF networks, and (2) entangled, less distinctively kinked (or curled) and twisted “soft looking” nanofibrils. These two major structures appeared in different features of CNF network such as “trees”, “net”, “flower”, single fibril, etc. Prolonged fibrillation can break the nanofibrils into nanowhiskers from the untwisted fibrils with high crystallinity. Energy input for mechanical fibrillation is on the order of 5–30 kWh/kg. The gradual reduction in network size of CNF with time may be used to fractionate CNF.

Mismatches between interacting mitochondrial and nuclear gene products in hybrids have been proposed to disproportionately contribute to the formation of early species boundaries. Under this model, genetic incompatibilities emerge when mitochondrial haplotypes are placed into a cellular context without their coevolved nuclear-encoded mitochondrial (n-mt) proteins. Although there is strong evidence that mitonuclear coevolution has contributed to reproductive isolation in some cases, it is less clear how far-reaching the effects of mitonuclear incompatibilities are in speciation. Does disrupting co-adapted mitonuclear genotypes have broad, genome-wide effects with numerous n-mt loci contributing to reproductive isolation? We leverage a system with several hybridizing species pairs ( fishes) that have known mitonuclear incompatibilities of large effect to ask whether a general signal of incompatibility is present when considering all n-mt genes. After dividing nuclear-encoded proteins into three classes based on level of interaction with mitochondrial gene products, we found only inconsistent statistical evidence for a difference between these classes in the degree of conserved mitonuclear ancestry. Our results imply that genome-wide scans focused on enrichment of broad functional gene classes may sometimes be insufficient for detecting a history of mitonuclear coevolution, even when strong selection is acting on mitonuclear incompatibilities at multiple loci.

Four researchers collaborated on this multisite qualitative case study that examined 11 novice art teachers negotiating their way through their first year of teaching. Participants in three states were selected through a criterion method sampling strategy. The subjects were employed in rural, urban, and suburban public school districts. Researchers conducted 3–4 structured interviews using the same time line and interview protocols during the 2005–2006 academic year. Results indicate that, as novice art teachers assimilated into their respective school cultures, logistical and classroom management issues were of primary concern. Successes reported included a sense of community with their students, improving dialogue about art, and showcasing their art program.

Tight regulation of chloroplast translation is essential for plant growth, development and environmental response. Active translation can result in stalling and collision of ribosomes, which have negative fitness consequences. However, the ways in which chloroplasts respond to these types of translational stressors remain unknown. Here, we identify two MutS2 proteins that act as critical players in plastid ribosome-associated quality control (RQC) in Arabidopsis. We found that both MutS2A and MutS2B are required to overcome specific antibiotic-induced ribosome stalling and collisions. Further, these proteins appear to be essential for tissue greening during de-etiolation, potentially due to increased translational demand during the transition from etioplast to chloroplast. Although bacterial homologs of MutS2 have been widely recognized for their role in regulating homologous recombination, we found only weak support for this function in Arabidopsis plastids. Therefore, these proteins, which are widely conserved among photosynthetic eukaryotes, appear to be central in the resolution of ribosome collisions and may play a critical role during times of increased translational demand.