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Split notochord syndrome (SNS) is a rare congenital defect of the central nervous system and has been associated with several anomalies affecting multiple organ systems. One association has been communication with the gastrointestinal tract and the spine, previously identified as a neuroenteric fistula (NEF). Here, the authors describe the unique case of a female infant with SNS and NEF treated with a multistage surgical repair. The three-stage operative plan included a two-stage repair of the defect and temporary subgaleal shunting followed by delayed ventriculoperitoneal shunt placement. The infant recovered well postsurgery and over a 5-year follow-up. A case description, surgical techniques, and rationale are reported. Additionally, a systematic review of the literature utilizing the MEDLINE database was performed.Treatment of SNS with NEF using a multidisciplinary multistaged approach to repair the intestinal defect, close the neural elements, and divert cerebrospinal fluid to the peritoneum is shown to be a safe and viable option for future cases.

One of the most significant challenges in the use of heterogeneous catalysts is the loss of activity and/or selectivity with time on stream, and researchers have explored different methods to overc...

Background: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. Patients and methods: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). Results: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. Conclusion: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling. CA extern

Python is an open, general-purpose programming language that is used in many tools, libraries and APIs for Building Performance Simulations (BPS). Advantages of Python in the context of digital twins are the simple and powerful capabilities to generate input files, automate processes, import libraries in many languages and a large number of useful modules. However, in order to use BPS tools and libraries with real time data, a comprehensive data model is required in which all necessary data such as geometry, system engineering, databases, sensors, or simulation parameters for the different BPS are defined. Python in combination with SIMULTAN as a suitable open Building Information Modelling (BIM) data model allows an effective use of these tools and libraries to perform and automate analyses. This paper presents a Python module that integrates the SIMULTAN model in Python and enables almost seamless integration with minor adaptations to existing tools or modules. The import is achieved using simple text-based templates for the data types and their mapping in the data model. The data model, the definition of the data types and the use of this module is demonstrated by calculating the trend of the CO2 concentration in a zone of a digital twin using real time data.

An asymptomatic 5-year-old male was diagnosed with severe coarctation of the aorta despite normal peak flow velocity with pathology identified on the basis of Doppler flow profile.

IntroductionThe shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methodsThis is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed ResultsThe monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all pConclusionsBased on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates.Trial registration numberNCT01794143.

Religion verschwindet im Nebel des Pluralen, verdunstet in der Hitze des Säkularen. So lautet eine gängige These, die an die moderne ‚Meistererzählung‘ von der Entzauberung der Welt und vom Untergang des Religiösen anknüpft. Doch dem postulierten Megatrend vom Verschwinden der Religion steht ihre Rückkehr in vielen Bereichen gesellschaftlichen Lebens entgegen. Die vermeintliche Säkularisierung sieht sich einer Resakralisierung gegenüber. Religion besitzt offenkundig jenseits ihrer vermeintlichen Entzauberung einen produktiven ‚Glutkern‘. Zu denken ist dabei an die Dimension der Transzendenz, die Genese und Durchsetzung von religiös geprägten Werten, die Bedeutung religiöser Symbolsysteme in scheinbar säkularisierten Gesellschaften oder auch Vorstellungen der Heiligkeit von Menschen, Göttern, Lebewesen und Dingen. Die Beiträge von Klaus Bieberstein, Ernst Peter Fischer, Hans Joas, Thomas Laubach, Angelika Neuwirth, Peter B. Steiner und Reinhard Zintl reflektieren diese spannungsvolle Lage und bieten Ansatzpunkte für einen neuen Dialog zwischen Säkularisierung und Sakralisierung. Religion disappears in the fog of plurality, vanishes in the heat of profanity. This is a common thesis that ties in with the modern "master narrative" of the disenchantment of the world and the decline of religion. But the postulated megatrend of the disappearance of religion is countered by its return in many areas of social life. The supposed secularization is confronted with a resacralization. Beyond its supposed disenchantment, religion obviously possesses a productive 'glowing core'. The dimension of transcendence, the genesis and enforcement of religiously shaped values, the significance of religious symbol systems in seemingly secularized societies, or even concepts of the sacredness of people, gods, living beings, and things are all worthy of consideration. The contributions by Klaus Bieberstein, Ernst Peter Fischer, Hans Joas, Thomas Laubach, Angelika Neuwirth, Peter B. Steiner and Reinhard Zintl reflect on this tense situation and offer starting points for a new dialogue between secularization and sacralization.

High-level cervical spinal cord injury (SCI) frequently leads to the development of severe sinus bradycardia and asystole. Conventionally, owing to their chronotropic effects, medical management has largely relied on the use of atropine and/or infusion of pressors such as epinephrine or dopamine as the first-line treatment. However, for severe symptomatic events refractory to medical therapy, cardiac pacemaker implantation may be required. In light of the limited data, found in the adult literature, use of methylxanthines such as theophylline has been suggested for the treatment of bradycardia or asystole in the setting of cervical SCI, but to our knowledge, this treatment approach has not been reported in very young children. We present a case of medical management of bradycardia-asystole episodes in a seven-year-old child who sustained cervical SCI after a motor vehicle accident (MVA). His clinical course was complicated by frequent episodes of symptomatic sinus bradycardia progressing to asystole. Episodes were responsive to atropine, but his events were recurrent and feared to be life-threatening if unobserved, and so pacemaker implantation was being considered. In the hope of averting the need for pacemaker implantation, he was started on enteral theophylline, with blood level monitoring and had remained in normal sinus rhythm without recurrence of severe bradycardic or asystole events for a latent period of 74 days. Subsequently, however, he underwent pacemaker placement.

Anomalous superior vena cava drainage is a rare congenital cardiac defect where the right superior vena cava anomalously drains into the left atrium causing a right to left shunt. We present a case of a 17-day-old male who presented with cyanosis without respiratory distress and was found to have a right superior vena cava draining anomalously into the left atrium.

Hair cells are mechanosensory cells that mediate the sense of hearing. These cells do not regenerate after damage in humans, but they are naturally replenished in non-mammalian vertebrates such as zebrafish. The zebrafish lateral line system is a useful model for characterizing sensory hair cell regeneration. The lateral line is comprised of hair cell-containing organs called neuromasts, which are linked together by a string of interneuromast cells (INMCs). INMCs act as progenitor cells that give rise to new neuromasts during development. INMCs can repair gaps in the lateral line system created by cell death. A method is described here for selective INMC ablation using a conventional laser-scanning confocal microscope and transgenic fish that express green fluorescent protein in INMCs. Time-lapse microscopy is then used to monitor INMC regeneration and determine the rate of gap closure. This represents an accessible protocol for cell ablation that does not require specialized equipment, such as a high-powered pulsed ultraviolet laser. The ablation protocol may serve broader interests, as it could be useful for the ablation of additional cell types, employing a tool set that is already available to many users. This technique will further enable the characterization of INMC regeneration under different conditions and from different genetic backgrounds, which will advance the understanding of sensory progenitor cell regeneration.

Summary Background People with mental disabilities are more likely to become subject to police violence than the general population, as shown by a review of the literature. Methodology A media search was performed for fatal confrontations between Israeli police or security officers and people with mental disabilities, in the years 2019–2020. Discussion Four lethal incidents and one severe but non-lethal incidents draw attention to the intersection of identities of the victims, who not only had disabilities but also belonged to minority groups. Systematic documentation and investigation of cases is lacking. Conclusion National authorities are requested to be transparent in their reporting and investigate cases of police violence. Health professionals are encouraged to document any incidents of violence by law enforcement personnel in medical files, in case of injury, with ICD-10 code Y35.

A requirement for the commercialization of power SiC transistors is their long term reliable operation under the hard-switching conditions and high temperatures encountered in the field. Normally ON 1200 V vertical-channel implanted-gate SiC junction field effect transistors (JFETs), designed for high-power bidirectional (four quadrant) solid-state-circuit-breaker (SSCB) applications, were repetitively pulse hard switched at 150 °C from a 1200 V blocking state to an ON-state current of 115 A, which is in excess of 13 times the JFET’s 250-W/cm2 rated current at 150 °C. The JFETs were fabricated in seven photolithographic levels with a single masked ion-implantation forming the p+ gates and guard rings, and with no epitaxial regrowth. The pulsed testing was performed using a low inductance $RLC$ circuit. In this circuit, energy initially stored in a capacitor is discharged in a load resistor through the JFET under test. The JFET hard-switch stressing included over 2.4 million 1200 V/115-A hard-switch events at 150 °C and at a repetition rate of 10 Hz. The peak energies and powers dissipated by the JFET at each hard-switch event were 73.2 mJ and 68.2 kW, respectively. The current rise rate was 166 A/ $\mu \text{s}$ and the pulse full width at half maximum (FWHM) was $1.8~\mu \text{s}$ . After over 2.4 million hard-switch events at 150 °C, the JFET blocking voltage characteristics remained unchanged while the ON-state conduction slightly improved, which indicate reliable operation. An optically triggered SSCB, based on these rugged JFET, is proposed.

This study was designed to itemize and analyze the classification of fracture types and their corresponding outcomes in an attempt to provide a better understanding of the current treatment methods. Two PubMed searches were performed using the words “periprosthetic distal femur fracture” and “periprosthetic supracondylar femur fracture” in studies that were published in the previous 10 years (2004–2014). Data from 41 articlesthat met the general inclusion criteria, were collected and categorized into fracture type and treatment method groupings. Healing outcome and complications were the two parameters used to analyze the data. Treatment techniques were grouped in the following categories: locking plate, non‐locking plate, intramedullary nail/rod, screw, blade plate, cerclage wires, allograft, external fixation, revision arthroplasty, non‐operative, and other. Classification systems by Lewis and Rorabeck, the Association for Osteosynthesis/Orthopedic Trauma Association (AO/OTA), Su et al., Neer et al., Kim et al., Backstein et al., and the Société Française de Chirurgie Orthopédique et Traumatologique were reported. In total 448 fractures were identified, of which Rorabeck type II was the most common fracture studied. The two most successful treatment options for periprosthetic distal femur fractures were locking plate (87%) and intramedullary nail/rod (84%). The most frequent complications associated with periprosthetic distal femur fractures included non/mal/delayed union and the need for revision. Locking plates used to treat Rorabeck type II fractures had a complication rate of 35% and those treated with intramedullary nailing had a higher complication rate of 53%. In conclusion, the most frequent type of periprosthetic distal femur fracture after total knee arthroplasty was Rorabeck type II. The most common treatments for these types of fractures are locked plating and intramedullary nailing, with similar healing rates of 87% and 84%, respectively. However, the complication rate for locked plating was lower than for intramedullary nailing.

GABA is a robust regulator of both developing and mature neural networks. It exerts many of its effects through GABAA receptors, which are heteropentamers assembled from a large array of subunits encoded by distinct genes. In mammals, there are 19 different GABAA subunit types, which are divided into the α, β, γ, δ, ε, π, θ and ρ subfamilies. The immense diversity of GABAA receptors is not fully understood. However, it is known that specific isoforms, with their distinct biophysical properties and expression profiles, tune responses to GABA. Although larval zebrafish are well-established as a model system for neural circuit analysis, little is known about GABAA receptors diversity and expression in this system. Here, using database analysis, we show that the zebrafish genome contains at least 23 subunits. All but the mammalian θ and ε subunits have at least one zebrafish ortholog, while five mammalian GABAA subunits have two zebrafish orthologs. Zebrafish contain one subunit, β4, which does not have a clear mammalian ortholog. Similar to mammalian GABAA receptors, the zebrafish α subfamily is the largest and most diverse of the subfamilies. In zebrafish there are eight α subunits, and RNA in situ hybridization across early zebrafish development revealed that they demonstrate distinct patterns of expression in the brain, spinal cord, and retina. Some subunits were very broadly distributed, whereas others were restricted to small populations of cells. Subunit-specific expression patterns were similar between zebrafish, frogs and rodents, which suggests that the roles of different GABAA receptor isoforms are largely conserved among vertebrates. This study provides a platform to examine isoform specific roles of GABAA receptors within zebrafish neural circuits and it highlights the potential of this system to better understand the remarkable heterogeneity of GABAA receptors.

Background Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. Study Design Observational prospective cohort study. Setting & Participants 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. Predictors Natural log–transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. Outcomes Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30μg/mg at 3 consecutive annual visits. Results Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. Limitations Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. Conclusions Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

Objectives To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function. Study design TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was a multicenter randomized trial of 3 treatments including 521 participants with type 2 diabetes, aged 10-17 years, and with 2-6 years of follow-up. Participants were 36% male, obese, and ethnically diverse. Annual serum concentrations of brain natriuretic peptide, troponin, tumor necrosis factor (TNF)-α, receptors 1 and 2 were related to blood pressure, body mass index, hemoglobin A1c, and left ventricular ejection fraction, diastolic function, relative wall thickness, and mass. Results Elevated concentrations of brain natriuretic peptide (≥100 pg/mL), TNF-α (≥5.6 pg/mL) and troponin (≥0.01 ng/mL), were present in 17.8%, 18.3%, and 34.2% of the cohort, respectively, at baseline, and in 15.4%, 17.1%, and 31.1% at the end of the study, with wide variability over time, without persistence in individuals or clear relationship to glycemia or cardiovascular structure/function. TNF receptors concentrations were increased at baseline and not significantly different from end-of-study concentrations. Adverse echocardiographic measures were more likely in the highest TNF receptor tertile (all P Conclusions Elevated serum concentrations of cardiac biomarkers were common in youth with type 2 diabetes, but their clinical significance is unclear and will require further long-term study. Trial registration ClinicalTrials.gov NCT00081328 .

The effects of extracorporeal membrane oxygenation (ECMO) support on renal function in children with critical illness are unknown. The objective of this study was to investigate the impact of ECMO on renal function among children in different age groups. We performed a single-center retrospective observational study in critically ill children ≤ 18 years supported on ECMO for refractory cardiac or pulmonary failure (2006-2012). The patient population was divided into four age groups for the purpose of comparisons. The Acute Kidney Injury Network's (AKIN's) validated, three-tiered staging system for acute kidney injury was used to categorize the degree of worsening renal function. Data on patient demographics, baseline characteristics, renal function parameters, dialysis, ultrafiltration, duration of mechanical cardiac support, and mortality were collected. Comparisons of baseline characteristics, duration of mechanical cardiac support, and renal function were made between the four age groups. During the study period, 311 patients qualified for inclusion, of whom 289 patients (94%) received venoarterial (VA) ECMO, 12 (4%) received venovenous (VV) ECMO, and 8 (3%) received both VV and VA ECMO. A total of 109 patients (36%) received ultrafiltration on ECMO, 58 (19%) received hemodialysis, and 51 (16%) received peritoneal dialysis. There was a steady and sustained improvement in renal function in all age groups during the ECMO run, with the maximum and longest-sustained improvement occurring in the oldest age group. Proportions of patients in different AKIN stages remained similar in the first 7 days after ECMO initiation. We demonstrate that renal dysfunction improves early after ECMO support. Irrespective of the underlying disease process or patient age, renal function improves in children with pulmonary or cardiac failure who are placed on ECMO.

The Grignard reaction of 2,3-O-isopropylidene-α-D-lyxo-pentodialdo-1,4-furanoside and benzylmagnesium chloride (or bromide) afforded a non-separable mixture of diastereomeric benzyl carbinols and diastereomeric o-tolyl carbinols. The latter resulted from an unexpected benzyl to o-tolyl rearrangement. The proportion of benzyl versus o-tolyl derivatives depended on the reaction conditions. Benzylmagnesium chloride afforded predominantly o-tolyl carbinols while the application of benzylmagnesium bromide led preferably to the o-tolyl carbinols only when used in excess or at higher temperatures. The structures of the benzyl and o-tolyl derivatives were confirmed unambiguously by NMR spectral data and X-ray crystallographic analysis of their 5-ketone analogues obtained by oxidation of the corresponding mixture of diastereomeric carbinols. A possible mechanism for the Grignard reaction leading to the benzyl→o-tolyl rearrangement is also proposed.

ObjectiveThere is cross-center variability with regard to timing repair of non–ductal-dependent tetralogy of Fallot (TOF). We hypothesized that earlier repair in the neonatal period is associated with increased mortality and morbidity.MethodsThis was a retrospective analysis of the Pediatric Health Information System of tetralogy of Fallot patients undergoing complete repair from 2004 through 2010 between the ages of 1 day to younger than 19 years. Patients with pulmonary valve atresia, those who received prostaglandin during hospital admission, and those who underwent prior shunt palliation were excluded.ResultsA total of 4698 patients met our inclusion criteria, of whom 202 were younger than 30 days old (group A), 861 were 31 to 90 days old (group B), 1796 were 91 to 180 days old (group C), and 1839 were older than 180 days (group D). In-hospital mortality, intensive care unit length of stay, and total hospital length of stay were significantly higher in group A. Patients in group A had a significantly increased postoperative requirement for mechanical ventilation, intravenous blood pressure support, medical diuresis, extracorporeal membrane oxygenation, gastrostomy tube insertion, heart catheterization, and surgical revision. Significant institutional variability was noted for timing of TOF complete repair, with one third of the centers performing 75% of the repairs at younger than 30 days old. The institutional approach to timing TOF complete repair showed no relation to surgical volume.ConclusionsAcross all centers analyzed, primary neonatal elective TOF repair (

Fusarium diseases of cereals, particularly wheat, are a persistent threat to food and feed safety andsecurity. Apart from yield losses, the contamination of the crop with Fusarium mycotoxins is ofgreat concern. Among other measures, the deployment of Fusarium-resistant cultivars plays a keyrole in integrated Fusarium control and the reduction of mycotoxin contamination in feed andfood. In this review, genetic diversity for Fusarium resistance in wheat and its close relatives,evaluation methods for assessing quantitative resistance and tools for breeding Fusarium-resistantcultivars are presented and critically discussed.Keywords: Fusarium head blight, Fusarium crown rot, Resistance breeding, Genetic diversity, Phenotypicselection, Marker-assisted selection, Genomic selection.Purpose of This ReviewFungal diseases of crops are a continuing threat for foodand feed security, possibly since domestication of agri-cultural plants. Plant diseases may lead to devastatingepidemics on food crops, such as the potato late blightepidemic in Ireland in the 1840s71850s. Although suchdramatic occurrences are rare, also less extreme butregular incidence of crop plant diseases leads to yieldlosses and reduces food and feed quality.This review summarizes published reports and somenot-yet published experiences and personal opinions onbreeding for Fusarium head blight (FHB) resistance inwheat. For many of the discussed aspects earlier articlesare available each with specific emphases. Phytopatho-logical aspects have been reviewed by Parry et al. [1].Reviews on conventional breeding for FHB resistancehave been published [2–4]. Placinta et al. [5] documentedthe worldwide occurrence and significance of Fusariummycotoxins. The first review on molecular markers forFHB resistance in wheat by Kolb et al. [6] summarized theearly findings in this field and later Anderson et al. [7]listed some of the more stable FHB resistance quantitativetrait loci (QTL). Bai and Shaner [8] reviewed the man-agement and resistance to FHB in wheat and barleyincluding knowledge on the genetics of FHB resistancemainly from a North American perspective. A compre-hensive overview about genetics and breeding for FHBresistance was provided by Buerstmayr et al. [9], whosummarized the findings of 52 QTL mapping studies, nineresearch articles on marker-assisted selection and sevenon marker-assisted germplasm evaluation. Two indepen-dently published QTL meta-analyses on this topic areavailable [10, 11] as well as an overview of FHB resistanceQTL found in European winter wheat [12]. A review byGoswami and Kistler [13] covers the most importanthead blight causing pathogen Fusarium graminearum.In addition, books and book chapters on Fusarium areavailable to the attentive reader. The monograph editedby Leonard and Bushnell [14] reports in 18 book chaptersa range of aspects on Fusarium diseases of small graincereals, including a characterization of the pathogen, theassociated mycotoxins, resistance breeding and othercontrol measures as well as the social and economicimpact of the disease. Brown and Proctor [15] edited arecent book describing the molecular biology of Fusariumfungi. Buerstmayr et al. published a recent book chapterabout breeding for FHB resistance in wheat [16] andabout genomics of FHB resistance [17]. A book chapterby Becher et al. [18] covers different aspects of FHB

A study was conducted to evaluate the effects of pre partum (PRE) and post partum (POST) dietary energy and nutrient supply (E) and their interactions on feed intake, performance and energy status in dairy cows of three breeds. In this experiment, the effects of three energy and nutrient supply levels (low (L), medium (M), high (H)), both pre-calving and post-calving, were investigated, using a 3×3 factorial arrangement of treatments. In both phases (84 days pre- and 105 days post-calving) E levels applied to a total of 81 multiparous cows of breeds Simmental (SI), Brown Swiss (BS) and Holstein–Friesian (HF; n=27 for each breed), were 75%, 100% and 125% of recommendations of the German Society of Nutrition Physiology (GfE). Dry matter intake (DMI) was restricted, if energy intake exceeded target values. Pre partum DMI and energy intake were different as designed, liveweight and body condition score (BCS) of SI cows were higher, but EB was lower, compared to BS and HF cows. Milk yield and composition were influenced by all three main experimental factors (EPRE, EPOST, breed). Energy-corrected milk yield was 25.6, 28.6 and 30.1 kg/day for LPRE, MPRE and HPRE as well as 21.5, 30.1 and 32.6 kg/day for LPOST, MPOST and HPOST, respectively. Numerically, only for milk protein content the interactions EPRE×EPOST and EPRE×breed reached significance. Impact of energy supply pre-calving was more pronounced when cows had lower energy supply post-calving and vice versa. On the other hand, milk yield response of cows to energy supply above requirements was greater for cows that were fed on a low energy level pre partum. Impact of energy level pre partum was higher for HF cows, showing that their milk production relies to a greater extent on mobilization of body reserves. Increasing energy supply pre partum led to a more negative energy balance post partum, mainly by increasing milk yield and content, whereas feed intake was slightly reduced. Increasing energy supply post partum enhanced milk yield as well as milk protein and lactose content. Calculated energy balance corresponded well with liveweight and BCS change. Response of milk yield to increasing energy supply followed the principle of diminishing returns, since energy was increasingly partitioned to body retention. Increasing energy supply pre partum enhances milk yield and content post partum, but exacerbates negative energy balance and its consequences.

[1] Tholeiite of the oldest oceanic crust was drilled during ODP Legs 129 and 185 at Hole 801C in the western Pacific. Fresh appearing submarine basaltic glass (SBG) was recovered from the tholeiites (∼167 Ma) which has been shown to be nearly ideal for determining absolute paleointensity. Paleointensities of the younger, off-axis, alkalic basalts (∼160 Ma), overlying the tholeiites, had been studied earlier. Here we report results from the older tholeiitic (on-axis) sequence. We subjected a total of 73 specimens from 17 cooling units to absolute paleointensity experiments. Of these, 30 specimens and six cooling unit averages met our strictest reliability criteria, yielding an average of 11.9 ± 3.9 μT. The bulk of evidence suggests a paleolatitude of the site of 14°S (with an uncertainty of 10°). This translates the intensity to a value for the virtual axial dipole moment of 28 ZAm2, slightly lower than values determined from the plagioclase crystals in the three cooling units of the younger alkalic basalts overlying the tholeiites (Tarduno & Cottrell, 2005). Our value is low when compared to the long-term median value of the field of 42 ZAm2. Our results and those of the published literature therefore support the contention of a low magnetic field strength in the Jurassic (average of 28 ± 14 ZAm2; N = 138 individual estimates), as initially suggested by Prevot et al. (1990). Our interpretation of the body of available data argue for low field strengths for the entire Jurassic extending into the early Cretaceous.

Dual antiplatelet therapy is essential for the management of acute coronary syndrome. In particular, combination therapy using aspirin with a platelet ADP (i.e. P2Y12 ) receptor inhibitor, such as clopidogrel, prasugrel or, more recently, ticagrelor, has been recommended for patients with acute coronary syndrome. Pharmacological agents that reversibly inhibit platelet aggregation without metabolic activation in the liver are believed to reduce cardiovascular mortality compared with the current drug of choice for antiplatelet therapy, namely clopidogrel. These findings are based on a multicentre, double-blind, double-dummy, randomized controlled trial. Numerous factors are postulated to contribute to the improved survival of patients who take ticagrelor compared with those taking clopidogrel, including the risk of myocardial infarction, heart failure, arrhythmia and bleeding. In addition, clopidogrel may lead to a much higher incidence of infection. Although ticagrelor has recently been approved for use in the US and exhibits superiority over other antiplatelet agents, certain concerns remain regarding its use, including lung injury and dyspnoea, thus raising the issue of its true superiority over clopidogrel or prasugrel. Recent studies into ticagrelor report conflicting data, with certain aspects of its mechanisms of action still not fully understood. Ticagrelor has beneficial effects following its clinical application, such as achieving overall higher reductions in mortality compared with the use of clopidogrel and prasugrel. Harmful effects associated with the use of ticagrelor include a higher incidence of dyspnoea and major bleeding compared with clopidogrel.

Background Governments wish to compare their performance in preventing serious injury. International comparisons based on hospital inpatient records are typically contaminated by variations in health services utilisation. To reduce these effects, a serious injury case definition has been proposed based on diagnoses with a high probability of inpatient admission (PrA). The aim of this paper was to identify diagnoses with estimated high PrA for selected developed countries. Methods The study population was injured persons of all ages who attended emergency department (ED) for their injury in regions of Canada, Denmark, Greece, Spain and the USA. International Classification of Diseases (ICD)-9 or ICD-10 4-digit/character injury diagnosis-specific ED attendance and inpatient admission counts were provided, based on a common protocol. Diagnosis-specific and region-specific PrAs with 95% CIs were calculated. Results The results confirmed that femoral fractures have high PrA across all countries studied. Strong evidence for high PrA also exists for fracture of base of skull with cerebral laceration and contusion; intracranial haemorrhage; open fracture of radius, ulna, tibia and fibula; pneumohaemothorax and injury to the liver and spleen. Slightly weaker evidence exists for cerebellar or brain stem laceration; closed fracture of the tibia and fibula; open and closed fracture of the ankle; haemothorax and injury to the heart and lung. Conclusions Using a large study size, we identified injury diagnoses with high estimated PrAs. These diagnoses can be used as the basis for more valid international comparisons of life-threatening injury, based on hospital discharge data, for countries with welldeveloped healthcare and data collection systems. © 2017, BMJ Publishing Group. All rights reserved.

A necessity for the successful commercialization of SiC power devices is their long term reliability under the switching conditions encountered in the field. Normally-ON 1200 V SiC JFETs were stressed in repetitive hard-switching conditions to determine their fault handling capabilities. The switching pulses were generated from an RLC circuit, where energy initially stored in capacitors discharges through the JFET into a resistive load. The hard-switching included one million repetitive pulsed hard-switching events at 25 °C from a drain blocking-voltage of 600-V to an on-state current of 67 A, and an additional one million 600-V/63-A pulsed hard-switching events at 150 °C. The JFET conduction and blocking-voltage characteristics are virtually unchanged after over two million hard switching events proving the devices are reliable for handling high surge-current faults like those encountered in bidirectional circuit breaker applications.°

Table of contents A1 68Ga-PSMA PET/CT in staging and restaging of Prostate Cancer Patients: comparative study with 18F-Choline PET/CT W Langsteger, A Rezaee, W Loidl, HS Geinitz, F Fitz, M Steinmair, G Broinger, L Pallwien-Prettner, M Beheshti A2 F18 Choline PET – CT: an accurate diagnostic tool for the detection of parathyroid adenoma? L Imamovic, M Beheshti, G Rendl, D Hackl, O Tsybrovsky, M Steinmair, K Emmanuel, F Moinfar, C Pirich, W Langsteger A3 [18F]Fluoro-DOPA-PET/CT in the primary diagnosis of medullary thyroid carcinoma A Bytyqi, G Karanikas, M Mayerhöfer, O Koperek, B Niederle, M Hartenbach A4 Variations of clinical PET/MR operations: An international survey on the clinical utilization of PET/MRI T Beyer, K Herrmann, J Czernin A5 Standard Dixon-based attenuation correction in combined PET/MRI: Reproducibility and the possibility of Lean body mass estimation I Rausch, P Rust, MD DiFranco, M Lassen, A Stadlbauer, ME Mayerhöfer, M Hartenbach, M Hacker, T Beyer A6 High resolution digital FDG PET/MRI imaging for assessment of ACL graft viability K Binzel, R Magnussen, W Wei, MU Knopp, DC Flanigan, C Kaeding, MV Knopp A7 Using pre-existing hematotoxicity as predictor for severe side effects and number of treatment cycles of Xofigo therapy A Leisser, M Nejabat, M Hartenbach, G Kramer, M Krainer, M Hacker, A Haug A8 QDOSE – comprehensive software solution for internal dose assessment Wencke Lehnert, Karl Schmidt, Sharok Kimiaei, Marcus Bronzel, Andreas Kluge A9 Clinical impact of Time-of-Flight on next-generation digital PET imaging of Yttrium-90 radioactivity following liver radioembolization CL Wright, K Binzel, J Zhang, Evan Wuthrick, Piotr Maniawski, MV Knopp A10 Snakes in patients! Lessons learned from programming active contours for automated organ segmentation M Blaickner, E Rados, A Huber, M Dulovits, H Kulkarni, S Wiessalla, C Schuchardt, RP Baum, B Knäusl, D Georg A11 Influence of a genetic polymorphism on brain uptake of the dual ABCB1/ABCG2 substrate [11C]tariquidar M Bauer, B Wulkersdorfer, W Wadsak, C Philippe, H Haslacher, M Zeitlinger, O Langer A12 Outcome prediction of temporal lobe epilepsy surgery from P-glycoprotein activity. Pooled analysis of (R)-[11C]-verapamil PET data from two European centres M Bauer, M Feldmann, R Karch, W Wadsak, M Zeitlinger, MJ Koepp, M-C Asselin, E Pataraia, O Langer A13 In-vitro and in-vivo characterization of [18F]FE@SNAP and derivatives for the visualization of the melanin concentrating hormone receptor 1 M Zeilinger, C Philippe, M Dumanic, F Pichler, J Pilz, M Hacker, W Wadsak, M Mitterhauser A14 Reducing time in quality control leads to higher specific radioactivity of short-lived radiotracers L Nics, B Steiner, M Hacker, M Mitterhauser, W Wadsak A15 In vitro 11C-erlotinib binding experiments in cancer cell lines with epidermal growth factor receptor mutations A Traxl, Thomas Wanek, Kushtrim Kryeziu, Severin Mairinger, Johann Stanek, Walter Berger, Claudia Kuntner, Oliver Langer A16 7-[11C]methyl-6-bromopurine, a PET tracer to measure brain Mrp1 function: radiosynthesis and first PET evaluation in mice S Mairinger, T Wanek, A Traxl, M Krohn, J Stanek, T Filip, M Sauberer, C Kuntner, J Pahnke, O Langer A17 18F labeled azidoglucose derivatives as “click” agents for pretargeted PET imaging D Svatunek, C Denk, M Wilkovitsch, T Wanek, T Filip, C Kuntner-Hannes, J Fröhlich, H Mikula A18 Bioorthogonal tools for PET imaging: development of radiolabeled 1,2,4,5-Tetrazines C Denk, D Svatunek, T Wanek, S Mairinger, J Stanek, T Filip, J Fröhlich, H Mikula, C Kuntner-Hannes A19 Preclinical evaluation of [18F]FE@SUPPY- a new PET-tracer for oncology T Balber, J Singer, J Fazekas, C Rami-Mark, N Berroterán-Infante, E Jensen-Jarolim, W Wadsak, M Hacker, H Viernstein, M Mitterhauser A20 Investigation of Small [18F]-Fluoroalkylazides for Rapid Radiolabeling and In Vivo Click Chemistry C Denk, D Svatunek, B Sohr, H Mikula, J Fröhlich, T Wanek, C Kuntner-Hannes, T Filip A21 Microfluidic 68Ga-radiolabeling of PSMA-HBED-CC using a flow-through reactor S Pfaff, C Philippe, M Mitterhauser, M Hartenbach, M Hacker, W Wadsak A22 Influence of 24-nor-ursodeoxycholic acid on hepatic disposition of [18F]ciprofloxacin measured with positron emission tomography T Wanek, E Halilbasic, M Visentin, S Mairinger, B Stieger, C Kuntner, M Trauner, O Langer A23 Automated 18F-flumazenil production using chemically resistant disposable cassettes P Lam, M Aistleitner, R Eichinger, C Artner A24 Similarities and differences in the synthesis and quality control of 177Lu-DOTA-TATE, 177Lu -HA-DOTA-TATE and 177Lu-DOTA-PSMA (PSMA-617) H Eidherr, C Vraka, A Haug, M Mitterhauser, L Nics, M Hartenbach, M Hacker, W Wadsak A25 68Ga- and 177Lu-labelling of PSMA-617 H Kvaternik, R Müller, D Hausberger, C Zink, RM Aigner A26 Radiolabelling of liposomes with 67Ga and biodistribution studies after administration by an aerosol inhalation system U Cossío, M Asensio, A Montes, S Akhtar, Y te Welscher, R van Nostrum, V Gómez-Vallejo, J Llop A27 Fully automated quantification of DaTscan SPECT: Integration of age and gender differences F VandeVyver, T Barclay, N Lippens, M Troch A28 Lesion-to-background ratio in co-registered 18F-FET PET/MR imaging – is it a valuable tool to differentiate between low grade and high grade brain tumor? L Hehenwarter, B Egger, J Holzmannhofer, M Rodrigues-Radischat, C Pirich A29 [11C]-methionine PET in gliomas - a retrospective data analysis of 166 patients N Pötsch, I Rausch, D Wilhelm, M Weber, J Furtner, G Karanikas, A Wöhrer, M Mitterhauser, M Hacker, T Traub-Weidinger A30 18F-Fluorocholine versus 18F-Fluorodeoxyglucose for PET/CT imaging in patients with relapsed or progressive multiple myeloma: a pilot study T Cassou-Mounat, S Balogova, V Nataf, M Calzada, V Huchet, K Kerrou, J-Y Devaux, M Mohty, L Garderet, J-N Talbot A31 Prognostic benefit of additional SPECT/CT in sentinel lymph node mapping of breast cancer patients S Stanzel, G Pregartner, T Schwarz, V Bjelic-Radisic, B Liegl-Atzwanger, R Aigner A32 Evaluation of diagnostic value of TOF-18F-FDG PET/CT in patients with suspected pancreatic cancer S Stanzel, F Quehenberger, RM Aigner A33 New quantification method for diagnosis of primary hyperpatahyroidism lesions and differential diagnosis vs thyropid nodular disease in dynamic scintigraphy A Koljević Marković, Milica Janković, V Miler Jerković, M Paskaš, G Pupić, R Džodić, D Popović A34 A rare case of diffuse pancreatic involvement in patient with merkel cell carcinoma detected by 18F-FDG MC Fornito, D Familiari A35 TSH-stimulated 18F-FDG PET/CT in the diagnosis of recurrent/metastatic radioiodine-negative differentiated thyroid carcinomas in patients with various thyroglobuline levels P Koranda, H Polzerová, I Metelková, L Henzlová, R Formánek, E Buriánková, M Kamínek A36 Breast Dose from lactation following I131 treatment WH Thomson, C Lewis A37 A new concept for performing SeHCAT studies with the gamma camera WH Thomson, J O’Brien, G James, A Notghi A38 Whole body F-18-FDG-PET and tuberculosis: sensitivity compared to x-ray-CT H Huber, I Stelzmüller, R Wunn, M Mandl, F Fellner, B Lamprecht, M Gabriel A39 Emerging role 18F-FDG PET-CT in the diagnosis and follow-up of the infection in heartware ventricular assist system (HVAD) MC Fornito, G Leonardi A40 Validation of Poisson resampling software WH Thomson, J O’Brien, G James A41 Protection of PET nuclear medicine personnel: problems in satisfying dose limit requirements J Hudzietzová, J Sabol, M Fülöp

The present study created a basis for development of a fast, non-destructive method to measure ascorbic acid content during various growth stages of three bell pepper cultivars: ‘Ever Green’, ‘No. 117’ and ‘Celica’. Fruit were tagged at the flowering stage and picked weekly during 9 weeks of growth, until fully ripe. Visible and near-infrared (VIS–NIR) spectra in the range 477–950 nm were obtained in reflectance mode from intact peppers with a USB2000 mini-spectrometer. Short-wave infrared (SWIR) spectra in the range 850–1888 nm were obtained in reflectance mode from the same sampled peppers with a Liga Spectrometer. Fruit flesh samples were cut from the area scanned for spectral measurements, and destructively analyzed for ascorbic acid content. The highest ascorbic acid content was measured in the green variety ‘Ever Green’ (148.1 mg per 100 g). Varieties ‘Ever Green’ and ‘No. 117’ accumulated significantly higher concentrations of ascorbic acid than ‘Celica’, and consistent and significant differences were found between the premature, green and mature stages of all three cultivars. Partial Least-Squares (PLS) regression was used in spectral model development. Comparisons were made between the PLS regression analysis of the reflectance spectra ( R ), its first derivative ( D 1 R ), the log(1/ R ) and its first ( D 1 log(1/ R )) and second derivative ( D 2 log(1/ R )). VIS–NIR and SWIR spectroscopy measurements showed good correlation ( r 2 = 0.76) with changes in ascorbic acid content. The PLS regression models were able to predict ascorbic acid content for all three cultivars, with 15.1–18.9 mg per 100 g cross-validation error (RPD = 2–2.4). The method offers potential for non-destructive detection of changes in ascorbic acid content during growth and maturation of intact bell peppers.

Although oaks (Quercus spp.) have historically dominated much of the forest land in eastern North America, a great deal of fragmentary and sometimes anecdotal evidence suggests that they have been yielding dominance in recent decades to other, typically more shade-tolerant species. Using FIA data, our work formally quantifies the change in oak abundance in the eastern U.S. during the period of 1980–2008. The results indicate that most areas in the eastern U.S. experienced some decline in oak abundance, but the decrease was not universal either geographically or among species. Declines were especially marked in the Central Hardwood Region, which lost oak abundance on 81% its forested area as measured by importance value (IV). Areas with a high oak abundance were more likely to see a reduction in abundance. Among all 25 species analyzed, eight species decreased significantly in IV while two increased. Both the top two most prevalent white oak species (white oak (Quercus alba) and post oak (Quercus stellata)) and red oak species (northern red oak (Quercus rubra) and black oak (Quercus velutina)) had significant decreases in density and IV. Water oak (Quercus nigra) is one of the red oak species that had a near universal increase of its abundance throughout its native range (83% of area). This study provided a comprehensive quantification of the dynamic of oak species in a regional-wide geographic context, which will provoke forest researchers and managers to revisit the oak decline problem by using knowledge from other regions and other species.

Objectives Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes. Study design In the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) multicenter trial, 285 participants failed to sustain glycemic control on randomized treatment (primary outcome, glycated hemoglobin A1c [HbA1c] at ≥8% for 6 months); 363 maintained glycemic control (never reached primary outcome). Statins were used for a low-density lipoprotein cholesterol of ≥130 mg/dL. Upon reaching the primary outcome, insulin was started. Changes in lipids and inflammatory markers (slopes over time) were examined. Results Progression of dyslipidemia was related to glycemic control. In those with the primary outcome, insulin therapy impacted HbA1c modestly, and dampened the increase in total cholesterol, low-density lipoprotein cholesterol, and total apolipoprotein B, although statin use increased from 8.6% to 22% year after the primary outcome. The increase in triglycerides and plasma nonesterified fatty acids stabilized after insulin was started, independent of HbA1c. There was an increase in high-sensitivity C-reactive protein that continued after insulin initiation, related to HbA1c and percent overweight. Conclusions Worsening dyslipidemia and inflammation over time raise concern regarding premature development of atherosclerosis in youth with type 2 diabetes. Insulin therapy has a limited benefit in the absence of glycemic control. Strategies to achieve better glycemic control are needed. Trial registration ClinicalTrials.gov : NCT00081328 .

1. Geographies of the Holocaust / Alberto Giordano, Anne Kelly Knowles, and Tim Cole 2. Mapping the SS Concentration Camps / Anne Kelly Knowles and Paul B. Jaskot, with Benjamin Perry Blackshear, Michael De Groot, and Alexander Yule 3. Retracing the "Hunt for Jews": A Spatio-Temporal Analysis of Arrests during the Holocaust in Italy / Alberto Giordano and Anna Holian 4. Killing on the Ground and in the Mind: The Spatialities of Genocide in the East / Waitman W. Beorn, with Anne Kelly Knowles 5. Bringing the Ghetto to the Jew: The Shifting Geography of the Budapest Ghetto / Tim Cole and Alberto Giordano 6. Visualizing the Archive: Building at Auschwitz as a Geographic Problem / Paul B. Jaskot, Anne Kelly Knowles, and Chester Harvey, with Benjamin Perry Blackshear 7. From the Camp to the Road: Representing the Evacuations from Auschwitz, January 1945 / Simone Gigliotti, Marc J. Masurovsky, and Erik Steiner 8. Afterword / Paul B. Jaskot and Tim Cole Contributors Index

The formation of (4R)-4-carbamoyl-4-[(4R)-3-O-benzyl-1,2-O-isopropylidene-beta-l-threofuranos-4-C-yl]-oxazolidin-2-one instead of expected imidazolidin-2,4-dione (hydantoin) derivative from 5-amino-5-cyano-5-deoxy-3-O-benzyl-1,2-O-isopropylidene-alpha-d-glucofuranose or 3-O-benzyl-1,2-O-isopropylidene-alpha-d-xylo-hexofuranos-5-ulose under Bucherer-Bergs reaction conditions is reported. Single crystal X-ray diffraction data revealed that (3)T(4) is the prefered conformation for the furanose ring, while E(2) and (2)T(1) conformations are adopted by the 1,3-dioxolane and 2-oxazolidinone five-membered rings, respectively.

In the title compounds, C(12)H(20)O(6), (I), and C(9)H(16)O(6), (II), the five-membered furanose ring adopts a (4)T(3) conformation and the five-membered 1,3-dioxolane ring adopts an E(3) conformation. The six-membered 1,3-dioxane ring in (I) adopts an almost ideal (O)C(3) conformation. The hydrogen-bonding patterns for these compounds differ substantially: (I) features just one intramolecular O-H...O hydrogen bond [O...O = 2.933 (3) A], whereas (II) exhibits, apart from the corresponding intramolecular O-H...O hydrogen bond [O...O = 2.7638 (13) A], two intermolecular bonds of this type [O...O = 2.7708 (13) and 2.7730 (12) A]. This study illustrates both the similarity between the conformations of furanose, 1,3-dioxolane and 1,3-dioxane rings in analogous isopropylidene-substituted carbohydrate structures and the only negligible influence of the presence of a 1,3-dioxane ring on the conformations of furanose and 1,3-dioxolane rings. In addition, in comparison with reported analogs, replacement of the -CH(2)OH group at the C1-furanose position by another group can considerably affect the conformation of the 1,3-dioxolane ring.

Budesonide (BUD) is a steroid with a low bioavailability, which has been used for the treatment of oral manifestations of chronic GVHD (cGVHD). We retrospectively evaluated the efficacy of BUD in the treatment of gastrointestinal cGVHD. Thirteen patients (median age 47 years) receiving BUD for the treatment of cGVHD after allogeneic hematopoietic SCT for hematological malignancies were evaluated for response. Five patients had isolated gastrointestinal cGVHD and 8 patients had mild multiorgan involvement including gastrointestinal manifestations. Six patients received CYA at the time of onset of cGVHD, which was continued during treatment with BUD. Treatment consisted of BUD, with an initial daily dose of 3 x 3 mg orally. Complete resolution of cGVHD was achieved in seven patients, and one patient achieved partial remission of cGVHD. One patient achieved complete resolution of gastrointestinal cGVHD, while systemic manifestations of cGVHD remained stable. Four patients progressed on BUD. Owing to the predominantly local effect, relapse of symptoms of cGVHD after withdrawal of immunosuppression (n=3) as well as progression of GVHD at other sites (n=3) has been observed. BUD represents a treatment option in mild-to-moderate cGVHD, which is well tolerated and associated with a high response rate in gastrointestinal cGVHD.

In the vertebrate blastula and gastrula the Nodal pathway is essential for formation of the primary germ layers and the organizer. Nodal autoregulatory feedback potentiates signaling activity, but mechanisms limiting embryonic Nodal ligand transcription are poorly understood. Here we describe a transcriptional switch mechanism mediated by FoxH1, the principle effector of Nodal autoregulation. FoxH1 contains a conserved engrailed homology (EH1) motif that mediates direct binding of groucho-related gene 4 (Grg4), a Groucho family corepressor. Nodal-dependent gene expression is suppressed by FoxH1, but enhanced by a FoxH1 EH1 mutant, indicating that the EH1 motif is necessary for repression. Grg4 blocks Nodal-induced mesodermal gene expression and Nodal autoregulation, suggesting that Grg4 limits Nodal pathway activity. Conversely, blocking Grg4 function in the ectoderm results in ectopic expression of Nodal target genes. FoxH1 and Grg4 occupy the Xnr1 enhancer, and Grg4 occupancy is dependent on the FoxH1 EH1 motif. Grg4 occupancy at the Xnr1 enhancer significantly decreases with Nodal activation or Smad2 overexpression, while FoxH1 occupancy is unaffected. These results suggest that Nodal-activated Smad2 physically displaces Grg4 from FoxH1, an essential feature of the transcriptional switch mechanism. In support of this model, when FoxH1 is unable to bind Smad2, Grg4 occupancy is maintained at the Xnr1 enhancer, even in the presence of Nodal signaling. Our findings reveal that FoxH1 mediates both activation and repression of Nodal gene expression. We propose that this transcriptional switch is essential to delimit Nodal pathway activity in vertebrate germ layer formation.

D-Lyxose derived nitrone 7 was found to effectively undergo an SmI2-mediated radical addition to methyl acrylate affording γ-N-hydroxylamino ester 8 with high diastereomeric control. The pyrrolidinone 9 was prepared in a single step from 8 involving N-O bond cleavage with Zn/AcOH and subsequent spontaneous cyclization. D-Xylose derived nitrone 10 afforded in the SmI2-induced coupling with methyl acrylate the γ-N-hydroxylamino ester 11 as minor product. The major product the nitrone 12 is formed by unusual reductive deoxygenation of the starting nitrone.