Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

PLIF surgery with titanium-coated PEEK or uncoated PEEK cages: a prospective randomised clinical and radiological study.

PURPOSE: This study aimed to compare clinical results and fusion rates of uncoated polyetheretherketone (PEEK) cages with titanium-coated PEEK cages in posterior lumbar interbody fusion (PLIF) surgery. METHODS: A prospective randomised study including 60 patients with one- or two-segment lumbar degenerative diseases. Patients received either titanium-coated PEEK cages (group A) or uncoated PEEK cages (group B). Fusion rates were evaluated on plain X-rays and CT scans after 6 and 12 months. Clinical follow-up (visual analogue scale, VAS; Oswestry Disability Index score, ODI; EQ-5D) was performed for 24 months. RESULTS: Fifty-five patients (92%) (36 female, 19 male) had a complete follow-up. There were no statistically significant differences in demographic, peri- or intraoperative data between groups A and B. ODI, VAS and EQ-5D improved significantly (p < 0.001) after surgery without statistically significant differences between the two groups. Overall, 65 operated segments could be evaluated for fusion (group A: 29 segments, group B: 36 segments, p = 0.6). Osseous integration of the cage surface improved significantly (p < 0.001) in both groups between 6 and 12 months after surgery. At 12-month follow-up, neither radiolucency nor signs of instability or dislocation were noted. Fusion was present in CT scans as follows: (a) bone growth through cage pores (A: 100%, B: 100%); (b) bone growth outside the cages (A: 48%, B: 61%; p = 0.3). CONCLUSIONS: PEEK and titanium-coated PEEK cages for PLIF produce equally favourable clinical and radiological results up to 24 months post-surgery. The fusion rate was not different.

Staged surgical treatment for infection of total disc arthroplasty: three cases and a narrative review of the literature.

Although total disc arthroplasty (TDA) is a common procedure for selected cases of degenerative disc disease, until today there are only two cases of TDA infections reported in the literature. We report three cases of postoperative TDA infections, two developed cutaneous fistulas. To eradicate the infectious site, a staged removal of the device, resolute debridement, and stabilization plus fusion is proposed. Surgeons are challenged by (1) major retroperitoneal vessels adherent to the device, (2) surrounding scar tissue, (3) accompanying retroperitoneal abscess, and (4) technical issues when removing and replacing the implant. A staged multidisciplinary team approach involving vascular and plastic surgery as well as spine specialists is mandatory to achieve good results.

Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints.

Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UHPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)4 and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.

Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation.

Genome-wide association studies identified numerous disease risk loci. Delineating molecular mechanisms influenced by cis-regulatory variants is essential to understand gene regulation and ultimately disease pathophysiology. Combining bioinformatics and public domain chromatin information with quantitative proteomics supports prediction of cis-regulatory variants and enabled identification of allele-dependent binding of both, transcription factors and coregulators at the type 2 diabetes associated PPARG locus. We found rs7647481A nonrisk allele binding of Yin Yang 1 (YY1), confirmed by allele-specific chromatin immunoprecipitation in primary adipocytes. Quantitative proteomics also found the coregulator RING1 and YY1 binding protein (RYBP) whose mRNA levels correlate with improved insulin sensitivity in primary adipose cells carrying the rs7647481A nonrisk allele. Our findings support a concept with diverse cis-regulatory variants contributing to disease pathophysiology at one locus. Proteome-wide identification of both, transcription factors and coregulators, can profoundly improve understanding of mechanisms underlying genetic associations.

Methoxypyrazine composition of Coccinellidae-tainted Riesling and Pinot noir wine from Germany.

BACKGROUND: Harmonia axyridis (multicolored Asian ladybeetle) and Coccinella septempunctata (seven-spot ladybeetle) (Coccinellidae) are found in many wine regions in Europe and the Americas, where they are responsible for a pronounced wine fault known as 'ladybug taint' when incorporated with grapes during harvest operations. Methoxypyrazines have been proposed in the literature as the compounds responsible for the taint. This study sought to expand on this identification and also determine the effectiveness of heating Coccinellidae-affected grape must prior to fermentation as a possible remedial intervention. Riesling and Pinot noir grapes were infested with H. axyridis or C. septempunctata at different densities and fermented to dryness. The Pinot noir was either must heated prior to fermentation or processed without heating (control). All wines were analyzed for 2-isopropyl-, 2-sec-butyl-, 2-isobutyl- and 2,5-dimethyl-3-methoxypyrazine using headspace solid phase microextraction/multidimensional gas chromatography/mass spectrometry. RESULTS: Concentrations of 2-isopropyl-3-methoxypyrazine increased with beetle density for both Coccinellidae species, while other methoxypyrazines showed inconsistent or no variation with infestations levels. Heating of Pinot noir grapes prior to fermentation resulted in a moderate decrease in all methoxypyrazines. CONCLUSION: These results provide direction for more targeted treatments aimed at remediating musts/wines affected by Coccinellidae and indicate that winegrowers do not need to differentiate between H. axyridis and C. septempunctata when making action threshold decisions in the vineyard or winery.

Accuracy quantification of a deformable image registration tool applied in a clinical setting.

The purpose of this study was to test the accuracy of a commercially available deformable image registration tool in a clinical situation. In addition, to demonstrate a method to evaluate the resulting transformation of such a tool to a reference defined by multiple experts. For 16 patients (seven head and neck, four thoracic, five abdominal), 30-50 anatomical landmarks were defined on recognizable spots of a planning CT and a corresponding fraction CT. A commercially available deformable image registration tool, Velocity AI, was used to align all fraction CTs with the respective planning CTs. The registration accuracy was quantified by means of the target registration error in respect to expert-defined landmarks, considering the interobserver variation of five observers. The interobserver uncertainty of the landmark definition in our data sets is found to be 1.2 ± 1.1 mm. In general the deformable image registration tool decreases the extent of observable misalignments from 4-8 mm to 1-4 mm for nearly 50% of the landmarks (to 77% in sum). Only small differences are observed in the alignment quality of scans with different tumor location. Smallest residual deviations were achieved in scans of the head and neck region (79%, ≤ 4 mm) and the thoracic cases (79%, ≤ 4 mm), followed by the abdominal cases (59%, ≤ 4 mm). No difference is observed in the alignment quality of different tissue types (bony vs. soft tissue). The investigated commercially available deformable image registration tool is capable of reducing a mean target registration error to a level that is clinically acceptable for the evaluation of retreatment plans and replanning in case of gross tumor change during treatment. Yet, since the alignment quality needs to be improved further, the individual result of the deformable image registration tool has still to be judged by the physician prior to application.

Training scenes: Taking science studies to the classroom.

Academic training, especially at the undergraduate level, is a marginal topic in science studies today. Scientific practices have commonly been approached through studies of research contexts-most visibly, the lab-and only sporadically through studies of the classroom or other teaching contexts. In this article, we draw attention to the pivotal role that academic training plays in the formation and reproduction of thought collectives. Such training, in shaping what students think about their field and what they understand as proper ways of doing science, is an important site of what we call epistemological enculturation. Based on a comprehensive literature review, we make several suggestions on how epistemological enculturation can be studied at the level of training scenes, a concept we develop in the article. This includes a discussion of the methodological as well as theoretical difficulties that occur when analysing academic training in action.

Toxicity of Pesticides Applied in European Vineyards on Anagyrus vladimiri and Trichogramma evanescens, Parasitoids of Planococcus ficus and Lobesia botrana.

Risk assessments of chemical pesticides toward natural enemies are crucial for ensuring sustainable grapevine-integrated pest management. In this context, laboratory experiments were conducted to evaluate the toxicity of four insecticides (lambda-cyhalothrin, flupyradifurone, acetamiprid, and cyantraniliprole) and one fungicide (spiroxamine) commonly applied in German (European) vineyards on the pupae and adults of both Anagyrus vladimiri, a parasitoid of the vine mealybug Planococcus ficus, and Trichogramma evanescens, a parasitoid of the European grapevine moth, Lobesia botrana. The tested pesticides did not significantly affect the development of the pupal stage inside mealybug mummies or the emergence of the parasitoid A. vladimiri. The pesticides flupyradifurone, acetamiprid, and spiroxamine resulted in the highest mortality percentages for all emerged A. vladimiri parasitoids at 8 and 10 days after treatment compared with either in lambda-cyhalothrin or cyantraniliprole. However, all pesticides, except the diamide insecticide cyantraniliprole, significantly affected the development of the pupal stage and the emergence of the parasitoid T. evanescens. The percentages of T. evanescens emergence following the application of the fungicide spiroxamine or either lambda-cyhalothrin or flupyradifurone were significantly higher than those observed in the acetamiprid treatment. Regarding direct contact toxicity, the highest percentages (100%) of A. vladimiri adult parasitoid mortality were obtained in the flupyradifurone, acetamiprid, and spiroxamine treatments, while the lowest mortality percentages were observed in lambda-cyhalothrin, cyantraniliprole, and untreated control treatments. According to the IOBC classes of toxicity, flupyradifurone, acetamiprid, and spiroxamine were classified as harmful, while both lambda-cyhalothrin and cyantraniliprole were classified as slightly harmful to A. vladimiri adults. As such, all pesticides had a significant impact on the survival of exposed T. evanescens adults. The highest percentages of adult T. evanescens mortality were obtained in the flupyradifurone, acetamiprid, and spiroxamine treatments, with the fungicide spiroxamine resulting in significantly higher mortality percentages than either flupyradifurone or acetamiprid, while the lowest mortality percentages were found in the lambda-cyhalothrin and cyantraniliprole treatments. Therefore, applying the insecticides acetamiprid and/or flupyradifurone and the fungicide spiroxamine should be avoided when A. vladimiri and/or T. evanescens are naturally present or released in grapes. The insights gained from these two easy-to-rear parasitoid species allow analogous conclusions to be drawn for closely related species in vineyards belonging to either family Encyrtidae or Trichogrammatidae, which are not easy to rear. Interestingly, using the safer insecticides lambda-cyhalothrin and/or cyantraniliprole could be compatible with both parasitoid species, which could be sustainably exploited in either conservation or augmentative biological control in vineyards.

Arthropods on grapes benefit more from fungicide reduction than from organic farming.

BACKGROUND: Pesticides are considered main contributors to global arthropod declines and therefore may decrease the provision of ecosystem services such as natural pest control. Organic farming and cultivating pest- and disease-resistant varieties can allow pesticide applications and their impacts on nontarget organisms and the environment to be reduced. We investigated the effects of organic versus conventional management and fungus-resistant versus susceptible wine grape varieties on arthropod biodiversity and pest control of grape berry moths in 32 vineyards in the Palatinate region, Germany. Hazard quotients of applied pesticides were calculated for each vineyard. RESULTS: The cultivation of fungus-resistant varieties led to significantly reduced hazard quotients and in turn enhanced abundances of natural enemies, particularly theridiid and philodromid spiders. Unexpectedly, organic management resulted in higher hazard quotients than conventional management and reduced numbers of natural enemies, particularly earwigs. Pest predation rates showed no significant differences between grape varieties or management types. CONCLUSION: Widespread benefits of organic management on arthropod biodiversity found in other crops were absent in our viticultural study region. This is likely due to the dominant role of fungal diseases in viticulture, which requires high numbers of fungicide treatments under both conventional and organic viticulture. Thus, fungicide reduction through the cultivation of fungus-resistant grape varieties is one key element to fostering the abundance of arthropods in general and beneficial arthropods in particular. Beyond vineyards, this is potentially relevant in numerous other crop types. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Neurological recovery after early versus delayed surgical decompression for acute traumatic spinal cord injury.

The aim of this study was to determine whether early surgical treatment results in better neurological recovery 12 months after injury than late surgical treatment in patients with acute traumatic spinal cord injury (tSCI). Patients with tSCI requiring surgical spinal decompression presenting to 17 centres in Europe were recruited. Depending on the timing of decompression, patients were divided into early (≤ 12 hours after injury) and late (> 12 hours and < 14 days after injury) groups. The American Spinal Injury Association neurological (ASIA) examination was performed at baseline (after injury but before decompression) and at 12 months. The primary endpoint was the change in Lower Extremity Motor Score (LEMS) from baseline to 12 months. The final analyses comprised 159 patients in the early and 135 in the late group. Patients in the early group had significantly more severe neurological impairment before surgical treatment. For unadjusted complete-case analysis, mean change in LEMS was 15.6 (95% confidence interval (CI) 12.1 to 19.0) in the early and 11.3 (95% CI 8.3 to 14.3) in the late group, with a mean between-group difference of 4.3 (95% CI -0.3 to 8.8). Using multiply imputed data adjusting for baseline LEMS, baseline ASIA Impairment Scale (AIS), and propensity score, the mean between-group difference in the change in LEMS decreased to 2.2 (95% CI -1.5 to 5.9). Compared to late surgical decompression, early surgical decompression following acute tSCI did not result in statistically significant or clinically meaningful neurological improvements 12 months after injury. These results, however, do not impact the well-established need for acute, non-surgical tSCI management. This is the first study to highlight that a combination of baseline imbalances, ceiling effects, and loss to follow-up rates may yield an overestimate of the effect of early surgical decompression in unadjusted analyses, which underpins the importance of adjusted statistical analyses in acute tSCI research.

Influence of diet on fecundity, immune defense and content of 2-isopropyl-3-methoxypyrazine in Harmonia axyridis Pallas.

Food type can affect all functional aspects of an insect's life. We investigated the effects of different diet regimes on life history parameters of the ladybird beetle Harmonia axyridis. Furthermore, we tested the importance of elytral color, sex, and diet on chemical and immune defense in this species. We also compared hemolymph from cohorts of H. axyridis and Coccinella septempunctata (Coleoptera: Coccinellidae) fed different diets to examine effects on the 2-isopropyl-3-methoxypyrazine (IPMP) content in these beetles. No effects of diet on the duration of larval development and on adult weight were found. We detected, however, significantly higher fecundity and oviposition rates when female H. axyridis were reared on pea aphids than when reared on eggs of Ephestia kuehniella. Males and females did not differ in their immune response. Elytral color affected both immune defense and chemical defense. The antimicrobial activity of the hemolymph differed only when morphotypes were tested against E. coli. Moreover, we observed an effect of elytral pigmentation on IPMP content. The succinea 2 type (orange without dots) had the lowest IPMP content in two out of three feeding regimes compared to the succinea 1 (orange with dots) type. Depending on diet, IPMP contents differed in both species leading to higher contents either in H. axyridis or C. septempunctata. Furthermore, aphid species ingested during larval development significantly affected IPMP content in adult beetles. These results implicate new aspects for risk assessment of H. axyridis in viticulture.

Using Malaise Traps and Metabarcoding for Biodiversity Assessment in Vineyards: Effects of Weather and Trapping Effort.

Metabarcoding is a powerful tool for ecological studies and monitoring that might provide a solution to the time-consuming taxonomic identification of the vast diversity of insects. Here, we assess how ambient weather conditions during Malaise trap exposure and the effort of trapping affect biomass and taxa richness in vineyards. Biomass varied by more than twofold with weather conditions. It increased with warmer and drier weather but was not significantly related with wind or precipitation. Taxa richness showed a saturating relationship with increasing trapping duration and was influenced by environmental and seasonal effects. Taxa accumulation was high, increasing fourfold from three days of monthly trap exposure compared to continuous trapping and nearly sixfold from sampling at a single site compared to 32 sites. The limited saturation was mainly due to a large number of singletons, such as rare species, in the metabarcoding dataset. Metabarcoding can be key for long-term insect monitoring. We conclude that single traps operated for up to ten days per month are suitable to monitor the presence of common species. However, more intensive trapping is necessary for a good representation of rare species in biodiversity monitoring. The data collected here can potentially guide the design of monitoring studies.

Late Implant Failure in Cervical Disc Arthroplasty (M6-C, Spinal Kinetics) Causing Radiculopathy and Myelopathy. / Spätes Versagen einer zervikalen Bandscheibenprothese (M6-C, Spinal Kinetics) mit Radikulomyelopathie.

Cervical disc arthroplasty (CDA) is an approved surgical treatment option in selected patients with cervical spinal disc degeneration. Even though CDA is a standard procedure since 20 years, there is a lack of information about long term performance. The published reoperation rates after CDA are low and comparable to anterior cervical fusion. The authors describe a severe failure and dysfunction with a partial core dislocation of a cervical prosthesis into the spinal canal (M6-C, Spinal Kinetics, Sunnyvale, CA, USA). Six years after implantation of a cTDR (cervical Total Disk Replacement) of the M6 type at C4/5 level, a 52 year-old women presented herself with new clinical signs of cervical myelopathy and radicular pain. Complete posterior dislocation of the central core of the implant into the spinal canal was identified as a cause. The failed device was removed completely and an ACCF (anterior cervical corpectomy and fusion) was performed. Intraoperatively, rupture of the posterior portion of the mesh tissue with posterior dislocation of the whole prosthesis core was detected. This is the second described case of a severe implant failure with core dislocation in this type of cTDR device. Even though there are thousands of successful implantations and middle term outcomes, it seems to be necessary to continue with long term radiological follow up to exclude similar failure in this type of prosthesis.

Rupture of the Superior Sagittal Sinus in Penetrating Head Injury-Management of a Rare Trauma Mechanism.

Civilian penetrating head injury caused by foreign objects is rare in Germany (Europe), but can result in complex neurovascular damage. We report on a patient who in suicidal intent inflicted on himself a penetrating brain injury near the vertex with a captive bolt gun. A laceration at the junction of the middle to the posterior third of the superior sinus occurred by bolt and bone fragments leading to critical stenosis and subsequent thrombosis. Upon surgery, the proximal and distal sinus openings were completely thrombosed. The sinus laceration was closed by suture and the intraparenchymal bone fragments were retrieved. Postoperative angiography disclosed persistent occlusion of the superior sagittal sinus. The patient did not develop any symptoms due to venous congestion (edema, hemorrhage), suggesting sufficient collateral venous outflow. The patient completely recovered despite the complexity of the lesion.

Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese.

BACKGROUNDInsulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODSIn this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21-59 years; BMI range 27.5-45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTSThe exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSIONOur study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATIONClinicalTrials.gov (NCT03151590).FUNDINGBMBF/DZD 01GI0925.

Reply to Schausberger, P. Not Seeing the Mites for the Hairs. Comment on "Möth et al. Unexpected Effects of Local Management and Landscape Composition on Predatory Mites and Their Food Resources in Vineyards. Insects 2021, 12, 180".

This is a reply to the comment from Schausberger [...].