Element Position Calibration for Matrix Array Transducers with Multiple Disjoint Piezoelectric Panels.

Two-dimensional ultrasound transducers enable the acquisition of fully volumetric data that have been demonstrated to provide greater diagnostic information in the clinical setting and are a critical tool for emerging ultrasound methods, such as super-resolution and functional imaging. This technology, however, is not without its limitations. Due to increased fabrication complexity, some matrix probes with disjoint piezoelectric panels may require initial calibration. In this manuscript, two methods for calibrating the element positions of the Vermon 1024-channel 8 MHz matrix transducer are detailed. This calibration is a necessary step for acquiring high resolution B-mode images while minimizing transducer-based image degradation. This calibration is also necessary for eliminating vessel-doubling artifacts in super-resolution images and increasing the overall signal-to-noise ratio (SNR) of the image. Here, we show that the shape of the point spread function (PSF) can be significantly improved and PSF-doubling artifacts can be reduced by up to 10 dB via this simple calibration procedure.

Cus2 enforces the first ATP-dependent step of splicing by binding to yeast SF3b1 through a UHM-ULM interaction.

Stable recognition of the intron branchpoint (BP) by the U2 snRNP to form the pre-spliceosome is the first ATP-dependent step of splicing. Genetic and biochemical data from yeast indicate that Cus2 aids U2 snRNA folding into the stem IIa conformation prior to pre-spliceosome formation. Cus2 must then be removed by an ATP-dependent function of Prp5 before assembly can progress. However, the location from which Cus2 is displaced and the nature of its binding to the U2 snRNP are unknown. Here, we show that Cus2 contains a conserved UHM (U2AF homology motif) that binds Hsh155, the yeast homolog of human SF3b1, through a conserved ULM (U2AF ligand motif). Mutations in either motif block binding and allow pre-spliceosome formation without ATP. A 2.0 Å resolution structure of the Hsh155 ULM in complex with the UHM of Tat-SF1, the human homolog of Cus2, and complementary binding assays show that the interaction is highly similar between yeast and humans. Furthermore, we show that Tat-SF1 can replace Cus2 function by enforcing ATP dependence of pre-spliceosome formation in yeast extracts. Cus2 is removed before pre-spliceosome formation, and both Cus2 and its Hsh155 ULM binding site are absent from available cryo-EM structure models. However, our data are consistent with the apparent location of the disordered Hsh155 ULM between the U2 stem-loop IIa and the HEAT repeats of Hsh155 that interact with Prp5. We propose a model in which Prp5 uses ATP to remove Cus2 from Hsh155 such that extended base-pairing between U2 snRNA and the intron BP can occur.

Asymptomatic uterus-like mass (ULM) of the extraperitoneal space - a case report of a rare finding with unusual clinical presentation and review of the literature.

The paper presents a case of a uterus-like mass (ULM), a rare type of tumour of the female reproductive system, which did not present any clinical symptoms described in other cases of ULMs. There are 35 reported cases of this type of tumour. It is defined as a lesion composed of smooth muscle-like stromal cells with a central cavity lined with endometrial type epithelium. There are three theories on the pathogenesis of ULMs which we discuss along with clinical presentation, diagnostic features, treatment options and potential oncological implications of this type of tumour, based on our case, and the review of the literature.

Polymorphism of the IL13 gene may be associated with Uterine leiomyomas in Slovenian women.

Uterine leiomyomas (ULM) are a common cause of solid pelvic tumors in women. Their etiopathogenesis remains unclear. Interleukins (ILs) and their receptors can influence tumor biology of ULM. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) exhibited in the genes IL4 (rs2070874), IL4R (rs1801275), IL12RB1 (rs11575934), IL12B (rs6887695), IL13 (rs20541) and IL23R (rs7517847) as risk factors for ULM in Slovenian women and to identify associations between corresponding clinical parameters and the analyzed SNPs. In addition, solitary and multiple ULM were compared to identify clinical and/or genetic parameters influencing their occurrence. We conducted a case-control study that included 181 women with leiomyomas and 133 control subjects. Genotyping of selected SNPs was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and high resolution melting (HRM) techniques. The TT genotype of rs20541 (IL13) was significantly associated with decreased risk of ULM compared to both the CC and CT genotypes [p = 0.018; odds ratio (OR) = 0.184; 95% confidence interval (95% CI) = 0.048-0.7121. Using genetic and clinical data to develop a predictive model with logistic regression, we found that adenomyosis, higher age at diagnosis, family history of ULM occurrence, earlier menarche, lower number of pregnancies and lower age at first sexual intercourse, the G allele and genotypes AG and GG of rs1801275 (IL4R) were associated with an increased risk of multiple ULM occurrence. We also found an association between rs20541 (IL13) and 17ß-estradiol serum levels in patients with multiple ULM (p 0.003). Our study showed, for the first time, that rs20541 (IL13) may contribute to susceptibility of ULM development and that rs1801275 (IL4R) can predispose patients to develop multiple ULM.

Subtyping of the Legionella pneumophila "Ulm" outbreak strain using the CRISPR-Cas system.

In 2009/2010 an outbreak of Legionnaires' disease with 64 cases including four fatalities took place in the city of Ulm/Neu-Ulm in Germany. L. pneumophila serogroup 1, mAb type Knoxville, sequence type (ST) 62 was identified as the epidemic strain. This strain was isolated from eight patients and from a cooling tower in the city of Ulm. Based on whole genome sequencing data from one patient strain, we identified an Lvh type IV secretion system containing a CRISPR-Cas system. The CRISPR sequence contains 38 spacer DNA sequences. We used these variable DNA spacers to further subtype the outbreak strain as well as six epidemiologically unrelated strains of CRISPR-Cas positive ST62 strains isolated at various regions in Germany. The first 12 spacer DNAs of eight patient isolates and three environmental isolates from the suspected source of infection were analyzed and found to be identical. Spacer DNAs were identified in further six epidemiologically unrelated patient isolates of L. pneumophila of ST62 in addition to the 12 "core" spacers. The presence of new spacer DNAs at the 5' site downstream of the first repeat indicates that these CRISPR-Cas systems seem to be functional. PCR analysis revealed that not all L. pneumophila sg1 ST62 strains investigated exhibited a CRISPR-Cas system. In addition, we could demonstrate that the CRISPR-Cas system is localized on a genomic island (LpuGI-Lvh) which can be excised from the chromosome and therefore may be transferable horizontally to other L. pneumophila strains.

Non-invasive ultrasound localization microscopy (ULM) in azoospermia: connecting testicular microcirculation to spermatogenic functions.

Rationale: Azoospermia is a significant reproductive challenge. Differentiating between non-obstructive azoospermia (NOA) and obstructive azoospermia (OA) is crucial as each type requires distinct management strategies. Testicular microcirculation plays a profound role in spermatogenic functions. However, current diagnostic methods are limited in their ability to effectively elucidate this crucial connection. Methods: We employed ultrasound localization microscopy (ULM) to visualize testicular microcirculation in NOA and OA patients and quantified the testicular hemodynamic parameters. Pearson correlation analysis was conducted to investigate the inner connection between parameters of testicular microcirculation and clinical spermatogenic functions. We conducted multiple logistic regression analysis to establish a new diagnostic model that integrates follicle-stimulating hormone (FSH) and mean vascular diameter to distinguish NOA from OA. Results: Our findings demonstrated significant differences in vascular parameters between NOA and OA, with NOA characterized by lower mean vascular diameter (p < 0.001), vessel density (p < 0.001), and fractal number (p < 0.001). Testicular volume showed a moderate positive correlation with mean vascular diameter (r = 0.419, p < 0.01) and vessel density (r = 0.415, p < 0.01); Mean vascular diameter exhibited negative correlations with both FSH (r = -0.214, p < 0.05) and age (r = -0.240, p < 0.05); FSH (r = -0.202, p < 0.05) and luteinizing hormone (LH) (r = -0.235, p < 0.05) were negatively correlated with mean blood flow velocity. The diagnostic model demonstrated an area under the curve (AUC) of 0.968. We also reported a method to map the vascular pressure distribution derived from the blood flow velocity generated by ULM. Conclusions: ULM provides a non-invasive and detailed assessment of testicular microvascular dynamics. The ULM-derived vascular parameters are able to connect testicular microcirculation to spermatogenic functions. The combination of FSH and mean vascular diameter enhances diagnostic precision and holds potential for distinguishing NOA from OA.

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells.

Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1mut) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1wt) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1wt function. To investigate if the pharmacological inhibition of U2AF1wt function can provoke drug-induced vulnerability of cells harboring U2AF1 mut , we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit (SF1-8) selectively inhibited growth of leukemia cell lines overexpressingU2AF1 mut and human primary MDS cells carrying U2AF1 mut . RNA-seq analysis of K562-U2AF1mut following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1 mut cells by inhibiting the U2AF1wt protein.

CDK11, a splicing-associated kinase regulating gene expression.

The ability of a cell to properly express its genes depends on optimal transcription and splicing. RNA polymerase II (RNAPII) transcribes protein-coding genes and produces pre-mRNAs, which undergo, largely co-transcriptionally, intron excision by the spliceosome complex. Spliceosome activation is a major control step, leading to a catalytically active complex. Recent work has showed that cyclin-dependent kinase (CDK)11 regulates spliceosome activation via the phosphorylation of SF3B1, a core spliceosome component. Thus, CDK11 arises as a major coordinator of gene expression in metazoans due to its role in the rate-limiting step of pre-mRNA splicing. This review outlines the evolution of CDK11 and SF3B1 and their emerging roles in splicing regulation. It also discusses how CDK11 and its inhibition affect transcription and cell cycle progression.

Assessment of coronary microcirculation alterations in a porcine model of no-reflow using ultrasound localization microscopy: a proof of concept study.

BACKGROUND: Coronary microvascular obstruction also known as no-reflow phenomenon is a major issue during myocardial infarction that bears important prognostic implications. Alterations of the microvascular network remains however challenging to assess as there is no imaging modality in the clinics that can image directly the coronary microvascular vessels. Ultrasound Localization Microscopy (ULM) imaging was recently introduced to map microvascular flows at high spatial resolution (∼10 µm). In this study, we developed an approach to image alterations of the microvascular coronary flow in ex vivo perfused swine hearts. METHODS: A porcine model of myocardial ischemia-reperfusion was used to obtain microvascular coronary alterations and no-reflow. Four female hearts with myocardial infarction in addition to 6 controls were explanted and placed immediately in a dedicated preservation and perfusion box manufactured for ultrasound imaging. Microbubbles (MB) were injected into the vasculature to perform Ultrasound Localization Microscopy (ULM) imaging and a linear ultrasound probe mounted on a motorized device was used to scan the heart on multiple slices. The coronary microvascular anatomy and flow velocity was reconstructed using dedicated ULM algorithms and analyzed quantitatively. FINDINGS: We were able to image the coronary microcirculation of ex vivo swine hearts at a resolution of tens of microns and measure flow velocities ranging from 10 mm/s in arterioles up to more than 200 mm/s in epicardial arteries. Under different aortic perfusion pressures, we measured in large arteries of a subset of control hearts an increase of flow velocity from 31 ± 11 mm/s at 87 mmHg to 47 ± 17 mm/s at 132 mmHg (N = 3 hearts, P < 0.05). This increase was compared with a control measurement with a flowmeter in the aorta. We also compared 6 control hearts to 4 hearts in which no-reflow was induced by the occlusion and reperfusion of a coronary artery. Using average MB velocity and average density of MB per unit of surface as two ULM quantitative markers of perfusion, we were able to detect areas of coronary no-reflow in good agreement with a control anatomical pathology analysis of the cardiac tissue. In the no-reflow zone, we measured an average perfusion of 204 ± 305 MB/mm2 compared to 3182 ± 1302 MB/mm2 in the surrounding re-perfused area. INTERPRETATION: We demonstrated this approach can directly image and quantify coronary microvascular obstruction and no-reflow on large mammal perfused hearts. This is a first step for noninvasive, quantitative and affordable assessment of the coronary microcirculation function and particularly coronary microvascular anatomy in the infarcted heart. This approach has the potential to be extended to other clinical situations characterized by microvascular dysfunction. FUNDING: This study was supported by the French National Research Agency (ANR) under ANR-21-CE19-0002 grant agreement.

Frame rate effects and their compensation on super-resolution microvessel imaging using ultrasound localization microscopy.

Ultrasound localization microscopy (ULM) breaks the diffraction limit and allows imaging microvasculature at micrometric resolution while preserving the penetration depth. Frame rate plays an important role for high-quality ULM imaging, but there is still a lack of review and investigation of the frame rate effects on ULM. This work aims to clarify how frame rate influences the performance of ULM, including the effects of microbubble detection, localization and tracking. The performance of ULM was evaluated using an in vivo rat brain dataset (15.6 MHz, 3 tilted plane waves (-5°, 0°, +5°), at a compounded frame rate of 1000 Hz) with different frame rates. Quantification methods, including Fourier ring correlation and saturation parameter, were applied to analyze the spatial resolution and reconstruction efficiency, respectively. In addition, effects on each crucial step in ULM processing were further analyzed. Results showed that when frame rates dropped from 1000 Hz to 250 Hz, the spatial resolution deteriorated from 9.9 µm to 15.0 µm. Applying a velocity constraint was able to improve the ULM performance, but inappropriate constraint may artificially result in high apparent resolution. For the dataset, compared with the results of 1000 Hz frame rate, the velocity was underestimated at 100 Hz with 47.18% difference and the saturation was reduced from 55.00% at 1000 Hz to 43.34% at 100 Hz. Analysis showed that inadequate frame rate generated unreliable microbubble detection, localization and tracking as well as incomplete track reconstruction, resulting in the deterioration in spatial resolution, the underestimation in velocity measurement and the decrease in saturation. Finally, a guidance of determining the frame rate requirement was discussed by considering the required spatial sampling points based on vessel morphology, clutter filtering method, tracking algorithm and acquisition time, which provides indications for future clinical application of ULM method.

Splicing quality control mediated by DHX15 and its G-patch activator SUGP1.

Pre-mRNA splicing is surveilled at different stages by quality control (QC) mechanisms. The leukemia-associated DExH-box family helicase hDHX15/scPrp43 is known to disassemble spliceosomes after splicing. Here, using rapid protein depletion and analysis of nascent and mature RNA to enrich for direct effects, we identify a widespread splicing QC function for DHX15 in human cells, consistent with recent in vitro studies. We find that suboptimal introns with weak splice sites, multiple branch points, and cryptic introns are repressed by DHX15, suggesting a general role in promoting splicing fidelity. We identify SUGP1 as a G-patch factor that activates DHX15's splicing QC function. This interaction is dependent on both DHX15's ATPase activity and on SUGP1's U2AF ligand motif (ULM) domain. Together, our results support a model in which DHX15 plays a major role in splicing QC when recruited and activated by SUGP1.

Model-free fast integral terminal sliding-mode control method based on improved fast terminal sliding-mode observer for PMSM with unknown disturbances.

This paper presents a novel model-free fast integral terminal sliding-mode control (MFFITSMC) method based on an improved fast terminal sliding-mode observer (IFTSMO) for permanent magnet synchronous motor (PMSM) drive system, which can effectively eliminate the impact caused by unknown disturbances, such as parameter perturbations and external disturbances. The PMSM mathematical model with unknown disturbances is first established, and the ultra-local model (ULM) of the PMSM speed loop is constructed. Next, the model-free fast integral terminal sliding-mode controller is designed in the speed loop based on the ULM. Then, the IFTSMO is designed to precisely estimate the unknown term of the ULM, and the estimated unknown term is fed back to the MFFITSMC controller to perform compensation for unknown disturbances in real time. Finally, compared with the proportional-integral (PI) control method and the conventional model-free sliding-mode control (MFSMC) method, the results of simulations and experiments demonstrate that the presented MFFITSMC method reduces the dependence on the precise model and achieves the purpose of anti-disturbance control of the PMSM drive system.

SAP30BP interacts with RBM17/SPF45 to promote splicing in a subset of human short introns.

Human pre-mRNA splicing requires the removal of introns with highly variable lengths, from tens to over a million nucleotides. Therefore, mechanisms of intron recognition and splicing are likely not universal. Recently, we reported that splicing in a subset of human short introns with truncated polypyrimidine tracts depends on RBM17 (SPF45), instead of the canonical splicing factor U2 auxiliary factor (U2AF) heterodimer. Here, we demonstrate that SAP30BP, a factor previously implicated in transcriptional control, is an essential splicing cofactor for RBM17. In vitro binding and nuclear magnetic resonance analyses demonstrate that a U2AF-homology motif (UHM) in RBM17 binds directly to a newly identified UHM-ligand motif in SAP30BP. We show that this RBM17-SAP30BP interaction is required to specifically recruit RBM17 to phosphorylated SF3B1 (SF3b155), a U2 small nuclear ribonucleoprotein (U2 snRNP) component in active spliceosomes. We propose a mechanism for splicing in a subset of short introns, in which SAP30BP guides RBM17 in the assembly of active spliceosomes.

Ultrasound super-resolution imaging with a hierarchical Kalman tracker.

Microbubble (MB) tracking plays an important role in ultrasound super-resolution imaging (SRI) by enabling velocity estimation and improving image quality. This work presents a new hierarchical Kalman (HK) tracker to achieve better performance at scenarios with high concentrations of MBs and high localization uncertainty. The method attempts to follow MBs with different velocity ranges using different Kalman filters. An extended simulation framework for evaluating trackers is also presented and used for comparison of the proposed HK tracker with the nearest-neighbor (NN) and Kalman (K) trackers. The HK tracks were most similar to the ground truth with the highest Jaccard similarity coefficient in 79% of the scenarios and the lowest root-mean-square error in 72% of the scenarios. The HK tracker reconstructed vessels with a more accurate diameter. In a scenario with an uncertainty of 51.2µm in MB localization, a vessel diameter of 250µm was estimated as 257µm by HK tracker, compared with 329µm and 389µm for the K and NN trackers. In the same scenario, the HK tracker estimated MB velocities with a relative bias down to 1.7% and a relative standard deviation down to 8.3%. Finally, the different tracking techniques were applied to in vivo data from rat kidneys, and trends similar to the simulations were observed. Conclusively, the results showed an improvement in tracking performance, when the HK tracker was employed in comparison with the NN and K trackers.

[Transition from a municipal hospital to a modern university clinic : The Urological Clinic Ulm under the direction of Prof. Dr. Hans-Dieter Marquardt]. / Der Wandel vom städtischen Krankenhaus zur modernen Universitätsklinik : Die Urologische Klinik Ulm unter Leitung von Prof. Dr. Hans-Dieter Marquardt.

On 1 September 1958, Prof. Dr. med. Hans-Dieter Marquardt was appointed chief physician of the largest urological hospital in Germany in terms of beds at the time. As the head of the clinic from 1958 until 1983; his skills and guidance were paramount for the smooth transition from a municipal hospital to a urological department of the University of Ulm; under his direction, the clinic developed into a well-known training center with special expertise in transurethral prostate surgery and a regionally and nationally important center for patient care. Professor Marquardt was a gifted physician and surgeon. He can be ranked as one of the pioneers in the field of endoscopic prostate surgery.

Fast super-resolution ultrasound microvessel imaging using spatiotemporal data with deep fully convolutional neural network.

Ultrasound localization microscopy (ULM) has been proposed to image microvasculature beyond the ultrasound diffraction limit. Although ULM can attain microvascular images with a sub-diffraction resolution, long data acquisition time and processing time are the critical limitations. Deep learning-based ULM (deep-ULM) has been proposed to mitigate these limitations. However, microbubble (MB) localization used in deep-ULMs is currently based on spatial information without the use of temporal information. The highly spatiotemporally coherent MB signals provide a strong feature that can be used to differentiate MB signals from background artifacts. In this study, a deep neural network was employed and trained with spatiotemporal ultrasound datasets to better identify the MB signals by leveraging both the spatial and temporal information of the MB signals. Training, validation and testing datasets were acquired from MB suspension to mimic the realistic intensity-varying and moving MB signals. The performance of the proposed network was first demonstrated in the chicken embryo chorioallantoic membrane dataset with an optical microscopic image as the reference standard. Substantial improvement in spatial resolution was shown for the reconstructed super-resolved images compared with power Doppler images. The full-width-half-maximum (FWHM) of a microvessel was improved from 133µm to 35µm, which is smaller than the ultrasound wavelength (73µm). The proposed method was further tested in anin vivohuman liver data. Results showed the reconstructed super-resolved images could resolve a microvessel of nearly 170µm (FWHM). Adjacent microvessels with a distance of 670µm, which cannot be resolved with power Doppler imaging, can be well-separated with the proposed method. Improved contrast ratios using the proposed method were shown compared with that of the conventional deep-ULM method. Additionally, the processing time to reconstruct a high-resolution ultrasound frame with an image size of 1024 × 512 pixels was around 16 ms, comparable to state-of-the-art deep-ULMs.

Hepatic alveolar echinococcosis: Comparative computed tomography study between two Chinese and two European centres.

The main endemic areas for alveolar echinococcosis (AE) are in Central Europe and Western China, and in >98% of cases, AE manifests in the liver. The aim of this work was to compare European and Chinese patient groups for number, size, and computed tomography (CT) appearance of hepatic AE lesions. A total of 200 CT scans of patients with hepatic AE were evaluated by four blinded, experienced radiologists from two European (Besancon, Ulm) and two Chinese centres (Xining, Urumqi). In addition to noting the number, size, and localisation of the lesions, the radiologists evaluated morphological appearance using the Echinococcus multilocularis Ulm Classification - CT scheme. Chinese patients were younger than European patients (36.8 ±â€¯13.2 vs. 63.5 ±â€¯17.7; p < 0.0001) and had significantly larger lesions (120.4 ±â€¯50.8 vs. 70.9 ±â€¯39.8; p < 0.0001). The morphological appearance of the lesions on CT differed significantly between the two groups (p < 0.05), as did the number of lesions (2.6 ±â€¯3.9 in European centres versus 3.8 ±â€¯5.0 in Chinese centres; p = 0.0062). Patient age and AE-related morphological manifestations differ between Europe and China, but the reasons for the differences are unknown.

Evaluation of intrahepatic manifestation and distant extrahepatic disease in alveolar echinococcosis.

BACKGROUND: The main endemic areas of alveolar echinococcosis (AE) are in Central Europe and Western China. Both the infiltration of intrahepatic vascular and bile duct structures as well as extrahepatic disease can lead to further complications and may increase morbidity in patients with AE. AIM: To evaluate vascular/biliary involvement in hepatic AE and its distant extrahepatic disease manifestations in an international collective was the aim. METHODS: Consecutively, five experienced examiners evaluated contrast-enhanced abdominal computed tomography (CT) scans for 200 patients with hepatic AE of each of four locations (n = 50) in Germany, France and China. Therefore, we retrospectively included the 50 most recent abdominal contrast-enhanced CT examinations at each center, performed because of hepatic AE from September 21, 2007 to March 21, 2018. AE liver lesions were classified according to the echinococcosis multilocularis Ulm classification for CT (EMUC-CT). Distant extrahepatic manifestations were documented either by whole body positron emission tomography-CT or with the addition of thoracic CT and cranial magnetic resonance imaging. Vascular/biliary involvement of the hepatic disease as well as the presence of distant extrahepatic manifestations were correlated with the EMUC-CT types of liver lesion. Statistical analysis was performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC, United States). RESULTS: Distant extrahepatic AE manifestations were significantly more frequent in China than in Europe (P = 0.0091). A significant relationship was found between the presence of distant extrahepatic disease and AE liver lesion size (P = 0.0075). Vascular/biliary structures were involved by the liver lesions significantly more frequently in China than in Europe (P < 0.0001), and vascular/biliary involvement depended on lesion size. Different morphological types of AE liver lesions led to varying frequencies of vascular/biliary involvement and were associated with different frequencies of distant extrahepatic manifestations: Vascular/biliary involvement as a function of lesions primary morphology ranged from 5.88% of type IV liver lesions to 100% among type III lesions. Type IV differed significantly in these associations from types I, II, and III (P < 0.0001). With respect to extrahepatic disease, the primary morphology types IV and V of liver lesions were not associated with any case of distant extrahepatic disease. In contrast, distant extrahepatic manifestations in types I-III were found to varying degrees, with a maximum of 22% for type III. CONCLUSION: Different CT morphological patterns of hepatic AE lesions influence vascular/biliary involvement and the occurrence of distant extrahepatic manifestations. There are intercontinental differences regarding the characteristics of AE manifestation.

[Venereal diseases in a "general practice" in the 17th and early 18th centuries]. / Venerische Erkrankungen in einer "Allgemeinarztpraxis" im 17. und frühen 18. Jahrhundert.

The diary of the town physician Johannes Franc (1649-1725), handwritten in Latin, gives-among other diseases-an overview of sexually transmitted infections affecting citizens in Ulm such as syphilis and gonorrhea. Franc reported on his own experiences in the diary and also included many theoretical details on the causes of the diseases and the corresponding therapies, including ethical considerations. Even in ancient times, there are indications of venereal diseases. However, at the latest with the outbreak of syphilis around the year 1495, the treatment and control of the spread of venereal diseases became an important task of medicine. Before gonococci were detected by Neisser in 1879, sexually transmitted diseases were generally seen as a single disease. However, at the beginning of the 18th century, there were several doctors who treated syphilis and gonorrhea as separate entities. Franc was one of them. Examining the milestones in the history of syphilis and gonorrhea, the present article reviews the existing theories that tried to explain the origins of these diseases. Franc's treatment patterns are illustrated. Franc's case reports indicate a fundamental change in the perception of STIs at the end of the 17th/beginning of the 18th century.

UHM-ULM interactions in the RBM39-U2AF65 splicing-factor complex.

RNA-binding protein 39 (RBM39) is a splicing factor and a transcriptional co-activator of estrogen receptors and Jun/AP-1, and its function has been associated with malignant progression in a number of cancers. The C-terminal RRM domain of RBM39 belongs to the U2AF homology motif family (UHM), which mediate protein-protein interactions through a short tryptophan-containing peptide known as the UHM-ligand motif (ULM). Here, crystal and solution NMR structures of the RBM39-UHM domain, and the crystal structure of its complex with U2AF65-ULM, are reported. The RBM39-U2AF65 interaction was confirmed by co-immunoprecipitation from human cell extracts, by isothermal titration calorimetry and by NMR chemical shift perturbation experiments with the purified proteins. When compared with related complexes, such as U2AF35-U2AF65 and RBM39-SF3b155, the RBM39-UHM-U2AF65-ULM complex reveals both common and discriminating recognition elements in the UHM-ULM binding interface, providing a rationale for the known specificity of UHM-ULM interactions. This study therefore establishes a structural basis for specific UHM-ULM interactions by splicing factors such as U2AF35, U2AF65, RBM39 and SF3b155, and a platform for continued studies of intermolecular interactions governing disease-related alternative splicing in eukaryotic cells.