Multidisciplinary surgical management of severe posterior compartment endometriosis.

BACKGROUND: Endometriosis is a chronic, inflammatory, and hormone-dependent disease that affects approximately 10% of women in reproductive age. Endometriosis is categorized into different types, as superficial, deep, and ovarian endometriosis. When deep endometriosis occurs, the sigmoid and rectum are often affected (Becker et al. in Hum Reprod Open, 2022, https://doi.org/10.1093/hropen/hoac009 ). In the following article, we aim to demonstrate stepwise surgery for stage IV endometriosis involving the anterior rectosigmoid. METHODS: We present the case of a 26-year-old obese (BMI 35.87) woman with severe posterior pelvic compartment endometriosis, persistent abdominal pain, and constipation. On preoperative MRI of the pelvis, a 13 cm conglomerate incorporating both ovaries (kissing ovaries), uterine serosa, and the anterior rectosigmoid was observed (Fig. 1). Accordingly, interdisciplinary laparoscopic surgery with a gynecologist and colorectal surgeon was planned. RESULTS: The total laparoscopic approach is demonstrated step by step in the video. CONCLUSIONS: Deep endometriosis is a rare condition. When involvement of other organs (e.g., the bowel) is suspected, preoperative endometriosis-specific imaging should be performed for optimal surgical planning. Experienced endometriosis multidisciplinary surgical teams can provide specialized and high-quality care for patients suffering from this debilitating disease (Luna Russo et al. in Minerva Ginecol, 2020, https://doi.org/10.23736/S0026-4784.20.04544-X ).

Coiled-Coil Peptide Beacon: A Tunable Conformational Switch for Protein Detection.

The understanding of protein folding and assembly is of central importance for the design of proteins and enzymes with novel or improved functions. Minimalistic model systems, such as coiled-coils, provide an excellent platform to improve this understanding and to construct novel molecular devices. Along those lines, we designed a conformational switch that is composed of two coiled-coil forming peptides and a central binding epitope. In the absence of a binding partner, this switch adopts a hairpin-like conformation that opens upon receptor binding. Variation of the coiled-coil length modulates the strength of the intramolecular constraint. The two conformational states of this switch have been linked with characteristic fluorescent properties, which enables the detection of the receptor in real-time.

Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor.

UNLABELLED: Survival of chronic lymphocytic leukemia (CLL) cells depends on stimuli provided by a suitable microenvironment. The factors and mechanisms providing this growth support for CLL cells are not fully understood. We found that plasma levels of macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, were elevated in CLL patients. Therefore, we characterized the functional role of MIF in a CLL mouse model. For this purpose, we crossed Eµ-TCL1 mice with MIF knockout (MIF-/-) mice. The resulting TCL1+/wtMIF/ mice showed a delayed onset of leukemia, reduced splenomegaly and hepatomegaly, and a longer survival than TCL1+/wtMIFwt/wt controls. Immunohistochemical examination of the lymphoid organs showed that the numbers of macrophages were significantly reduced in the spleen and bone marrow of TCL1+/wtMIF/ mice compared with TCL1+/wtMIFwt/wt controls. Mechanistic studies in vitro revealed that the absence of MIF rendered CLL cells more susceptible to apoptosis. Accordingly, incubation with an anti-MIF antibody reduced the survival of CLL cells on a macrophage feeder layer. In addition, the migratory activity of TCL1+/wtMIF/ macrophages was decreased compared with TCL1+/wtMIFwt/wt macrophages. Taken together, our results provide evidence that MIF supports the development of CLL by enhancing the interaction of CLL cells with macrophages. KEY POINTS: Targeted deletion of the gene for macrophage migration inhibitory factor (MIF) delays development of chronic lymphocytic leukemia and prolongs survival in mice. MIF recruits leukemia-associated macrophages to spleen or liver.

Standard and cardiac-gated phase-contrast magnetic resonance imaging in the clinical course of patients with Chiari malformation Type I.

OBJECT: The causal treatment of Chiari malformation Type I (CM-I) consists of removing the obstruction of CSF flow at the level of the foramen magnum. Cerebrospinal fluid flow can be visualized using dynamic phase-contrast MR imaging. Because there is only a paucity of studies evaluating CSF dynamics in the region of the spinal canal on the basis of preoperative and postoperative measurements, the authors investigated the clinical usefulness of cardiacgated phase-contrast MR imaging in patients with CM-I. METHODS: Ninety patients with CM-I underwent preoperative MR imaging of CSF pulsation. Syringomyelia was present in 59 patients and absent in 31 patients. Phase-contrast MR imaging of the entire CNS was used to investigate 22 patients with CM-I before surgery and after a mean postoperative period of 12 months (median 12 months, range 3-33 months). In addition to the dynamic studies, absolute flow velocities, the extension of the syrinx, and tonsillar descent were also measured. RESULTS: The changes in pulsation were highly significant in the region of the (enlarged) cistern (p = 0.0005). Maximum and minimum velocities (the pulsation amplitude) increased considerably in the region where the syrinx was largest in diameter. The changes of pulsation in these patients were significant in the subarachnoid space in all spinal segments but not in the syrinx itself and in the central canal. CONCLUSIONS: The demonstration of CSF flow pulsation can contribute to assessments of surgical outcomes. The results presented here, however, raise doubts about current theories on the pathogenesis of syringomyelia.

The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein.

Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic suitability has been called into question due to its "risky" profile as a tumor suppressor. To evaluate PTEN function and its various roles in disease a number of molecules have so far been developed. However, intrinsic problems associated with phosphatase inhibition and PTEN's complex regulation via post-translational modifications hinder straightforward access to selective modulators. For this reason, central questions associated with PTEN targeting remain unanswered. In this perspective, we summarize current PTEN-targeting strategies and discuss potential approaches to modulate its functional dose, considering all stages of PTEN biogenesis from direct protein modulation to the targeting of relevant miRNAs as well as the PTEN gene and mRNA.

Structural Analysis of the Interaction between the Bacterial Cell Division Proteins FtsQ and FtsB.

Most bacteria and archaea use the tubulin homologue FtsZ as its central organizer of cell division. In Gram-negative Escherichia coli bacteria, FtsZ recruits cytosolic, transmembrane, periplasmic, and outer membrane proteins, assembling the divisome that facilitates bacterial cell division. One such divisome component, FtsQ, a bitopic membrane protein with a globular domain in the periplasm, has been shown to interact with many other divisome proteins. Despite its otherwise unknown function, it has been shown to be a major divisome interaction hub. Here, we investigated the interactions of FtsQ with FtsB and FtsL, two small bitopic membrane proteins that act immediately downstream of FtsQ. We show in biochemical assays that the periplasmic domains of E. coli FtsB and FtsL interact with FtsQ, but not with each other. Our crystal structure of FtsB bound to the ß domain of FtsQ shows that only residues 64 to 87 of FtsB interact with FtsQ. A synthetic peptide comprising those 24 FtsB residues recapitulates the FtsQ-FtsB interactions. Protein deletions and structure-guided mutant analyses validate the structure. Furthermore, the same structure-guided mutants show cell division defects in vivo that are consistent with our structure of the FtsQ-FtsB complex that shows their interactions as they occur during cell division. Our work provides intricate details of the interactions within the divisome and also provides a tantalizing view of a highly conserved protein interaction in the periplasm of bacteria that is an excellent target for cell division inhibitor searches.IMPORTANCE In most bacteria and archaea, filaments of FtsZ protein organize cell division. FtsZ forms a ring structure at the division site and starts the recruitment of 10 to 20 downstream proteins that together form a multiprotein complex termed the divisome. The divisome is thought to facilitate many of the steps required to make two cells out of one. FtsQ and FtsB are part of the divisome, with FtsQ being a central hub, interacting with most of the other divisome components. Here we show for the first time in detail how FtsQ interacts with its downstream partner FtsB and show that mutations that disturb the interface between the two proteins effectively inhibit cell division.

Obesity is not associated with recurrent venous thromboembolism in elderly patients: Results from the prospective SWITCO65+ cohort study.

BACKGROUND: Whether obesity is associated with recurrent venous thromboembolism (VTE) in elderly patients is unknown. OBJECTIVES: To examine the association between two obesity measures, the body mass index (BMI) and the waist circumference (WC), and recurrent VTE in elderly patients. PATIENTS/METHODS: We studied 986 patients aged ≥65 years with an acute VTE from a prospective multicenter cohort study (09/2009-12/2013). The BMI was determined and categorized as <25, 25 to <30, or ≥30 kg/m2. The WC was categorized as <80 cm in women (w)/<94 cm in men (m), 80 to <88 cm (w)/94 to <102 cm (m), or ≥88 cm (w)/≥102 cm (m). We examined the association between the BMI and the WC and the time to a first symptomatic recurrent VTE using competing risk regression, adjusting for known risk factors of VTE recurrence and periods of anticoagulation. RESULTS: The mean follow-up was 28 months. The 3-year cumulative incidence of recurrent VTE did not vary by BMI and was 17.6% for a BMI <25 kg/m2, 11.5% for a BMI 25 to <30 kg/m2, and 16.9% for a BMI ≥30 kg/m2 (P = 0.09). The 3-year cumulative incidence of recurrent VTE did not vary by WC. After adjustment, neither the BMI (sub-hazard ratio [SHR] 1.02, 95% confidence interval [CI 0.98-1.05]) nor the WC (SHR 1.01, 95% CI 0.99-1.02) was associated with recurrent VTE. CONCLUSIONS: Measures of body weight were not associated with recurrent VTE in our cohort. Obesity does not appear to be a predictor of recurrent VTE in the elderly.

Plant cysteine oxidases are dioxygenases that directly enable arginyl transferase-catalysed arginylation of N-end rule targets.

Crop yield loss due to flooding is a threat to food security. Submergence-induced hypoxia in plants results in stabilization of group VII ETHYLENE RESPONSE FACTORs (ERF-VIIs), which aid survival under these adverse conditions. ERF-VII stability is controlled by the N-end rule pathway, which proposes that ERF-VII N-terminal cysteine oxidation in normoxia enables arginylation followed by proteasomal degradation. The PLANT CYSTEINE OXIDASEs (PCOs) have been identified as catalysts of this oxidation. ERF-VII stabilization in hypoxia presumably arises from reduced PCO activity. We directly demonstrate that PCO dioxygenase activity produces Cys-sulfinic acid at the N terminus of an ERF-VII peptide, which then undergoes efficient arginylation by an arginyl transferase (ATE1). This provides molecular evidence of N-terminal Cys-sulfinic acid formation and arginylation by N-end rule pathway components, and a substrate of ATE1 in plants. The PCOs and ATE1 may be viable intervention targets to stabilize N-end rule substrates, including ERF-VIIs, to enhance submergence tolerance in agriculture.