Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers

The Italian TREETALKER NETWORK (ITT-Net): continuous large scale monitoring of tree functional traits and vulnerabilities to climate change

20openItalian coauthor/editorThe Italian TREETALKER NETWORK (ITT-Net) aims to respond to one of the grand societal challenges: the impact of climate changes on forests ecosystem services and forest dieback. The comprehension of the link between these phenomena requires to complement the most classical approaches with a new monitoring paradigm based on large scale, single tree, high frequency and long-term monitoring tree physiology, which, at present, is limited by the still elevated costs of multi-sensor devices, their energy demand and maintenance not always suitable for monitoring in remote areas. The ITT-Net network will be a unique and unprecedented worldwide example of real time, large scale, high frequency and long-term monitoring of tree physiological parameters. By spring 2020, as part of a national funded project (PRIN) the network will have set 37 sites from the north-east Alps to Sicily where a new low cost, multisensor technology “the TreeTalker®” equipped to measure tree radial growth, sap flow, transmitted light spectral components related to foliage dieback and physiology and plant stability (developed by Nature 4.0), will monitor over 600 individual trees. A radio LoRa protocol for data transmission and access to cloud services will allow to transmit in real time high frequency data on the WEB cloud with a unique IoT identifier to a common database where big data analysis will be performed to explore the causal dependency of climate events and environmental disturbances with tree functionality and resilience. With this new network, we aim to create a new knowledge, introducing a massive data observation and analysis, about the frequency, intensity and dynamical patterns of climate anomalies perturbation on plant physiological response dynamics in order to: 1) characterize the space of “normal or safe tree operation mode” during average climatic conditions; 2) identify the non-linear tree responses beyond the safe operation mode, induced by extreme events, and the tipping points; 3) test the possibility to use a high frequency continuous monitoring system to identify early warning signals of tree stress which might allow to follow tree dynamics under climate change in real time at a resolution and accuracy that cannot always be provided through forest inventories or remote sensing technologies.openCastaldi, S.; Antonucci, S.; Asgharina, S.; Battipaglia, G.; Belelli Marchesini, L.; Cavagna, M.; Chini, I.; Cocozza, C.; Gianelle, D.; La Mantia, T.; Motisi, A.; Niccoli, F.; Pacheco Solana, A.; Sala, G.; Santopuoli, G.; Tonon, G.; Tognetti, R.; Zampedri, R.; Zorzi, I.; Valentini, R.Castaldi, S.; Antonucci, S.; Asgharina, S.; Battipaglia, G.; Belelli Marchesini, L.; Cavagna, M.; Chini, I.; Cocozza, C.; Gianelle, D.; La Mantia, T.; Motisi, A.; Niccoli, F.; Pacheco Solana, A.; Sala, G.; Santopuoli, G.; Tonon, G.; Tognetti, R.; Zampedri, R.; Zorzi, I.; Valentini, R

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Urinary Tract Endometriosis: A Multidisciplinary Fight Against a Silent Enemy

Study Objective: To demonstrate the safety and feasibility of laparoscopic robotic assisted approach to urinary tract endometriosis.Design: This is an educational video to explain the main steps of robotic assisted ureteroneocystostomy owing to endometriosis.Setting: Tertiary care university hospital. A patient written consent was obtained on March 9, 2021. The local institutional review board confirmed that the video met the ethical criteria.Interventions: Laparoscopic robotic assisted resection of uterosacral ligament endometriotic nodule, left terminal partial ureterectomy, partial cystectomy, and ureteroneocystostomy.Conclusion: This video shows a stepwise approach to laparoscopic robotic assisted urinary tract endometriosis management demonstrating its feasibility and safety. Urinary tract endometriosis affect only the 0.3% to 6% of women affected by endometriosis, among which the most common localization is the bladder (84%-90%) [1]. The ureteral compression is rare but can lead to obstruction up to silent loss of renal function [2], which is one of the main factors to take into account in the management of this disease [3]. (C) 2022 Published by Elsevier Inc. on behalf of AAGL