Structural insights into VirB-DNA complexes reveal mechanism of transcriptional activation of virulence genes

VirB activates transcription of virulence genes in Shigella flexneri by alleviating heat-stable nucleoid-structuring protein-mediated promoter repression. VirB is unrelated to the conventional transcriptional regulators, but homologous to the plasmid partitioning proteins. We determined the crystal structures of VirB HTH domain bound by the cis-acting site containing the inverted repeat, revealing that the VirB-DNA complex is related to ParB-ParS-like complexes, presenting an example that a ParB-like protein acts exclusively in transcriptional regulation. The HTH domain of VirB docks DNA major groove and provides multiple contacts to backbone and bases, in which the only specific base readout is mediated by R167. VirB only recognizes one half site of the inverted repeats containing the most matches to the consensus for VirB binding. The binding of VirB induces DNA conformational changes and introduces a bend at an invariant A-tract segment in the cis-acting site, suggesting a role of DNA remodeling. VirB exhibits positive cooperativity in DNA binding that is contributed by the C-terminal domain facilitating VirB oligomerization. The isolated HTH domain only confers partial DNA specificity. Additional determinants for sequence specificity may reside in N- or C-terminal domains. Collectively, our findings support and extend a previously proposed model for relieving heat-stable nucleoid-structuring protein-mediated repression by Vir

Haplotype affinities resolve a major component of goat (<i>Capra hircus</i>) MtDNA D-loop diversity and reveal specific features of the Sardinian stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity. We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.</br

Solid molecular hydrogen: The Broken Symmetry Phase

By performing constant-pressure variable-cell ab initio molecular dynamics simulations we find a quadrupolar orthorhombic structure, of $Pca2_1$ symmetry, for the broken symmetry phase (phase II) of solid H2 at T=0 and P =110 - 150 GPa. We present results for the equation of state, lattice parameters and vibronic frequencies, in very good agreement with experimental observations. Anharmonic quantum corrections to the vibrational frequencies are estimated using available data on H2 and D2. We assign the observed modes to specific symmetry representations.Comment: 5 pages (twocolumn), 4 Postscript figures. To appear in Phys. Rev. Let

Different outcome of six homozygotes for prothrombin A20210A gene variant

Prothrombin G20210A gene variant (FII G20210A) is a risk factor for venous thrombotic disease while conflicting results have been reported for the risk of arterial thrombotic events. However, vascular episodes were absent in up to 40% of the 67 homozygotes for the G20210A described so far, which indicates that the clinical expression depends on additional risk/trigger factors. We describe six homozygotes for the G20210A variant, among which the first pair of siblings (cases n. 3 and 4) reported so far that displayed a strongly heterogeneous clinical outcome. Case 1, a female of 27 years, developed a full thrombosis of common femoral, superficial and popliteal veins. She assumed oral contraceptives in the last two years. Case n. 2, 34 years old, suffered of recurrent pregnancy loss in absence of any causative alteration. Cases n. 3 and n. 5 experienced arterial thrombotic disease, i.e., juvenile myocardial infarction (40 years old) and stroke (48 years old), respectively, in absence of other risk factors. Finally, cases n. 4 and 6 identified as homozygotes for the FII G20210A variant being consanguineous of symptomatic subjects bearing the variant, did not experience any episode of venous nor arterial disease. Both of them have chronic liver disease with an impairement of the prothrombin time INR. Thus, homozygotes for the G20210A are at risk for arterial (in addition to venous) thromobotic events; chronic liver disease might modulate this risk

Nano-Bio-Technology and Sensing Chips: New Systems for Detection in Personalized Therapies and Cell Biology

Further advances in molecular medicine and cell biology also require new electrochemical systems to detect disease biomarkers and therapeutic compounds. Microelectronic technology offers powerful circuits and systems to develop innovative and miniaturized biochips for sensing at the molecular level. However, microelectronic biochips proposed in the literature often do not show the right specificity, sensitivity, and reliability required by biomedical applications. Nanotechnology offers new materials and solutions to improve the surface properties of sensing probes. The aim of the present paper is to review the most recent progress in Nano-Bio-Technology in the area of the development of new electrochemical systems for molecular detection in personalized therapy and cell culture monitoring

The acute phase management of spinal cord injury affecting polytrauma patients : the ASAP study

Publisher Copyright: © 2022, The Author(s).Background: Few data on the management of acute phase of traumatic spinal cord injury (tSCI) in patients suffering polytrauma are available. As the therapeutic choices in the first hours may have a deep impact on outcome of tSCI patients, we conducted an international survey investigating this topic. Methods: The survey was composed of 29 items. The main endpoints of the survey were to examine: (1) the hemodynamic and respiratory management, (2) the coagulation management, (3) the timing of magnetic resonance imaging (MRI) and spinal surgery, (4) the use of corticosteroid therapy, (5) the role of intraspinal pressure (ISP)/spinal cord perfusion pressure (SCPP) monitoring and (6) the utilization of therapeutic hypothermia. Results: There were 171 respondents from 139 centers worldwide. A target mean arterial pressure (MAP) target of 80–90 mmHg was chosen in almost half of the cases [n = 84 (49.1%)]. A temporary reduction in the target MAP, for the time strictly necessary to achieve bleeding control in polytrauma, was accepted by most respondents [n = 100 (58.5%)]. Sixty-one respondents (35.7%) considered acceptable a hemoglobin (Hb) level of 7 g/dl in tSCI polytraumatized patients. An arterial partial pressure of oxygen (PaO2) of 80–100 mmHg [n = 94 (55%)] and an arterial partial pressure of carbon dioxide (PaCO2) of 35–40 mmHg [n = 130 (76%)] were chosen in most cases. A little more than half of respondents considered safe a platelet (PLT) count > 100.000/mm3 [n = 99 (57.9%)] and prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 times the normal control [n = 85 (49.7%)] in patients needing spinal surgery. MRI [n = 160 (93.6%)] and spinal surgery [n = 158 (92.4%)] should be performed after intracranial, hemodynamic, and respiratory stabilization by most respondents. Corticosteroids [n = 103 (60.2%)], ISP/SCPP monitoring [n = 148 (86.5%)], and therapeutic hypothermia [n = 137 (80%)] were not utilized by most respondents. Conclusions: Our survey has shown a great worldwide variability in clinical practices for acute phase management of tSCI patients with polytrauma. These findings can be helpful to define future research in order to optimize the care of patients suffering tSCI.Peer reviewe

Acute mesenteric ischemia : updated guidelines of the World Society of Emergency Surgery

Acute mesenteric ischemia (AMI) is a group of diseases characterized by an interruption of the blood supply to varying portions of the intestine, leading to ischemia and secondary inflammatory changes. If untreated, this process may progress to life-threatening intestinal necrosis. The incidence is low, estimated at 0.09-0.2% of all acute surgical admissions, but increases with age. Although the entity is an uncommon cause of abdominal pain, diligence is required because if untreated, mortality remains in the range of 50%. Early diagnosis and timely surgical intervention are the cornerstones of modern treatment to reduce the high mortality associated with this entity. The advent of endovascular approaches in parallel with modern imaging techniques is evolving and provides new treatment options. Lastly, a focused multidisciplinary approach based on early diagnosis and individualized treatment is essential. Thus, we believe that updated guidelines from World Society of Emergency Surgery are warranted, in order to provide the most recent and practical recommendations for diagnosis and treatment of AMI.Peer reviewe

Haplotype Affinities Resolve a Major Component of Goat (Capra hircus) MtDNA D-Loop Diversity and Reveal Specific Features of the Sardinian Stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity

ECLAPTE: Effective Closure of LAParoTomy in Emergency-2023 World Society of Emergency Surgery guidelines for the closure of laparotomy in emergency settings

Laparotomy incisions provide easy and rapid access to the peritoneal cavity in case of emergency surgery. Incisional hernia (IH) is a late manifestation of the failure of abdominal wall closure and represents frequent complication of any abdominal incision: IHs can cause pain and discomfort to the patients but also clinical serious sequelae like bowel obstruction, incarceration, strangulation, and necessity of reoperation. Previous guidelines and indications in the literature consider elective settings and evidence about laparotomy closure in emergency settings is lacking. This paper aims to present the World Society of Emergency Surgery (WSES) project called ECLAPTE (Effective Closure of LAParoTomy in Emergency): the final manuscript includes guidelines on the closure of emergency laparotomy

The Global Alliance for Infections in Surgery : defining a model for antimicrobial stewardship-results from an international cross-sectional survey

Background: Antimicrobial Stewardship Programs (ASPs) have been promoted to optimize antimicrobial usage and patient outcomes, and to reduce the emergence of antimicrobial-resistant organisms. However, the best strategies for an ASP are not definitively established and are likely to vary based on local culture, policy, and routine clinical practice, and probably limited resources in middle-income countries. The aim of this study is to evaluate structures and resources of antimicrobial stewardship teams (ASTs) in surgical departments from different regions of the world. Methods: A cross-sectional web-based survey was conducted in 2016 on 173 physicians who participated in the AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections) project and on 658 international experts in the fields of ASPs, infection control, and infections in surgery. Results: The response rate was 19.4%. One hundred fifty-six (98.7%) participants stated their hospital had a multidisciplinary AST. The median number of physicians working inside the team was five [interquartile range 4-6]. An infectious disease specialist, a microbiologist and an infection control specialist were, respectively, present in 80.1, 76.3, and 67.9% of the ASTs. A surgeon was a component in 59.0% of cases and was significantly more likely to be present in university hospitals (89.5%, p <0.05) compared to community teaching (83.3%) and community hospitals (66.7%). Protocols for pre-operative prophylaxis and for antimicrobial treatment of surgical infections were respectively implemented in 96.2 and 82.3% of the hospitals. The majority of the surgical departments implemented both persuasive and restrictive interventions (72.8%). The most common types of interventions in surgical departments were dissemination of educational materials (62.5%), expert approval (61.0%), audit and feedback (55.1%), educational outreach (53.7%), and compulsory order forms (51.5%). Conclusion: The survey showed a heterogeneous organization of ASPs worldwide, demonstrating the necessity of a multidisciplinary and collaborative approach in the battle against antimicrobial resistance in surgical infections, and the importance of educational efforts towards this goal.Peer reviewe