Prediction and observation of an antiferromagnetic topological insulator.

Magnetic topological insulators are narrow-gap semiconductor materials that combine non-trivial band topology and magnetic order1. Unlike their nonmagnetic counterparts, magnetic topological insulators may have some of the surfaces gapped, which enables a number of exotic phenomena that have potential applications in spintronics1, such as the quantum anomalous Hall effect2 and chiral Majorana fermions3. So far, magnetic topological insulators have only been created by means of doping nonmagnetic topological insulators with 3d transition-metal elements; however, such an approach leads to strongly inhomogeneous magnetic4 and electronic5 properties of these materials, restricting the observation of important effects to very low temperatures2,3. An intrinsic magnetic topological insulator-a stoichiometric well ordered magnetic compound-could be an ideal solution to these problems, but no such material has been observed so far. Here we predict by ab initio calculations and further confirm using various experimental techniques the realization of an antiferromagnetic topological insulator in the layered van der Waals compound MnBi2Te4. The antiferromagnetic ordering  that MnBi2Te4  shows makes it invariant with respect to the combination of the time-reversal and primitive-lattice translation symmetries, giving rise to a ℤ2 topological classification; ℤ2 = 1 for MnBi2Te4, confirming its topologically nontrivial nature. Our experiments indicate that the symmetry-breaking (0001) surface of MnBi2Te4 exhibits a large bandgap in the topological surface state. We expect this property to eventually enable the observation of a number of fundamental phenomena, among them quantized magnetoelectric coupling6-8 and axion electrodynamics9,10. Other exotic phenomena could become accessible at much higher temperatures than those reached so far, such as the quantum anomalous Hall effect2 and chiral Majorana fermions3.

Exploitation of the host exocyst complex by bacterial pathogens.

Intracellular bacterial pathogens remodel the plasma membrane of eukaryotic cells in order to establish infection. A common and well-studied mechanism of plasma membrane remodelling involves bacterial stimulation of polymerization of the host actin cytoskeleton. Here, we discuss recent results showing that several bacterial pathogens also exploit the host vesicular trafficking pathway of 'polarized exocytosis' to expand and reshape specific regions in the plasma membrane during infection. Polarized exocytosis is mediated by an evolutionarily conserved octameric protein complex termed the exocyst. We describe examples in which the bacteria Listeria monocytogenes, Salmonella enterica serovar Typhimurium, and Shigella flexneri co-opt the exocyst to promote internalization into human cells or intercellular spread within host tissues. We also discuss results showing that Legionella pneumophila or S. flexneri manipulate exocyst components to modify membrane vacuoles to favour intracellular replication or motility of bacteria. Finally, we propose potential ways that pathogens manipulate exocyst function, discuss how polarized exocytosis might promote infection and highlight the importance of future studies to determine how actin polymerization and polarized exocytosis are coordinated to achieve optimal bacterial infection.

SIAH1 modulates antiviral immune responses by targeting deubiquitinase USP19.

Tight control of the type I interferon (IFN) signaling pathway is critical for maintaining host innate immune responses, and the ubiquitination and deubiquitination of signaling molecules are essential for signal transduction. Deubiquitinase ubiquitin-specific protein 19 (USP19) is known to be involved in deubiquitinating Beclin1, TRAF3, and TRIF for downregulation of the type I IFN signaling. Here, we show that SIAH1, a cellular E3 ubiquitin ligase that is involved in multicellular pathway, is a potent positive regulator of virus-mediated type I IFN signaling that maintains homeostasis within the antiviral immune response by targeting USP19. In the early stages of virus infection, stabilized SIAH1 directly interacts with the USP19 and simultaneously mediates K27-linked ubiquitination of 489, 490, and 610 residues of USP19 for proteasomal degradation. Additionally, we found that USP19 specifically interacts with MAVS and deubiquitinates K63-linked ubiquitinated MAVS for negative regulation of type I IFN signaling. Ultimately, we identified that SIAH1-mediated degradation of USP19 reversed USP19-mediated deubiquitination of MAVS, Beclin1, TRAF3, and TRIF, resulting in the activation of antiviral immune responses. Taken together, these findings provide new insights into the molecular mechanism of USP19 and SIAH1, and suggest a critical role of SIAH1 in antiviral immune response and homeostasis.

Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Recalibration of Framingham risk for a local population of Sri Lanka.

BACKGROUND: Cardiovascular Diseases (CVD) account for the highest number of deaths and disability globally and within Sri Lanka. A CVD risk prediction tool is a simple means of early identification of high-risk groups which is a cost-effective preventive strategy, especially for resource-poor countries. Distribution of risk factor levels varies in different regions even within the same country, thus a common risk estimation tool for the country may give false local predictions. Since there are few published data related to Sri Lanka the aim of this study was to recalibrate the Framingham equation according to the local risk factor profile of a population in the Kurunegala region in Sri Lanka. METHOD: A cross-sectional study was conducted with the participation of 1 102 persons from the Kurunegala Regional Director of Health Services area and the data was collected using an interviewer-administered questionnaire, anthropometric, blood pressure, and biochemical measurements. CVD risk was estimated using Framingham original and recalibrated CVD risk assessment methods. Current CVD mortality and morbidity data and the recalibration method conducted by the method described by Wilson and colleagues were used for calculations. RESULTS: Original and recalibrated Framingham CVD risk scores predicted 55.5% (N = 612) and 62.3% (N = 687) to be having less than 10% CVD risk respectively. Further, the original and recalibrated CVD Risk Scores predicted 2.2% (N = 24) and 1.8% (N = 20) to be having CVD risk more than 40% respectively. CONCLUSION: These findings show an over prediction of the CVD risk with the original Framingham risk calculations which signifies the importance of development of a region-specific risk prediction tool using local risk factor data in Sri Lanka which will prevent unnecessary expenditure to manage people without risk of CVD.

State of transition to Ministry of Health governance of prison healthcare in the Council of Europe region.

OBJECTIVES: This study aimed to examine timebound prison healthcare governance amendments and current structures in Europe two decades after the World Health Organization (WHO) Declaration on Prison Health as part of Public Health adopted in Moscow on 24 October 2003 (Moscow Declaration), which recommended prison health care be closely linked with public health systems to ensure quality prison health care, connected health surveillance, and continuity of care. STUDY DESIGN: We present here a regional evolutionary mapping of the Council of Europe Member State transfer of prison healthcare governance to the auspices of the Ministry of Health. METHODS: The European Committee for the Prevention of Torture database and WHO Regional Office for Europe Health In Prison European Database were scrutinised for Council of Europe (CoE) Member State status regarding the Ministry responsible for prison healthcare governance and if this had changed since the adoption of the Moscow Declaration in 2003. RESULTS: As of October 2023, completed transfer of governance to the Ministry of Health nationally is documented in 13 CoE Member States and in one CoE Member State candidate (Kosovo). Partial transfer is documented in Spain (Catalonia and Basque Autonomous Community) and Switzerland (cantons of Geneva, Valais, Vaud, Neuchatel, and Basel-Stadt). Three CoE Member States operate joint governance of prison health care between Ministries (Malta, Portugal, Türkiye). Transfer is a lengthy process (up to 10 years). CONCLUSIONS: Successful transition requires political commitment, cooperation, needs assessment, resourcing, and evaluation. Monitoring of cost and prison healthcare standards, due process for complaints, and cooperation with independent/Committee against Torture inspections is critical.

Climate footprint assessment of plastic waste pyrolysis and impacts on the Danish waste management system.

Increased plastic recycling is necessary to reduce environmental impacts related to manufacturing and end-of-life of plastic products, however, mechanical recycling (MR) - currently the most widespread recycling option for plastic waste - is limited by quality requirements for inputs and reduced quality of outputs. In this study, pyrolysis of plastic waste is assessed against MR, municipal solid waste incineration (MSWI) and fuel substitution through climate footprint assessment (CFA) based on primary data from pyrolysis of plastic waste sourced from Danish waste producers. Results of the CFA are scaled to the Danish plastic waste resource in an impact assessment of current Danish plastic waste management, and scenarios are constructed to assess reductions through utilization of pyrolysis. Results of the CFA show highest benefits utilizing pyrolysis for monomer recovery (-1400 and -4800 kg CO2e per ton polystyrene (PS) and polymethyl methacrylate (PMMA), respectively) and MR for single polymer polyolefins (-1000 kg CO2e per ton PE). The two management options perform similarly with mixed plastic waste (200 kg CO2e per ton plastic waste). MSWI has the highest impact (1600-2200 kg CO2e per ton plastic waste) and should be avoided when alternatives are available. Scaling the results of the CFA to the full Danish plastic waste resource reveals an impact of 0.79 Mt CO2e in year 2020 of current plastic waste management. Utilizing pyrolysis to manage MR residues reduces the system impact by 15%. Greater reductions are possible through increased separation of plastic from residual waste. The best performance is achieved through a combination of MR and pyrolysis.

Pharmacological labour pain interventions: South African midwives' perspective.

BACKGROUND: Women of childbearing age feel great about giving birth, but the pain could be excruciating depending on their pain tolerances. Midwives requires obstetrical knowledge and skills such as pain management during labour and safety. We explored midwives' perspectives on the utilisation of pharmacological pain alleviation interventions during labour in selected hospitals in Matjhabeng Municipality, Free State province, South Africa. A qualitative study was undertaken, involving a sample of ten midwives, using a semi-structured interview guide. The interviews were audio-recorded and transcribed verbatim. Tesch's open coding data analysis method was applied to analyse the data. The midwives were restricted to use Pethidine and Phenergan prescribed by doctors for labour pain relief, which disrupted labour pain management and obliged them either to wait for a physician or follow telephone instructions. According to the midwives, women taking Pethidine and Phenergan encountered adverse effects and discomfort. Midwives identified high workload, inadequate personnel, lack of skill and knowledge, lack of medication availability, and lack of infrastructure as the primary challenges of administering pharmacological methods to women in labour. The lack of standing orders, which delays the administration of medications pending a physician's prescription, constituted an additional difficulty. In the instance that Pethidine and Phenergan were unavailable or ineffective for some women, the midwives recommended that women be administered alternative pharmacological pain relievers. They also advocated for institutionalization of pharmacological guidelines allowing them to use their discretion when treating labour pain. Midwives can only utilise a few standardised and regulated pharmacological medications for labour pain management. The midwives' ability to administer pharmacological pain relief during labour was hampered by a high workload burden, insufficient staff, lack of skill and understanding, drug unavailability, and inadequate infrastructure. Midwives advocated for supported guidelines that would allow them to treat labour pain at their discretion. Intersectoral stakeholders are required to improve midwife skills and attitudes. Health facilities need to train and supply analgesics to midwives. Midwives ought to be familiar with pharmacological pain relievers.

Quantifying spatiotemporal dynamics in the Kolonnawa marsh of Colombo, Sri Lanka.

Kolonnawa marsh (KM) is an important wetland ecosystem in Colombo district, Sri Lanka that provides essential ecosystem services, and has undergone significant changes over recent decades due to continuous exploitation and reclamation. The values of wetlands are disregarded by decision-makers, despite the fact that they are crucial for improving the quality of water and offer chances for relaxation and amusement in metropolitan areas. Underestimation of the value of wetlands contributes to their continuing deterioration and inevitable loss. Investigating the changes in wetlands can provide crucial information for decision-making. This study aimed to monitor the spatiotemporal land-cover dynamics of KM with the prospect prediction as reduced total extent of KM gradually with time and marsh area being transformed into terrestrial vegetation with time. The collective images from Google Earth (2000 to 2021) and drone data (2022) were analyzed with the GIS application. Subsequently, 50-m2 grid squares with unique cell IDs are designed to link among land cover maps for spatiotemporal land-cover change analysis. Then, we calculate land cover category: surface water, marsh, and terrestrial vegetation proportions for each map in 50-m2 grid cells. Statistical comparison of the land cover changes in grid square cells shows that each land cover category has significant change with the time. The results showed that the reduction of KM marsh resulting in land cover changes has a positive implication on wetland degradation. Thus, interventions should be made for the restoration and sustainable management of KM.

Effect of the Combination of Exercise and Metformin on Osteocalcin, Insülin, Interleukin-6, Glucose Levels, and Body Weights in Rats.

BACKGROUND: Exercise or exercise capacity is a vital physiological function. It is known that certain cytokines support muscle function during exercise and, as a result, increase exercise capacity. AIMS: In this study, the effect of metformin administered in combination with exercise on osteocalcin (OCN), insulin, and interleukin-6 (IL-6) levels in rats was investigated. METHODS: Forty-two male Wistar rats were used in this study. The animals were randomly divided into six groups: control (CONT), only exercise (EXE), metformin_100 mg/kg (Met100), metformin_200 mg/kg (Met200), metformin_100 mg/kg+exercise (Met100+EXE), and metformin_200 mg/kg+exercise (Met200+EXE). A 10-week intervention was conducted, excluding exercise training. During the experiment, the groups receiving metformin application (100 or 200 mg/kg) were administered with metformin. At the end of the study, serum samples were collected from the rats to determine the levels of osteocalcin, insulin, and IL-6 using the enzyme-linked immunosorbent assay method. In addition, glucose levels and body weights were evaluated. GraphPad Prism was used for the analyses. RESULTS: The OCN and insulin levels of the Met100+EXE and Met200+EXE groups were found to be higher compared to the CONT, Met100, and Met200 groups (P < 0.05). The IL-6 level of the EXE group was determined to be higher than that of the CONT, Met100, and Met200 groups (P < 0.01). It was observed that both exercise and the individual or combined application of metformin resulted in lower blood glucose levels compared to the CONT group. The mean body weight of the EXE group was higher than that of the other groups. CONCLUSION: The combined application of metformin and exercise has increased osteocalcin and insulin levels compared to metformin application alone.

Perceptions of the COVID-19 Vaccine and Willingness to Receive Vaccination among Health Workers in Nigeria: A Cross-sectional Study.

BACKGROUND: COVID-19 vaccine hesitancy is a major barrier to vaccine uptake, and the achievement of herd immunity is required to reduce morbidity and mortality and protect the most vulnerable populations. In Nigeria, COVID-19 vaccine hesitancy has been high, and uptake remains very low. Healthcare workers (HCWs) in Nigeria can help support public health efforts to increase vaccine uptake. AIM: This study evaluates Nigerian HCWs' acceptance and intent to recommend the COVID-19 vaccine. SUBJECTS AND METHODS: Cross-sectional survey among 1,852 HCWs in primary, secondary, and tertiary care settings across Nigeria. Respondents included doctors, nurses, pharmacy workers, and clinical laboratory professionals who have direct clinical contact with patients in various healthcare settings. A 33-item questionnaire was used in the study, with two of the questions focused on the COVID-19 vaccine. The responses to the two questions were analyzed using Chi-square (c2) tests and independent t-tests to determine the acceptance of the vaccine. RESULTS: The majority of respondents were younger than 34 years (n = 1,227; 69.2%) and primarily worked in hospitals (n = 1,278; 72.0%). Among the respondents, 79.2% (n = 1,467) endorsed the COVID-19 vaccine as a critical tool in reducing the impact of the disease, and 76.2% (n = 1,412) will accept and recommend the vaccine to their patients. The younger HCWs were more likely to endorse and recommend the vaccine to their patients. CONCLUSION: There is a moderately high COVID-19 vaccine acceptance rate among HCWs surveyed in our study. The confidence of HCWs in its use and their willingness to recommend it to their patients can provide a potentially useful element in increasing acceptance by the larger population in Nigeria.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Cerebral abscesses with odontogenic origin: a population-based cohort study.

OBJECTIVES: Recent studies have indicated that cerebral abscess (CA) patients with odontogenic origin are on the rise. However, CA patients are often poorly characterized and with an unknown etiologic background. The purpose of this study is to identify and characterize CA patients that may have an odontogenic origin based on microbiologic, radiographic, and/or clinical findings. MATERIALS AND METHODS: This is a population-based cohort study analyzing retrospective and prospective data from CA patients. Radiographic examinations of panoramic radiographs (PRs) or computed tomography (CT) scans were conducted. CA patients characterized with odontogenic origin required the fulfilment of the following criteria on admission: (1) Oral pathologic conditions were the only bacterial infections present, (2) oral microorganisms were isolated in the purulent exudate from the brain, and (3) radiographically and/or clinical recordings of oral pathologic conditions. RESULTS: A total of 44 patients could be included in this study of which 25 (57%) were characterized as having CA with a likely odontogenic origin. Type two diabetes (T2D) (p = 0.014) and microorganisms of the Streptococcus anginosus group (SAG) (p < 0.01) were overrepresented in patients with CAs of odontogenic origin. CONCLUSIONS: Odontogenic infections may cause CAs to a greater extent than previously assumed. T2D was overrepresented among patients with odontogenic CA. When microorganisms of the SAG were isolated from the brain pus, CA patients had a predisposing odontogenic or sinus infection. CLINICAL RELEVANCE: The identification of patients with a likely odontogenic CA will contribute to understanding the etiology of the infectious disease and highlighting the importance of preserving oral health.

DEPRESSION AND MEDICATION ADHERENCE AMONG ALDER ADULTS WITH SELECTED CHRONIC MEDICAL CONDITIONS IN MAIDUGURI, NIGERIA.

Introduction: Older adults constitute a rapidly growing population whose healthcare needs are unique, with a higher prevalence of physical and psychiatric morbidities. A knowledge gap exists regarding the association of chronic medical conditions with Depression and how they affect medication adherence. This may be linked to their chronic nature and impacts on the mood of older adults. This study assessed Depression among older adults with Hypertension, Diabetes Mellitus, and Arthritis; and compared its relationship with medication adherence in the speciality clinics of UMTH, Maiduguri. Methods: A comparative cross-sectional analytic study was employed to recruit 327 older adults aged≥60years for six months. They were proportionally distributed into groups of Hypertension only (140), Diabetes only (85), Arthritis only (43), hypertension and diabetes (59). The socio- clinical proforma, Geriatric Depression Scale (GDS-30), and Morisky Medication Adherence Scale (MMAS-8) were administered. Data were analysed using SPSS version 26.0. The mean adherence scores for those with depression were compared with the mean scores of those without depression using a t-test. Results: The study found that the mean medication adherence score was lower in those with depression than those without depression. The difference is significant among the group with arthritis only (t = 1.943 and p-value = 0.049) where those with depression had an adherence score (2.299 ± 0.500) while those without depression scored (3.177 ± 1.267); and also, among the group with HTN + DM (t = 2.769, p-value = 0.006) where those with depression had an adherence score (2.000 ± 0.001) while those without depression scored (4.299 ±2.026). Conclusion: Depression is associated with low medication adherence in older adults with chronic medical conditions. This underscores the need for consultation-liaison practice and proactivity in assessing for depression in older adults with chronic conditions to improve their adherence.

Listeria monocytogenes Co-Opts the Host Exocyst Complex To Promote Internalin A-Mediated Entry.

The bacterial pathogen Listeria monocytogenes induces its internalization (entry) into intestinal epithelial cells through interaction of its surface protein, internalin A (InlA), with the human cell-cell adhesion molecule, E-cadherin. While InlA-mediated entry requires bacterial stimulation of actin polymerization, it remains unknown whether additional host processes are manipulated to promote internalization. Here, we show that interaction of InlA with E-cadherin induces the host membrane-trafficking process of polarized exocytosis, which augments uptake of Listeria. Imaging studies revealed that exocytosis is stimulated at sites of InlA-dependent internalization. Experiments inhibiting human N-ethylmaleimide-sensitive factor (NSF) demonstrated that exocytosis is needed for efficient InlA-mediated entry. Polarized exocytosis is mediated by the exocyst complex, which comprises eight proteins, including Sec6, Exo70, and Exo84. We found that Exo70 was recruited to sites of InlA-mediated entry. In addition, depletion of Exo70, Exo84, or Sec6 by RNA interference impaired entry without affecting surface levels of E-cadherin. Similar to binding of InlA to E-cadherin, homophilic interaction of E-cadherin molecules mobilized the exocyst and stimulated exocytosis. Collectively, these results demonstrate that ligation of E-cadherin induces exocytosis that promotes Listeria entry, and they raise the possibility that the exocyst might also control the normal function of E-cadherin in cell-cell adhesion.

Shigella flexneri subverts host polarized exocytosis to enhance cell-to-cell spread.

Shigella flexneri is a gram-negative bacterial pathogen that causes dysentery. Critical for disease is the ability of Shigella to use an actin-based motility (ABM) process to spread between cells of the colonic epithelium. ABM transports bacteria to the periphery of host cells, allowing the formation of plasma membrane protrusions that mediate spread to adjacent cells. Here we demonstrate that efficient protrusion formation and cell-to-cell spread of Shigella involves bacterial stimulation of host polarized exocytosis. Using an exocytic probe, we found that exocytosis is locally upregulated in bacterial protrusions in a manner that depends on the Shigella type III secretion system. Experiments involving RNA interference (RNAi) indicate that efficient bacterial protrusion formation and spread require the exocyst, a mammalian multi-protein complex known to mediate polarized exocytosis. In addition, the exocyst component Exo70 and the exocyst regulator RalA were recruited to Shigella protrusions, suggesting that bacteria manipulate exocyst function. Importantly, RNAi-mediated depletion of exocyst proteins or RalA reduced the frequency of protrusion formation and also the lengths of protrusions, demonstrating that the exocyst controls both the initiation and elongation of protrusions. Collectively, our results reveal that Shigella co-opts the exocyst complex to disseminate efficiently in host cell monolayers.

Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation.

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.

Puberty disorders among ART-conceived singletons: a Nordic register study from the CoNARTaS group.

STUDY QUESTION: Do ART-conceived children have an increased risk for puberty disorders? SUMMARY ANSWER: Both ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys. WHAT IS KNOWN ALREADY: Some physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited. STUDY DESIGN, SIZE, DURATION: A register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994-2014), Finland (1990-2014), Norway (2002-2015) and Sweden (1985-2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: There were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29-1.64) and late puberty (aHR 1.47, 95% CI: 1.21-1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29-1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24-1.95). LIMITATIONS, REASONS FOR CAUTION: Using reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers' own puberty characteristics and BMI, as well as children's BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility. WIDER IMPLICATIONS OF THE FINDINGS: This large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway's Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium 'Family Formation in Flux-Causes, Consequences and Possible Futures', funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Delineation of molecular interactions of plant growth promoting bacteria induced ß-1,3-glucanases and guanosine triphosphate ligand for antifungal response in rice: a molecular dynamics approach.

BACKGROUND: The plant growth is influenced by multiple interactions with biotic (microbial) and abiotic components in their surroundings. These microbial interactions have both positive and negative effects on plant. Plant growth promoting bacterial (PGPR) interaction could result in positive growth under normal as well as in stress conditions. METHODS: Here, we have screened two PGPR's and determined their potential in induction of specific gene in host plant to overcome the adverse effect of biotic stress caused by Magnaporthe grisea, a fungal pathogen that cause blast in rice. We demonstrated the glucanase protein mode of action by performing comparative modeling and molecular docking of guanosine triphosphate (GTP) ligand with the protein. Besides, molecular dynamic simulations have been performed to understand the behavior of the glucanase-GTP complex. RESULTS: The results clearly showed that selected PGPR was better able to induce modification in host plant at morphological, biochemical, physiological and molecular level by activating the expression of ß-1,3-glucanases gene in infected host plant. The docking results indicated that Tyr75, Arg256, Gly258, and Ser223 of glucanase formed four crucial hydrogen bonds with the GTP, while, only Val220 found to form hydrophobic contact with ligand. CONCLUSIONS: The PGPR able to induce ß-1,3-glucanases gene in host plant upon pathogenic interaction and ß-1,3-glucanases form complex with GTP by hydrophilic interaction for induction of defense cascade for acquiring resistance against Magnaporthe grisea.

Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. METHODS: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely 'Universal screening', 'High-risk-based screening' (i.e. screening of high-risk women only), 'Low-risk-based screening' (i.e. treatment of high-risk population and screening of remaining women) and 'Nullipara screening' (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening ('No screening, treat high-risk group'). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden ('No screening'). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33-36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with 'No screening') and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. RESULTS: All interventions had better health outcomes than did 'No screening', with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was 'Low-risk-based screening', irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). 'Low-risk-based screening' at Cx1 was cost-effective, while 'Low-risk-based screening' at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for 'Low-risk-based screening' at Cx1 and 36 800 USD for 'Low-risk-based screening' at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that 'Low-risk-based screening' at Cx1 is cost-effective compared with 'No screening' was 71%. CONCLUSION: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.