Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1.

PIF1 is a conserved helicase and G4 DNA binding and unwinding enzyme, with roles in genome stability. Human PIF1 (hPIF1) is poorly understood, but its functions can become critical for tumour cell survival during oncogene-driven replication stress. Here we report the discovery, via an X-ray crystallographic fragment screen (XChem), of hPIF1 DNA binding and unwinding inhibitors. A structure was obtained with a 4-phenylthiazol-2-amine fragment bound in a pocket between helicase domains 2A and 2B, with additional contacts to Valine 258 from domain 1A. The compound makes specific interactions, notably through Leucine 548 and Alanine 551, that constrain conformational adjustments between domains 2A and 2B, previously linked to ATP hydrolysis and DNA unwinding. We next synthesized a range of related compounds and characterized their effects on hPIF1 DNA-binding and helicase activity in vitro, expanding the structure activity relationship (SAR) around the initial hit. A systematic analysis of clinical cancer databases is also presented here, supporting the notion that hPIF1 upregulation may represent a specific cancer cell vulnerability. The research demonstrates that hPIF1 is a tractable target through 4-phenylthiazol-2-amine derivatives as inhibitors of its helicase action, setting a foundation for creation of a novel class of anti-cancer therapeutics.

Molecular similarities between the genes for Trypanosoma cruzi microtubule-associated proteins, mammalian interferons, and TRIMs.

Initial studies using bioinformatics analysis revealed DNA sequence similarities between Trypanosoma cruzi GenBank® M21331, coding for Antigen 36 (Ag 36), and tripartite motif (TRIM) genes. TRIM40 showed 9.7% identity to GenBank M21331, and four additional TRIM genes had identities greater than 5.0%. TRIM37 showed a continuous stretch of identity of 12 nucleotides, that is, at least 25% longer than any of the other TRIMs. When we extended our analysis on the relationships of GenBank M21331 to further innate immune genes, using the Needleman-Wunsch (NW) algorithm for alignment, identities to human IFN-α, IFN-ß, and IFN-γ genes of 13.6%, 12.6%, and 17.9%, respectively, were found. To determine the minimum number of genes coding for proteins closely related to Ag 36, a BLAST-p search was conducted with it versus the T. cruzi genome. The BLAST-p search revealed that T. cruzi GenBank M21331 had 14 gene sequences homologous to microtubule-associated protein (MAP) genes with 100% amino acid sequence identity. To verify the similarities in non-human genes, a study comparing TRIM21 region sequences among mammalian species to the comparable human TRIM21 region showed that related sequences were also present in 11 mammalian species. The MAP genes homologous to Ag 36 form a family of at least 14 genes which mimic human immune genes in the IFN and TRIM families. This mimicry is of gene sequences and not their protein products or epitopes. These results appear to be the first description of molecular mimicry of immune genes in humans by a protozoan parasite.

Incidence of Ipsilateral Femoral Neck and Shaft Fractures in Pediatric and Adolescent Patients.

OBJECTIVES: To identify the incidence, patient characteristics, and effectiveness of radiographic screening methods for detecting ipsilateral femoral neck and shaft fractures in pediatric and adolescent trauma patients. DESIGN: Retrospective cohort study. SETTING: This study was conducted at a tertiary pediatric trauma hospital. PATIENT SELECTION CRITERIA: Patients younger than 18 years treated for a femoral shaft fracture between 2004 and 2018 were reviewed. Pathologic (metabolic bone disease or bone lesion), periprosthetic, and penetrating traumatic femoral shaft fractures were excluded. OUTCOME MEASUREMENTS AND COMPARISONS: Patient demographics, mechanisms of injury, treatment methods, and associated injuries were analyzed. Pretreatment x-rays and computed tomography (CT) scans were reviewed for the identification of ipsilateral femoral neck and shaft fractures. RESULTS: Among the 840 pediatric patients included in this study, 4 patients (0.5%) sustained ipsilateral femoral neck and shaft fractures. All the femoral neck fractures were observed in adolescents (aged 13-17 years) and involved in high-energy traumas. In adolescents involved in high-energy trauma, the incidence increased to 1.7%. Pretreatment sensitivity of both x-rays and CT scans was only 50% for the detection of femoral neck fractures. CONCLUSIONS: This study reveals that ipsilateral femoral neck and shaft fractures in pediatric patients are rare, occurring in adolescents involved in high-energy trauma. The findings suggest the need for a selective, rather than routine, use of CT scans based on the patient's age and the mechanism of injury. The use of alternative imaging methods such as magnetic resonance imaging should be considered to balance diagnostic accuracy while minimizing radiation exposure. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Infratubercle Anterior Closing Wedge Osteotomy Corrects Sagittal Alignment without Affecting Coronal Alignment or Patellar Height.

Background: Excessive posterior tibial slope (PTS) has been associated with a higher risk of graft failure after anterior cruciate ligament reconstruction (ACLR). Although anterior closing wedge osteotomy (ACWO) can reduce the PTS, it may also change the coronal alignment and patellar height. Purpose: To elucidate the radiological outcomes after infratubercle ACWO, specifically to evaluate its influence on perioperative changes in patellar height. Methods: Patients who underwent infratubercle ACWO with combined ACLR with a minimum follow-up of 3 months were included. Surgery was indicated when the PTS was greater than 12°. Radiological evaluation included measurements of the hip-knee-ankle angle (HKA), PTS, femoral patellar height index (FPHI), and Caton-Deschamps index (CDI) preoperatively and 3 months postoperatively. Patellar height was classified as patella baja, normal, or alta based on CDI values. Knee recurvatum was measured preoperatively and at final follow-up. Results: A total of 21 patients with a mean age of 21.6 ± 3.0 years were included. Although HKA did not significantly change, significant corrections were achieved in the PTS from 14.5° ± 1.6° to 5.7° ± 1.0° (p < 0.001). No significant change in FPHI was found (preoperative: 1.33 ± 0.11 vs postoperative: 1.30 ± 0.09). Patellar height categories showed no significant differences pre- and postoperatively, while three patients (14.3%) changed their patellar height category (all moved up one category). Knee recurvatum increased significantly from 4.9° ± 2.9° preoperatively to 7.8° ± 3.1° at the final follow-up (p < 0.001). Conclusions: Precise sagittal correction was achieved after infratubercle ACWO without altering the coronal alignment and patella height. Level of Evidence: IV, Case series.

Structural basis for DNA recognition by a viral genome-packaging machine.

DNA recognition is critical for assembly of double-stranded DNA viruses, particularly for the initiation of packaging the viral genome into the capsid. The key component that recognizes viral DNA is the small terminase protein. Despite prior studies, the molecular mechanism for DNA recognition remained elusive. Here, we address this question by identifying the minimal site in the bacteriophage HK97 genome specifically recognized by the small terminase and determining the structure of this complex by cryoEM. The circular small terminase employs an entirely unexpected mechanism in which DNA transits through the central tunnel, and sequence-specific recognition takes place as it emerges. This recognition stems from a substructure formed by the N- and C-terminal segments of two adjacent protomers which are unstructured when DNA is absent. Such interaction ensures continuous engagement of the small terminase with DNA, enabling it to slide along the DNA while simultaneously monitoring its sequence. This mechanism allows locating and instigating packaging initiation and termination precisely at the specific cos sequence.

Factors influencing integrated disease surveillance and response system in selected districts in the Eastern Region of Ghana.

BACKGROUND: Ghana adopted the Integrated Disease Surveillance and Response (IDSR) system, which is an integration of the various programs in the surveillance system and can contain disease outbreaks and pandemics. Implementation of the IDSR is influenced by several factors which can affect its functionality and ability to contain disease outbreaks. This study assessed the factors influencing the IDSR system in selected districts in the Eastern Region of Ghana. METHOD: A cross-sectional study was conducted between February-March, 2022 in Fanteakwa North, Abuakwa South and New Juaben South districts in the Eastern Region of Ghana among health care workers who are involved in IDRS activities. Both primary and secondary data were collected and analyzed using descriptive statistics and regression analysis at 0.05 significant level with 95% confidence interval. RESULTS: Three hundred and forty-seven (347) health care workers participated in the study with 56.2% (195/347) indicating that rumor registers were available at the health facilities. Most of the respondents (64.8%, 225/347) had means of transport for disease surveillance activities while majority (61.9%, 215/347) had case-based forms for case investigation. About half (51.9%, 180/347) of the participants revealed that they did not receive any feedback from the next higher level in the past year. Availability of transport for IDSR activities was almost 3.4 times more likely to contribute positively to IDSR system compared to facilities without transport (AOR = 3.36; 95% CI = 1.44-7.83; p = 0.005). Respondents who have the capacity to apply case definition are 2 times more likely to contribute to an effective IDSR system compared to health workers who cannot apply case definition (AOR = 1.94; 95% CI = 1.17-3.21; p = 0.013). Respondents who did not receive feedback from the next higher level were 52% less likely to have an effective IDSR system compared to respondents who received feedback from the next higher level (AOR = 0.48; 95% CI = 0.23-1.00; p = 0.05). CONCLUSION: Effective operation of IDSR is affected by the application of case definition and means of transport at health facilities. In addition, the capacity of health care workers to provide feedback can influence the smooth operation of the IDSR in the studied area in Ghana.

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma.

Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity to NMT inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that NMTs are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS-mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation, and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter translocase of inner mitochondrial membrane 17 homolog A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis NMT-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas. SIGNIFICANCE: KRAS-mutant lung carcinomas with LKB1 and/or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos and thus has the potential to kill apoptosis and ferroptosis-resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas.

Viral Genomic DNA Packaging Machinery.

Tailed double-stranded DNA bacteriophage employs a protein terminase motor to package their genome into a preformed protein shell-a system shared with eukaryotic dsDNA viruses such as herpesviruses. DNA packaging motor proteins represent excellent targets for antiviral therapy, with Letermovir, which binds Cytomegalovirus terminase, already licensed as an effective prophylaxis. In the realm of bacterial viruses, these DNA packaging motors comprise three protein constituents: the portal protein, small terminase and large terminase. The portal protein guards the passage of DNA into the preformed protein shell and acts as a protein interaction hub throughout viral assembly. Small terminase recognises the viral DNA and recruits large terminase, which in turn pumps DNA in an ATP-dependent manner. Large terminase also cleaves DNA at the termination of packaging. Multiple high-resolution structures of each component have been resolved for different phages, but it is only more recently that the field has moved towards cryo-EM reconstructions of protein complexes. In conjunction with highly informative single-particle studies of packaging kinetics, these structures have begun to inspire models for the packaging process and its place among other DNA machines.

A stargate mechanism of Microviridae genome delivery unveiled by cryogenic electron tomography.

Single-stranded DNA bacteriophages of the Microviridae family are major components of the global virosphere. Microviruses are highly abundant in aquatic ecosystems and are prominent members of the mammalian gut microbiome, where their diversity has been linked to various chronic health disorders. Despite the clear importance of microviruses, little is known about the molecular mechanism of host infection. Here, we have characterized an exceptionally large microvirus, Ebor, and provide crucial insights into long-standing mechanistic questions. Cryogenic electron microscopy of Ebor revealed a capsid with trimeric protrusions that recognise lipopolysaccharides on the host surface. Cryogenic electron tomography of the host cell colonized with virus particles demonstrated that the virus initially attaches to the cell via five such protrusions, located at the corners of a single pentamer. This interaction triggers a stargate mechanism of capsid opening along the 5-fold symmetry axis, enabling delivery of the virus genome. Despite variations in specific virus-host interactions among different Microviridae family viruses, structural data indicate that the stargate mechanism of infection is universally employed by all members of the family. Startlingly, our data reveal a mechanistic link for the opening of relatively small capsids made out of a single jelly-roll fold with the structurally unrelated giant viruses.

Patient Satisfaction with Nonopioid Postoperative Analgesia in Head and Neck Surgery: A Prospective Randomized Trial.

OBJECTIVE: To evaluate patients' satisfaction with opioid versus opioid-sparing postoperative analgesia in patients undergoing outpatient head and neck surgery. STUDY DESIGN: Prospective randomized trial. SETTING: Tertiary care academic hospital. METHODS: Adult patients undergoing outpatient head and neck surgery were randomly assigned to 1 of 3 analgesic regimens. First- and second-line medications were the following by group (1) Hydrocodone-acetaminophen with ibuprofen, (2) ibuprofen with hydrocodone-acetaminophen, and (3) ibuprofen with acetaminophen. Preoperative counseling was provided to patients regarding expected pain and proper medication use. Postoperative questionnaires were administered to assess satisfaction. RESULTS: One hundred three patients were enrolled in the study (mean age, 56.5 years; women, 75 [73%]). The mean satisfaction score with the pain regimen assigned was similar between the 3 groups (scale 0-10, [7.7, 8.3, 8.5, P = .46]). A similar percentage of patients in each group reported that surgery was more painful than anticipated (25%, 32%, 26%, P = .978), and a similar percentage of patients reported willingness to utilize the same analgesic regimen following future surgeries (75%, 83%, 76%, P = .682). Additional questions evaluating the side effect profile, maximum and minimum pain scores, and difficulty of recovery were not statistically different between the 3 groups. CONCLUSION: In the postoperative population for outpatient head and neck surgeries, there was no significant difference in patient satisfaction and pain control between the opioid and nonopioid arms. Providers should discuss opioid-sparing regimens preoperatively with patients and describe them as effective in providing adequate pain control without a significant impact on patient's perception of care.

Variability Between Full-Length Lateral Radiographs and Standard Short Knee Radiographs When Evaluating Posterior Tibial Slope in Revision ACL Patients.

Background: Increased posterior tibial slope (PTS) has been identified as a risk factor for failure after anterior cruciate ligament (ACL) reconstruction. Correction of PTS may improve outcomes after revision ACL reconstruction. There are conflicting reports demonstrating the measurement of the PTS on standard short knee (SSK) radiographs versus full-length lateral (FLL) radiographs including the entire tibia. Purpose/Hypothesis: To compare PTS measurements between SSK and FLL radiographs in patients who failed primary ACL reconstruction. It was hypothesized that there would be high variability between the SSK and FLL radiographic measurements. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The medial and lateral PTS were measured on the SSK and FLL radiographs of 33 patients with failed primary ACL reconstructions. All measurements were performed by 2 trained independent observers (A.A.M., J.S.), and inter- and intraobserver reliability were calculated using the intraclass correlation coefficient (ICC). Measurements recorded by the observer with the higher intraobserver ICC were used for comparison of the PTS on SSK versus FLL radiographs. Results: Both the inter- and the intraobserver reliability values of the PTS measurements were excellent. There was a significant difference in mean PTS on the medial plateau as measured on the SSK and FLL radiographs (11.2°± 5.3° vs 12.5°± 4.6°; P = .03), with the FLL radiographs demonstrating higher PTS. There was also a significant difference in the mean PTS on the lateral plateau as measured on SSK versus FLL radiographs (10.7°± 4.3° vs 12.2°± 4°, respectively; P = .01), with the FLL radiographs demonstrating higher PTS. Notably, 66.67% of the absolute measurements for PTS on the medial plateau differed by ≥2°, with variability as high as 8.5°. Conclusion: Results indicated that FLL and SSK radiographs are not interchangeable measurements for PTS associated with failed ACL reconstruction. Because FLL radiographs demonstrate less variability than SSK radiographs, we recommend obtaining them to evaluate these complex patients.

Induction of genetic variability of maize genotypes through radiation revealed mutants resistant to maize streak disease.

The absence of genetic variability among crop genotypes is an impediment to breeding progress, hence mutagenesis could serve as a useful tool to create genetic variation to obtain desirable traits of interest. In this study, four maize genotypes, Obatampa, Dapango, Pann 54 and Honampa which were susceptible to maize streak disease (MSD) were acutely irradiated at 254.3 Gy, using a cobalt 60 (60Co) at a rate of 300 Gy/hr. The irradiated seeds were planted with their parental controls at streak disease highly endemic environment. Field trials for the selected maize genotypes were conducted from the M1 to M4 generations to screen for MSD resistance and improved grain yield. Sixteen putative mutants and four individual parental controls were selected across the four maize genotypes at the end of the M4 generation based on disease severity score and yield indices. Detailed morphological screening and field evaluation of putative mutants showing improved plant architecture, increased grain yield and resistance to maize streak disease were tagged and selected. Obatanpa-induced-genotype was the best mutant identified with a grain yield of 6.8 t ha-1. Data on days to 50% flowering indicated that all 16 putative mutants were maturing plants.

Risk Factors and Outcomes Associated with Gaps in Care in Children with Congenital Heart Disease.

Adults with congenital heart disease (CHD) benefit from cardiology follow-up at recommended intervals of ≤ 2 years. However, benefit for children is less clear given limited studies and unclear current guidelines. We hypothesize there are identifiable risks for gaps in cardiology follow-up in children with CHD and that gaps in follow-up are associated with differences in healthcare utilization. Our cohort included children < 10 years old with CHD and a healthcare encounter from 2008 to 2013 at one of four North Carolina (NC) hospitals. We assessed associations between cardiology follow-up and demographics, lesion severity, healthcare access, and educational isolation (EI). We compared healthcare utilization based on follow-up. Overall, 60.4% of 6,969 children received cardiology follow-up within 2 years of initial encounter, including 53.1%, 58.1%, and 79.0% of those with valve, shunt, and severe lesions, respectively. Factors associated with gaps in care included increased drive time to a cardiology clinic (Hazard Ratio (HR) 0.92/15-min increase), EI (HR 0.94/0.2-unit increase), lesion severity (HR 0.48 for shunt/valve vs severe), and older age (HR 0.95/month if < 1 year old and 0.94/year if > 1 year old; p < 0.05). Children with a care gap subsequently had more emergency department (ED) visits (Rate Ratio (RR) 1.59) and fewer inpatient encounters and procedures (RR 0.51, 0.35; p < 0.05). We found novel factors associated with gaps in care for cardiology follow-up in children with CHD and altered health care utilization with a gap. Our findings demonstrate a need to mitigate healthcare barriers and generate clear cardiology follow-up guidelines for children with CHD.

Surgery for nonlocalizing hyperparathyroidism in high volume center.

BACKGROUND: Patients with nonlocalizing hyperparathyroidism pose a significant challenge to surgeons when undergoing neck exploration for parathyroidectomy. METHODS: We evaluated 536 patients that had parathyroidectomy for primary hyperparathyroidism (PHPT) from 2005 to 2018 at a single tertiary academic center, and 155 (29%) had standard nonlocalizing preoperative imaging (negative ultrasound and sestamibi scans). RESULTS: There were a total of 102 (66%) non-ectopic single adenomas in the nonlocalizing group and 325 (85%) single adenomas in the localizing group. There was no significant difference (p = 0.09) in adenoma quadrant between localizing and nonlocalizing single adenomas, but the most common location in both groups was right inferior. Patients with nonlocalizing scans were more likely to have double adenomas (21% vs. 9%, p < 0.001), ectopic glands (10% vs. 5%, p = 0.052), and multi-gland disease (13% vs. 8%, p = 0.002). CONCLUSION: Nonlocalizing PHPT patients experienced similar cure and complication rates as localizing PHPT, but required more bilateral explorations and increased operative time.

Quantitative Aggregation of Microbiome Sequencing Data Provides Insights into the Associations between the Skin Microbiome and Psoriasis.

Although prior studies have reported distinct skin microbiome profiles associated with psoriasis, differences in methods and analyses limit generalizable conclusions. Individual studies have actually reported conflicting findings; for example, Propionibacterium and Staphylococcus have been significantly associated with both psoriatic lesions and healthy skin. Qualitative reviews have attempted to summarize this body of work, but there is great variability across the studies' findings and methods. To better unify these data, we created a meta-analysis of all publicly available datasets by utilizing a uniform bioinformatics pipeline and reference database to investigate associations of the skin microbiome in psoriasis. A total of 977 skin swab samples (341 lesional, 295 nonlesional, and 341 healthy) from 6 studies were analyzed. The aggregated analysis revealed a higher relative abundance of microorganisms, including Staphylococcus aureus and Corynebacterium simulans, among others, from patients with psoriasis than those from healthy swab samples; in addition, Cutibacterium acnes, Lawsonella unclassified, and S warneri were significantly higher in healthy samples. Furthermore, comparison of functional pathways predicted from 16S gene markers showed that L-ornithine biosynthesis and L-histidine biosynthesis were lower in psoriatic lesions than in healthy controls. Taken together, this meta-analysis allows for a more generalizable association between the skin microbiome and psoriasis.

Clinical significance of prostate cancer identified by transperineal standard template biopsy in men with nonsuspicious multiparametric magnetic resonance imaging.

OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) of the prostate has excellent sensitivity in detecting clinically significant prostate cancer (csCaP). However, whether a negative mpMRI in patients with a clinical suspicion of CaP can omit a confirmatory biopsy remains less understood and without consensus. Transperineal (TP) standard template biopsy (SBx) provides an effective approach to CaP detection. Our aim is to provide a comprehensive understanding of the CaP characteristics detected through TP SBx that are systematically overlooked by mpMRI. METHODS: We conducted a retrospective analysis of all men who underwent prebiopsy mpMRI and subsequent a 20-core TP SBx at our hospital from September 2019 to February 2021. Patients with suspicious mpMRI received a combined TP SBx and targeted biopsy (TBx) (suspicious group), while those without suspicious (negative) mpMRI and who proceeded to biopsy, received TP SBx only (nonsuspicious group). A negative mpMRI was defined as the absence of suspicious findings and/or the presence of low-risk areas with a PI-RADS score of ≤2. Subsequently, we compared and evaluated the clinical and biopsy characteristics between these 2 groups. RESULTS: We identified 301 men in suspicious group and 215 men in nonsuspicious group. The overall CaP detection rate and csCaP detection rate by TP SBx were 74.1%, 38.9% for suspicious group and 43.3%, 14.9% for nonsuspicious group, respectively. csCaP NPV of mpMRI was 85.1% with a csCaP prevalence 28.9%. The greatest percentage of cancer involvement (GPC) in biopsy core from nonsuspicious group was significantly lower than those of suspicious group (40% vs. 50%, p = 0.005), In multivariate logistic analysis, only PSAD > 0.15 ng/ml/cc was identified as an independent and significant predictor of csCaP in nonsuspicious group. CONCLUSION: Within our cohort, false-negative rates of mpMRI for csCaP are substantial, reaching 15%. Nonsuspicious cases may contain a large volume tumor since the high GPC of SBx. For cases with nonsuspicious imaging and higher PSAD, a confirmatory biopsy may be necessary due to the increased risk of missed csCaP by mpMRI.

Myocardial Oedema as a Consequence of Viral Infection and Persistence-A Narrative Review with Focus on COVID-19 and Post COVID Sequelae.

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed.

Pelvic tilt affects superolateral coverage, but not superomedial coverage of the femoral head following periacetabular osteotomy.

BACKGROUND: Pelvic tilt is an important sagittal parameter that varies greatly among individuals. The objective of this study was to quantify the effect of pelvic tilt on femoral head coverage and range of motion in a dysplastic population following periacetabular osteotomy. METHODS: Twenty-three dysplastic hips from 19 patients (17 female, 2 male) were included in this study. Three-dimensional models were reconstructed using pre-operative CT images, and patient-specific neutral pelvic tilt was obtained on an anteroposterior X-ray. Following a simulated periacetabular osteotomy, the pelvic tilt was changed from -15° to +15°, and the effects on femoral head coverage and hip range of motion was quantified using a customized MATLAB program. FINDINGS: Pelvic tilt did not significantly affect total femoral head coverage (P > 0.2). However, a 15° anterior tilt from neutral resulted in a 17.72 ± 9.45% increase in anterolateral coverage and a 23.96 ± 7.48% decrease in posterolateral coverage (P < 0.0001), as well as an 18.2 ± 8.4° loss of internal rotation at 90° of hip flexion. Contrarily, posterior pelvic tilt led to a 26.79 ± 9.04% reduction in anterolateral coverage (P < 0.0001) and an 18.02 ± 9.57% increase in posterolateral coverage (P < 0.0001), and the maximum internal rotation increased 11.8 ± 3.7°. INTERPRETATION: While pelvic tilt did not affect total femoral head coverage, it had a significant impact on the distribution of coverage within the superolateral region of the femoral head. Anterior pelvic tilt led to increased anterolateral coverage, but also had a negative impact on hip range of motion. An optimal surgical plan should achieve adequate coverage while not significantly limiting the patient's mobility.

Regulatory and Interacting Partners of PDLIM7 in Thyroid Cancer.

Enigma protein, encoded by the PDLIM7 gene, is overexpressed in thyroid cancer in a stage-dependent manner, suggesting a potential involvement in the initiation and progression of thyroid cancer. The Enigma interacts with several cellular pathways, including PI3K/AKT, MDM2, and BMP-1. The Enigma is regulated by microRNAs. Specifically, we showed that the Enigma protein upregulation corresponds to the downregulation of Let-7 family genes. There is limited research on the interactions and regulation of the Enigma with other proteins/genes in thyroid cancer tissues, indicating a gap in current knowledge. Our aim is to establish the Enigma as a biomarker. We also aim to study the interacting partners of the Enigma signaling pathways and their probable miRNA regulation in thyroid cancer progression. Using Western blotting, densitometric analysis, immunoprecipitation (IP), and reverse IP, we detected the protein expression and protein-protein interactions in the corresponding papillary thyroid carcinomas (PTCs). Utilizing real-time qPCR assay and Pearson's correlation test, we highlighted the correlation between PDLIM7 and Let-7g gene expression in the same tissues. The results showed the differential upregulations of the Enigma protein in different stages of PTCs compared to benign tissues along with AKT, VDR, BMP-1, and MDM2 proteins. Loss of DBP was observed in a subset of PTCs. Strong interactions of the Enigma with PI3K/AKT and MDM2 were noted, along with a weaker BMP-1 interaction. Pearson's correlation coefficient analysis between PDLIM7 and let-7g gene expression was significant (p < 0.05); however, there was a weak inverse correlation (r = -0.27). The study suggests the potential utility of the PDLIM7-qPCR assay as a biomarker for thyroid cancer. The Enigma's interactions with key signaling pathways may provide valuable insights into the development of thyroid cancer. The study contributes to understanding the molecular mechanisms involving the Enigma protein in thyroid cancer and highlights its potential as a biomarker.

Jorvik: A membrane-containing phage that will likely found a new family within Vinavirales.

Although membrane-containing dsDNA bacterial viruses are some of the most prevalent predators in aquatic environments, we know little about how they function due to their intractability in the laboratory. Here, we have identified and thoroughly characterized a new type of membrane-containing bacteriophage, Jorvik, that infects the freshwater mixotrophic model bacterium Rhodobacter capsulatus. Jorvik is extremely virulent, can persist in the host integrated into the RuBisCo operon and encodes two experimentally verified cell wall hydrolases. Jorvik-like prophages are abundant in the genomes of Alphaproteobacteria, are distantly related to known viruses of the class Tectiliviricetes, and we propose they should be classified as a new family. Crucially, we demonstrate how widely used phage manipulation methods should be adjusted to prevent loss of virus infectivity. Our thorough characterization of environmental phage Jorvik provides important experimental insights about phage diversity and interactions in microbial communities that are often unexplored in common metagenomic analyses.