A Krüppel-like factor is required for development and regeneration of germline and yolk cells from somatic stem cells in planarians.

Sexually reproducing animals segregate their germline from their soma. In addition to gamete-producing gonads, planarian and parasitic flatworm reproduction relies on yolk cell-generating accessory reproductive organs (vitellaria) supporting development of yolkless oocytes. Despite the importance of vitellaria for flatworm reproduction (and parasite transmission), little is known about this unique evolutionary innovation. Here, we examine reproductive system development in the planarian Schmidtea mediterranea, in which pluripotent stem cells generate both somatic and germ cell lineages. We show that a homolog of the pluripotency factor Klf4 is expressed in primordial germ cells (PGCs), presumptive germline stem cells (GSCs), and yolk cell progenitors. Knockdown of this klf4-like (klf4l) gene results in animals that fail to specify or maintain germ cells; surprisingly, they also fail to maintain yolk cells. We find that yolk cells display germ cell-like attributes and that vitellaria are structurally analogous to gonads. In addition to identifying a new proliferative cell population in planarians (yolk cell progenitors) and defining its niche, our work provides evidence supporting the hypothesis that flatworm germ cells and yolk cells share a common evolutionary origin.

Frequentmers - a novel way to look at metagenomic next generation sequencing data and an application in detecting liver cirrhosis.

Early detection of human disease is associated with improved clinical outcomes. However, many diseases are often detected at an advanced, symptomatic stage where patients are past efficacious treatment periods and can result in less favorable outcomes. Therefore, methods that can accurately detect human disease at a presymptomatic stage are urgently needed. Here, we introduce "frequentmers"; short sequences that are specific and recurrently observed in either patient or healthy control samples, but not in both. We showcase the utility of frequentmers for the detection of liver cirrhosis using metagenomic Next Generation Sequencing data from stool samples of patients and controls. We develop classification models for the detection of liver cirrhosis and achieve an AUC score of 0.91 using ten-fold cross-validation. A small subset of 200 frequentmers can achieve comparable results in detecting liver cirrhosis. Finally, we identify the microbial organisms in liver cirrhosis samples, which are associated with the most predictive frequentmer biomarkers.

Unstained Tissue Imaging and Virtual Hematoxylin and Eosin Staining of Histologic Whole Slide Images.

Tissue structures, phenotypes, and pathology are routinely investigated based on histology. This includes chemically staining the transparent tissue sections to make them visible to the human eye. Although chemical staining is fast and routine, it permanently alters the tissue and often consumes hazardous reagents. On the other hand, on using adjacent tissue sections for combined measurements, the cell-wise resolution is lost owing to sections representing different parts of the tissue. Hence, techniques providing visual information of the basic tissue structure enabling additional measurements from the exact same tissue section are required. Here we tested unstained tissue imaging for the development of computational hematoxylin and eosin (HE) staining. We used unsupervised deep learning (CycleGAN) and whole slide images of prostate tissue sections to compare the performance of imaging tissue in paraffin, as deparaffinized in air, and as deparaffinized in mounting medium with section thicknesses varying between 3 and 20 µm. We showed that although thicker sections increase the information content of tissue structures in the images, thinner sections generally perform better in providing information that can be reproduced in virtual staining. According to our results, tissue imaged in paraffin and as deparaffinized provides a good overall representation of the tissue for virtually HE-stained images. Further, using a pix2pix model, we showed that the reproduction of overall tissue histology can be clearly improved with image-to-image translation using supervised learning and pixel-wise ground truth. We also showed that virtual HE staining can be used for various tissues and used with both 20× and 40× imaging magnifications. Although the performance and methods of virtual staining need further development, our study provides evidence of the feasibility of whole slide unstained microscopy as a fast, cheap, and feasible approach to producing virtual staining of tissue histology while sparing the exact same tissue section ready for subsequent utilization with follow-up methods at single-cell resolution.

Numerical analysis of magnetohydrodynamics in an Eyring-Powell hybrid nanofluid flow on wall jet heat and mass transfer.

The customization of hybrid nanofluids to achieve a particular and controlled growth rate of thermal transport is done to meet the needs of applications in heating and cooling systems, aerospace and automotive industries, etc. Due to the extensive applications, the aim of the current paper is to derive a numerical solution to a wall jet flow problem through a stretching surface. To study the flow problem, authors have considered a non-Newtonian Eyring-Powell hybrid nanofluid with water and CoFe2O4and TiO2nanoparticles. Furthermore, the impact of a magnetic field and irregular heat sink/source are studied. To comply with the applications of the wall jet flow, the authors have presented the numerical solution for two cases; with and without a magnetic field. The numerical solution is derived with a similarity transformation and MATLAB-based bvp4c solver. The value of skin friction for wall jet flow at the surface decreases by more than 50% when the magnetic fieldMA=0.2is present. The stream function value is higher for the wall jet flow without the magnetic field. The temperature of the flow rises with the dominant strength of the heat source parameters. The results of this investigation will be beneficial to various applications that utilize the applications of a wall jet, such as in car defrosters, spray paint drying for vehicles or houses, cooling structures for the CPU of high-processor laptops, sluice gate flows, and cooling jets over turbo-machinery components, etc.

Acute Pancreatitis and Myocardial Infarction: A Narrative Review.

BACKGROUND: Acute pancreatitis can rarely present with electrocardiographic changes that imitate myocardial ischemia. Even rarer is for acute pancreatitis to present with ST segment elevation in contiguous leads, suggestive of an acute coronary syndrome. In this comprehensive review article, we highlight diagnostic challenges and examine possible pathophysiological causes as seen through 34 total cases in which acute pancreatitis has been found to mimic an acute myocardial infarction. SUMMARY: It has been shown that regardless of the severity of acute pancreatitis, it can be associated with myocardial injury of varying presentation. Thus far, there have been 34 total cases where acute pancreatitis presented with electrocardiographic changes consistent with acute myocardial infarction without true coronary artery thrombosis. An inferior wall ST-elevation myocardial infarction pattern was the most frequently demonstrated. Many hypotheses have been proposed as to the mechanism of injury including decreased coronary perfusion, direct myocyte damage by pancreatic proteolytic enzymes, indirect parasympathetic injury, electrolyte derangements, and coronary vasospasms. Given the complexity of the clinical presentation, thorough subjective and objective evaluation can be vital in guiding to diagnosis and possibly more invasive testing. KEY MESSAGES: It is imperative that clinicians are aware that acute pancreatitis can mimic an acute myocardial infarction. Although we have started to better understand the pathological mechanisms for this phenomenon, further research focused on specific molecular target areas is needed.

Implementing a unique immersive near-peer-led clinical skills educational bootcamp for early-year clinical medical students.

We establish the development of a unique immersive clinical skills bootcamp for third-year medical students, with formal teaching under five key themes: procedural skills day, examinations, imaging, data interpretation and prescribing. Lastly a simulation event was developed to allow the participants to bring the different themes together, in order to successfully manage an acutely unwell patient for their stage of learning using the newly learnt skills. A 4-week bootcamp was developed and delivered to students. A curriculum was developed based on student's precourse answers to specific questions. Pre and post bootcamp questionnaires were used to assess participants confidence and knowledge using a 5-point Likert scale. A combination of objective structured examination, didactic lectures and group-based discussions were utilised. Tutors' teaching performance was also analysed. A focus group was held post bootcamp. Bootcamp was delivered to 15 students. Feedback was overwhelmingly positive. Students were more confident in all of the five key domains post bootcamp. All students feel more equipped to take opportunities that arise on medical wards as a result of the skills learnt. Participants were receptive to the combination of teaching methods used. All students would recommend this course to their peers. Early-year clinical students successfully received an immersive goal-directed course with formal teaching. The near-peer teaching model improved participants educational experience. We were able to successfully demonstrate that near-peer teaching is effective when it is goal directed, and further when it addresses areas of medical education whereby there is a disparity in the formal teaching available.

The Baffle Length Effects on the Natural Convection in Nanofluid-Filled Square Enclosure with Sinusoidal Temperature.

The proper process of applying heat to many technological devices is a significant challenge. There are many nanofluids of different sizes used inside the system. The current study combines this potential to improve convection effects, considering numerical simulations of natural convection using Cu/water nanofluids in a square enclosure with bottom blocks embedded in baffles. The enclosure consists of two vertical walls with isothermal boundary conditions; the left wall is the sinusoidal heat source, whereas the right wall is cooled. The investigations dealt with the influences of nanoparticle concentration, Rayleigh number, baffle length, and thermal conductivity ratioon isotherms, stream functions, and average Nusselt number. The results present that, when the Rayleigh number rises, the fluid flow velocity increases, and the heat transfer improves. Furthermore, the baffle length case (Lb = 0.3) provides higher heat transfer characteristics than other baffle height cases.

Molecular mechanisms underlying enhanced hemichannel function of a cataract-associated Cx50 mutant.

Connexin-50 (Cx50) is among the most frequently mutated genes associated with congenital cataracts. Although most of these disease-linked variants cause loss of function because of misfolding or aberrant trafficking, others directly alter channel properties. The mechanistic bases for such functional defects are mostly unknown. We investigated the functional and structural properties of a cataract-linked mutant, Cx50T39R (T39R), in the Xenopus oocyte system. T39R exhibited greatly enhanced hemichannel currents with altered voltage-gating properties compared to Cx50 and induced cell death. Coexpression of mutant T39R with wild-type Cx50 (to mimic the heterozygous state) resulted in hemichannel currents whose properties were indistinguishable from those induced by T39R alone, suggesting that the mutant had a dominant effect. Furthermore, when T39R was coexpressed with Cx46, it produced hemichannels with increased activity, particularly at negative potentials, which could potentially contribute to its pathogenicity in the lens. In contrast, coexpression of wild-type Cx50 with Cx46 was associated with a marked reduction in hemichannel activity, indicating that it may have a protective effect. All-atom molecular dynamics simulations indicate that the R39 substitution can form multiple electrostatic salt-bridge interactions between neighboring subunits that could stabilize the open-state conformation of the N-terminal (NT) domain while also neutralizing the voltage-sensing residue D3 as well as residue E42, which participates in loop gating. Together, these results suggest T39R acts as a dominant gain-of-function mutation that produces leaky hemichannels that may cause cytotoxicity in the lens and lead to development of cataracts.

Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains.

KEY POINTS: Gap junctions formed by different connexins are expressed throughout the body and harbour unique channel properties that have not been fully defined mechanistically. Recent structural studies by cryo-electron microscopy have produced high-resolution models of the related but functionally distinct lens connexins (Cx50 and Cx46) captured in a stable open state, opening the door for structure-function comparison. Here, we conducted comparative molecular dynamics simulation and electrophysiology studies to dissect the isoform-specific differences in Cx46 and Cx50 intercellular channel function. We show that key determinants Cx46 and Cx50 gap junction channel open stability and unitary conductance are shaped by structural and dynamic features of their N-terminal domains, in particular the residue at the 9th position and differences in hydrophobic anchoring sites. The results of this study establish the open state Cx46/50 structural models as archetypes for structure-function studies targeted at elucidating the mechanism of gap junction channels and the molecular basis of disease-causing variants. ABSTRACT: Connexins form intercellular communication channels, known as gap junctions (GJs), that facilitate diverse physiological roles, from long-range electrical and chemical coupling to coordinating development and nutrient exchange. GJs formed by different connexin isoforms harbour unique channel properties that have not been fully defined mechanistically. Recent structural studies on Cx46 and Cx50 defined a novel and stable open state and implicated the amino-terminal (NT) domain as a major contributor for isoform-specific functional differences between these closely related lens connexins. To better understand these differences, we constructed models corresponding to wildtype Cx50 and Cx46 GJs, NT domain swapped chimeras, and point variants at the 9th residue for comparative molecular dynamics (MD) simulation and electrophysiology studies. All constructs formed functional GJ channels, except the chimeric Cx46-50NT variant, which correlated with an introduced steric clash and increased dynamical behaviour (instability) of the NT domain observed by MD simulation. Single channel conductance correlated well with free-energy landscapes predicted by MD, but resulted in a surprisingly greater degree of effect. Additionally, we observed significant effects on transjunctional voltage-dependent gating (Vj gating) and/or open state dwell times induced by the designed NT domain variants. Together, these studies indicate intra- and inter-subunit interactions involving both hydrophobic and charged residues within the NT domains of Cx46 and Cx50 play important roles in defining GJ open state stability and single channel conductance, and establish the open state Cx46/50 structural models as archetypes for structure-function studies targeted at elucidating GJ channel mechanisms and the molecular basis of cataract-linked connexin variants.

Transfer Learning Assisted Classification and Detection of Alzheimer's Disease Stages Using 3D MRI Scans.

Alzheimer's disease effects human brain cells and results in dementia. The gradual deterioration of the brain cells results in disability of performing daily routine tasks. The treatment for this disease is still not mature enough. However, its early diagnosis may allow restraining the spread of disease. For early detection of Alzheimer's through brain Magnetic Resonance Imaging (MRI), an automated detection and classification system needs to be developed that can detect and classify the subject having dementia. These systems also need not only to classify dementia patients but to also identify the four progressing stages of dementia. The proposed system works on an efficient technique of utilizing transfer learning to classify the images by fine-tuning a pre-trained convolutional network, AlexNet. The architecture is trained and tested over the pre-processed segmented (Grey Matter, White Matter, and Cerebral Spinal Fluid) and un-segmented images for both binary and multi-class classification. The performance of the proposed system is evaluated over Open Access Series of Imaging Studies (OASIS) dataset. The algorithm showed promising results by giving the best overall accuracy of 92.85% for multi-class classification of un-segmented images.

Observation of Cleft Palate in an Individual with SOX11 Mutation: Indication of a Role for SOX11 in Human Palatogenesis.

OBJECTIVE: Point mutations and deletions within the SOX11 gene have recently been described in individuals with a rare variant of Coffin-Siris syndrome, OMIM 615866, an intellectual disability syndrome with associated features of nail hypoplasia, microcephaly, and characteristic facial features including a wide mouth and prominent lips. PARTICIPANT: We describe a further patient with a mutation in SOX11 and phenotype resembling mild Coffin-Siris syndrome. RESULTS: This boy had a cleft palate, a feature not previously seen in other patients with SOX11 mutations. CONCLUSION: We discuss This adds to the current evidence that SOX11 is a gene involved in palatogenesis.

Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis.

BACKGROUND: Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review. METHODS: Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis. RESULTS: Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13-2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93-1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12-2.55), with no effect seen when restricted to studies which adjusted for key covariates. CONCLUSION: A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

Low-grade infections in nonarthroplasty shoulder surgery.

BACKGROUND: Recent studies have identified the diagnostic challenge of low-grade infections after shoulder arthroplasty surgery. Infections after nonarthroplasty procedures have not been reported. This study assessed patient-related risk factors, outcomes, and clinical presentation of low-grade infection after open and arthroscopic nonarthroplasty shoulder surgery. METHODS: The cases of 35 patients presenting with suspected low-grade infection were reviewed. Biopsy specimens taken at revision surgery were cultured in the sterile environment of a class II laminar flow cabinet and incubated for a minimum of 14 days at a specialist orthopedic microbiology laboratory. Patient-related factors (age, occupation, injection), index surgery, and infection characteristics (onset of symptoms, duration to diagnosis, treatment) were analyzed. RESULTS: Positive cultures were identified in 21 cases (60.0%), of which 15 were male patients (71%). Of all patients with low-grade infection, 47.6% were male patients between 16 and 35 years of age. Propionibacterium acnes and coagulase-negative staphylococcus were the most common organisms isolated (81.1% [n = 17] and 23.8% [n = 5], respectively). Of 14 negative culture cases, 9 were treated with early empirical antibiotics (64.3%); 7 patients reported symptomatic improvement (77.8%). Of 5 patients treated with late empirical antibiotics, 4 stated improvement. Patients presented with symptoms akin to resistant postoperative frozen shoulder (persistent pain and stiffness, unresponsive to usual treatments). CONCLUSION: Young male patients are at greatest risk for low-grade infections after arthroscopic and open nonarthroplasty shoulder surgery. P. acnes was the most prevalent organism. Patients presented with classic postoperative frozen shoulder symptoms, resistant to usual treatments. Interestingly, 78.6% of patients with negative cultures responded positively to empirical treatment.

Use of the"bogota bag"for closure of open abdominal wound after exploratory laparotomy - our experience at Mayo Hospital Lahore.

OBJECTIVE: To assess the efficacy of Bogota bag for closure of open abdominal wounds after laparotomy where the primary closure cannot be achieved and other closure techniques are not available. METHODS: The descriptive study was conducted at Mayo Hospital, Lahore, Pakistan, from September 2011 to February2015, and comprised patients who underwent laparotomy and peritoneal cavities and who could not be closed primarily because of various reasons like traumatic loss and oedematous gut. They were managed with Bogota bag for abdominal closure. SPSS 18 was used for statistical analysis. RESULTS: Of the 55 patients, 37(67.27%) were male and 18(32.73%) were female. There was traumatic loss in 34(61.8%), oedematous gut and omentum in 15(27.27%) and gangrenous abdominal wall in 6(10.9%) patients. Bogota bag was applied in all (100%) of them. In 19(34.55%) patients, delayed primary closure was possible, so the Bogota was used temporarily. In 36(65.45%) cases managed with Bogota bag, healing occurred by granulation tissue or skin grafting/flaps were applied and these patients developed hernia. Five (9.09%) patients developed small bowel fistula which was managed conservatively. No patient developed complication due to exposure or abdominal compartment. There were 7(12.8%) postoperative deaths due to the disease process and were unrelated to the closure technique. CONCLUSIONS: Bogota bag was an effective means of closure of open abdominal wound and prevented the complications due to open abdominal wounds or closure under tension.

Quantitative computed tomography-derived clusters: redefining airway remodeling in asthmatic patients.

BACKGROUND: Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. OBJECTIVES: The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. METHODS: Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. RESULTS: Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm(3) [SD, 112.6 mm(3)], 259.0 mm(3) [SD, 53.3 mm(3)], 366.4 mm(3) [SD, 195.3 mm(3)], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. CONCLUSIONS: Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies.

Understanding the impact of sisu on workforce and well-being: A machine learning-based analysis.

This study investigates the construct of sisu, a Finnish attribute representing mental resilience and fortitude when confronted with difficult situations. By leveraging advanced analytical methods and explainable Artificial Intelligence, we gain insights into how sisu factors influence well-being, work efficiency, and overall health. We investigate how the beneficial aspects of sisu contribute significantly to mental and physical health, satisfaction, and professional accomplishments. Conversely, we analyze the harmful sisu and its adverse impacts on the same domains. Our findings, including intriguing trends related to age, educational level, emotional states, and gender, pave the way for developing tailored solutions and initiatives to nurture the beneficial aspects of sisu and curtail the damaging consequences of sisu within professional settings and personal welfare.

Virtual staining for histology by deep learning.

In pathology and biomedical research, histology is the cornerstone method for tissue analysis. Currently, the histological workflow consumes plenty of chemicals, water, and time for staining procedures. Deep learning is now enabling digital replacement of parts of the histological staining procedure. In virtual staining, histological stains are created by training neural networks to produce stained images from an unstained tissue image, or through transferring information from one stain to another. These technical innovations provide more sustainable, rapid, and cost-effective alternatives to traditional histological pipelines, but their development is in an early phase and requires rigorous validation. In this review we cover the basic concepts of virtual staining for histology and provide future insights into the utilization of artificial intelligence (AI)-enabled virtual histology.

Data-driven insights can transform women's reproductive health.

This perspective explores the transformative potential of data-driven insights to understand and address women's reproductive health conditions. Historically, clinical studies often excluded women, hindering comprehensive research into conditions such as adverse pregnancy outcomes and endometriosis. Recent advances in technology (e.g., next-generation sequencing techniques, electronic medical records (EMRs), computational power) provide unprecedented opportunities for research in women's reproductive health. Studies of molecular data, including large-scale meta-analyses, provide valuable insights into conditions like preterm birth and preeclampsia. Moreover, EMRs and other clinical data sources enable researchers to study populations of individuals, uncovering trends and associations in women's reproductive health conditions. Despite these advancements, challenges such as data completeness, accuracy, and representation persist. We emphasize the importance of holistic approaches, greater inclusion, and refining and expanding on how we leverage data and computational integrative approaches for discoveries so that we can benefit not only women's reproductive health but overall human health.

Synergistic effect of silicon and arbuscular mycorrhizal fungi reduces cadmium accumulation by regulating hormonal transduction and lignin accumulation in maize.

Cadmium (Cd) stress causes serious damage to plants, inducing various physiological and biochemical disruptions that lead to reduced plant biomass and compromised growth. The study investigated the combined effects of silicon (Si) and arbuscular mycorrhizal fungi (AMF) on mitigating Cd stress in plants, revealing promising results in enhancing plant tolerance to Cd toxicity. Under Cd stress, plant biomass was significantly reduced (-33% and -30% shoot and root dry weights) as compared to control. However, Si and AMF application ameliorated this effect, leading to increased shoot and root dry weights (+47% and +39%). Furthermore, Si and AMF demonstrated their potential in reducing the relative Cd content (-43% and -36% in shoot and root) in plants and positively influencing plant colonization (+648%), providing eco-friendly and sustainable strategies to combat Cd toxicity in contaminated soils. Additionally, the combined treatment in the Cd-stressed conditions resulted in notable increases in saccharide compounds and hormone levels in both leaf and root tissues, further enhancing the plant's resilience to Cd-induced stress. Si and AMF also played a vital role in positively regulating key lignin biosynthesis genes and altering lignin-related metabolites, shedding light on their potential to fortify plants against Cd stress. These findings underscore the significance of Si and AMF as promising tools in addressing Cd toxicity and enhancing plant performance in Cd-contaminated environments.