Correction: Multicriteria decision making attributes and estimation of physicochemical properties of kidney cancer drugs via topological descriptors.

[This corrects the article DOI: 10.1371/journal.pone.0302276.].

Multicriteria decision making attributes and estimation of physicochemical properties of kidney cancer drugs via topological descriptors.

Based on topological descriptors, QSPR analysis is an incredibly helpful statistical method for examining many physical and chemical properties of compounds without demanding costly and time-consuming laboratory tests. Firstly, we discuss and provide research on kidney cancer drugs using topological indices and done partition of the edges of kidney cancer drugs which are based on the degree. Secondly, we examine the attributes of nineteen drugs casodex, eligard, mitoxanrone, rubraca, and zoladex, etc and among others, using linear QSPR model. The study in the article not only demonstrates a good correlation between TIs and physical characteristics with the QSPR model being the most suitable for predicting complexity, enthalpy, molar refractivity, and other factors and a best-fit model is attained in this study. This theoretical approach might benefit chemists and professionals in the pharmaceutical industry to forecast the characteristics of kidney cancer therapies. This leads towards new opportunities to paved the way for drug discovery and the formation of efficient and suitable treatment options in therapeutic targeting. We also employed multicriteria decision making techniques like COPRAS and PROMETHEE-II for ranking of said disease treatment drugs and physicochemical characteristics.

Survival Outcome of Retroperitoneal Sarcomas Treated With a Surgery-First Approach: A Single-Center Experience.

Background Retroperitoneal sarcomas (RPS) are rare and complex tumors originating from the retroperitoneal space, an anatomical region nestled behind the abdominal cavity and shielded by the posterior abdominal wall. Late clinical presentation is a hallmark of retroperitoneal sarcomas. The symptoms are often nonspecific, and nodal metastases are rare. Computed tomography (CT) remains the investigation of choice, and a preoperative biopsy is usually not needed. Surgical resection remains the mainstay of treatment, along with adjuvant radiation and chemotherapy. Survival rates are in general poor, even after complete resection. In this study, we attempt to shed some light on the clinicopathological profiling of retroperitoneal sarcomas and their survival outcomes. Objective The objective of this study is to assess the demographic, clinical, and pathological profiling of patients with retroperitoneal sarcoma and to study the survival of patients with retroperitoneal sarcoma. Methodology We conducted a hospital-based retrospective observational study in a tertiary care center in South India between January 2011 and January 2021. We included all patients with histopathologically proven retroperitoneal sarcoma. Metastatic cases and those who underwent chemotherapy or radiation prior to presentation were excluded. Their demographics, pathological reports, and survival were followed up and collected, and statistical analysis was done. Results The study included 16 cases with retroperitoneal sarcomas across the decade in which the data was collected, confirming the rarity of the tumor, out of which more than 40% of patients were above the age of 60. The most common symptom was found to be a bloating sensation in nine patients, followed by abdominal pain in three patients. Seventy-five percent of the patients were found to have a T4 (i.e., a size of more than 15 cm) tumor at presentation. Well-differentiated liposarcoma was found to be the most common pathological variant accounting for 25% of the cases. The mean survival was found to be 8.05 years, which dropped to 5.74 years in Grade 3 tumors. Conclusion Retroperitoneal sarcomas are rare tumors of which liposarcoma is the most common variant. A significant reduction in the mean survival was identified in Grade 3 sarcomas compared to the cumulative survival time of Grade 1 and Grade 2 retroperitoneal sarcomas.

Progenitor cell isolation from mouse epididymal adipose tissue and sequencing library construction.

Here, we present a protocol to isolate progenitor cells from mouse epididymal visceral adipose tissue and construct bulk RNA and assay for transposase-accessible chromatin with sequencing (ATAC-seq) libraries. We describe steps for adipose tissue collection, cell isolation, and cell staining and sorting. We then detail procedures for both ATAC-seq and RNA sequencing library construction. This protocol can also be applied to other tissues and cell types directly or with minor modifications. For complete details on the use and execution of this protocol, please refer to Liu et al. (2023).1.

Private Equity: The Bad and the Ugly.

Private equity's (PE) presence has grown within dermatology over the last decade, creating a new landscape for dermatologists to navigate. Although dermatology PE-backed groups (DPEGs) claim to partner with physicians and improve health care delivery, their actions show that investment returns and profits are prioritized. The history of PE in medicine, the corporate practice of medicine, maturation of the dermatology market, monopolistic practices, overleveraging of nonphysician practitioners, dependence on debt, training under PE, and professional and lifestyle considerations are discussed. Dermatologists should be wary of DPEGs in order to protect the profession and patients.

Interleukin-6 stimulates in vitro development of late-stage ovine embryos.

The effect of interleukin-6 (IL-6) supplementation during the different phases of in vitro embryo culturing (IVC) on embryo development and embryonic gene expression was studied in ovine. IL-6 was added to IVC medium during the late phases (72-192 h; 5, 10, and 25 ng/ml IL-6) or entire period (0-192 h; 10 ng/ml IL-6) of IVC to determine its effect on embryo development. Further, the effect of IL-6 (10 ng/ml) supplementation at the 72 h of IVC on gene expressions associated with JAK/STAT signalling and pluripotency in 8-16 cell embryos (1 h post-supplementation) and compact morulae (48 h post-supplementation), and apoptosis and primitive endoderm (PrE) development in compact morulae was investigated. The supplementation of 10 ng/ml IL-6 during the late phases of IVC significantly (P < 0.05) increased blastocyst formation (35.2 ±â€¯1.52%) compared to the control (21.1 ±â€¯1.11%), and 5 ng/ml (25.9 ±â€¯2.98%) or 25 ng/ml (16.5 ±â€¯0.73%) IL-6 groups. Conversely, IL-6 (10 ng/ml) treatment throughout the IVC period significantly (P < 0.05) decreased the rate of cleavage (55.4 ±â€¯1.57%) and blastocyst formation (14.5 ±â€¯1.28%) compared to the control group (65.8 ±â€¯1.35% and 21.5 ±â€¯0.97%, respectively). In 8-16 cell embryos and compact morulae, the IL-6 treatment significantly (P < 0.05) affected the expression of genes associated with JAK/STAT signalling and pluripotency. Further, the treatment significantly (P < 0.05) downregulated BAX and CASP3, and upregulated GATA6 expression in compact morulae. In conclusion, IL-6 supplementation affected the in vitro development of ovine embryos in a dose- and time-dependent manner. The beneficial effect of IL-6 on the development of late-stage embryos was mediated through the changes in gene expressions associated with JAK/STAT signalling, pluripotency, apoptosis and PrE development.

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling.

Toll-like receptor 4 (TLR4) is an integral factor in the initiation of the innate immune response and plays an important role in cardiovascular diseases such as hypertension and myocardial infarction. Previous studies from our lab demonstrated that central TLR4 blockade reduced cardiac TLR4 expression, attenuated hypertension, and improved cardiac function. However, the contribution of cardiac specific TLR4 to the development of hypertension and cardiac remodeling is unknown. Therefore, we hypothesized that cardiomyocyte specific knockdown of TLR4 would have beneficial effects on hypertension, cardiac hypertrophy, and remodeling. To test this hypothesis, cardiomyocyte-specific TLR4 knockdown (cTLR4KO) mice were generated by crossing floxed TLR4 mice with Myh6-Cre mice, and subjected to angiotensin II (Ang II, 1 µg/kg/min or vehicle for 14 days) hypertension model. Blood pressure measurements using radio telemetry revealed no differences in baseline mean arterial pressure between control littermates and cTLR4KO mice (103 ± 2 vs. 105 ± 3 mmHg, p > 0.05). Ang II-induced hypertension (132 ± 2 vs. 151 ± 3 mmHg, p < 0.01) was attenuated and cardiac hypertrophy (heart/body weight; 4.7 vs. 5.8 mg/g, p < 0.01) was prevented in cTLR4KO mice when compared with control mice. In addition, the level of myocardial fibrosis was significantly reduced, and the cardiac function was improved in cTLR4KO mice infused with Ang II. Furthermore, cardiac inflammation, as evidenced by elevated gene expression of TNF, IL-6, and MCP-1 in the left ventricle, was attenuated in cTLR4KO mice infused with Ang II. Together, this data revealed a protective role for cardiomyocyte-specific deletion of TLR4 against Ang II-induced hypertension and cardiac dysfunction through inhibition of proinflammatory cytokines.

Challenges in the combination of radiotherapy and immunotherapy for breast cancer.

INTRODUCTION: Immunotherapy (IT) is showing promise in the treatment of breast cancer, but IT alone only benefits a minority of patients. Radiotherapy (RT) is usually included in the standard of care for breast cancer patients and is traditionally considered as a local form of treatment. The emerging knowledge of RT-induced systemic immune response, and the observation that the rare abscopal effect of RT on distant cancer metastases can be augmented by IT, have increased the enthusiasm for combinatorial immunoradiotherapy (IRT) for breast cancer patients. However, IRT largely follows the traditional sole RT and IT protocols and does not consider patient specificity, although patients' responses to treatment remain heterogeneous. AREAS COVERED: This review discusses the rationale of IRT for breast cancer, the current knowledge, challenges, and future directions. EXPERT OPINION: The synergy between RT and the immune system has been observed but not well understood at the basic level. The optimal dosages, timing, target, and impact of biomarkers are largely unknown. There is an urgent need to design efficacious pre-clinical and clinical trials to optimize IRT for cancer patients, maximize the synergy of radiation and immune response, and explore the abscopal effect in depth, taking into account patients' personal features.

Tcf21 marks visceral adipose mesenchymal progenitors and functions as a rate-limiting factor during visceral adipose tissue development.

Distinct locations of different white adipose depots suggest anatomy-specific developmental regulation, a relatively understudied concept. Here, we report a population of Tcf21 lineage cells (Tcf21 LCs) present exclusively in visceral adipose tissue (VAT) that dynamically contributes to VAT development and expansion. During development, the Tcf21 lineage gives rise to adipocytes. In adult mice, Tcf21 LCs transform into a fibrotic or quiescent state. Multiomics analyses show consistent gene expression and chromatin accessibility changes in Tcf21 LC, based on which we constructed a gene-regulatory network governing Tcf21 LC activities. Furthermore, single-cell RNA sequencing (scRNA-seq) identifies the heterogeneity of Tcf21 LCs. Loss of Tcf21 promotes the adipogenesis and developmental progress of Tcf21 LCs, leading to improved metabolic health in the context of diet-induced obesity. Mechanistic studies show that the inhibitory effect of Tcf21 on adipogenesis is at least partially mediated via Dlk1 expression accentuation.

The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects the majority of the world population and causes lifelong latent infection. HCMV has been shown to exacerbate cardiovascular diseases, including myocarditis, vascular sclerosis, and transplant vasculopathy. Recently, we have shown that murine CMV (MCMV) recapitulates the cardiovascular dysfunction observed in patients with HCMV-induced myocarditis. To understand the viral mechanisms involved in CMV-induced heart dysfunction, we further characterized cardiac function in response to MCMV and examined virally encoded G-protein-coupled receptor homologs (vGPCRs) US28 and M33 as potential factors that promote infection in the heart. We hypothesized that the CMV-encoded vGPCRs could exacerbate cardiovascular damage and dysfunction. Three viruses were used to evaluate the role of vGPCRs in cardiac dysfunction: wild-type MCMV, a M33-deficient virus (∆M33), and a virus with the M33 open reading frame (ORF) replaced with US28, an HCMV vGPCR (i.e., US28+). Our in vivo studies revealed that M33 plays a role in promoting cardiac dysfunction by increasing viral load and heart rate during acute infection. During latency, ΔM33-infected mice demonstrated reduced calcification, altered cellular gene expression, and less cardiac hypertrophy compared with wild-type MCMV-infected mice. Ex vivo viral reactivation from hearts was less efficient in ΔM33-infected animals. HCMV protein US28 expression restored the ability of the M33-deficient virus to reactivate from the heart. US28+ MCMV infection caused damage to the heart comparable with wild-type MCMV infection, suggesting that the US28 protein is sufficient to complement the function of M33 in the heart. Altogether, these data suggest a role for vGPCRs in viral pathogenesis in the heart and thus suggest that vGPCRs promote long-term cardiac damage and dysfunction.

Conditioned place avoidance is associated with a distinct hippocampal phenotype, partly preserved pattern separation, and reduced reactive oxygen species production after stress.

Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Non-Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation-associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non-Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non-Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress-paired context.

Entropy Related to K-Banhatti Indices via Valency Based on the Presence of C6H6 in Various Molecules.

Entropy is a measure of a system's molecular disorder or unpredictability since work is produced by organized molecular motion. Shannon's entropy metric is applied to represent a random graph's variability. Entropy is a thermodynamic function in physics that, based on the variety of possible configurations for molecules to take, describes the randomness and disorder of molecules in a given system or process. Numerous issues in the fields of mathematics, biology, chemical graph theory, organic and inorganic chemistry, and other disciplines are resolved using distance-based entropy. These applications cover quantifying molecules' chemical and electrical structures, signal processing, structural investigations on crystals, and molecular ensembles. In this paper, we look at K-Banhatti entropies using K-Banhatti indices for C6H6 embedded in different chemical networks. Our goal is to investigate the valency-based molecular invariants and K-Banhatti entropies for three chemical networks: the circumnaphthalene (CNBn), the honeycomb (HBn), and the pyrene (PYn). In order to reach conclusions, we apply the method of atom-bond partitioning based on valences, which is an application of spectral graph theory. We obtain the precise values of the first K-Banhatti entropy, the second K-Banhatti entropy, the first hyper K-Banhatti entropy, and the second hyper K-Banhatti entropy for the three chemical networks in the main results and conclusion.

Directly Observed Care: Crossing the Chasm of Quality Measurement.

After more than two decades of national attention to quality improvement in US healthcare, significant gaps in quality remain. A fundamental problem is that current approaches to measure quality are indirect and therefore imprecise, focusing on clinical documentation of care rather than the actual delivery of care. The National Academy of Medicine (NAM) has identified six domains of quality that are essential to address to improve quality: patient-centeredness, equity, timeliness, efficiency, effectiveness, and safety. In this perspective, we describe how directly observed care-a recorded audit of clinical care delivery-may address problems with current quality measurement, providing a more holistic assessment of healthcare delivery. We further show how directly observed care has the potential to improve each NAM domain of quality.

Functional Outcome of Varus Derotation Osteotomy in Legg-Calve-Perthes Disease: Can It Be Justified in Late-Presenting Disease?

BACKGROUND: Legg-Calve-Perthes disease (LCPD) in children older than seven years has often been associated with accelerated progress and poor outcome. The results of varus derotation osteotomy (VDRO) of the proximal femur in this cohort are not consistently predictable. This study was aimed at assessing the functional outcome of VDRO for hip containment in children with late-presenting LCPD. MATERIALS AND METHODS: A quasi-prospective observational study was conducted to determine the functional outcomes of children with late-presenting unilateral LCPD who underwent VDRO between 2016 and 2021, with a minimum follow-up of two years. A retrospective chart review followed by a patient/parent-reported outcome measure using the Paediatric Outcome Data Collection Instrument (PODCI) was utilised. RESULTS: Thirteen children were included in this study, with a mean age of 8.30 years (range: 7-12 years; SD: -1.493). Three children were in the early stages of the disease, modified Elizabethtown I and IIA (1 and 2, respectively). The majority of the children were in Stage IIB of the modified Elizabethtown staging (n=6), followed by Stage IIIA (n=4). The two children presenting in Stage IV of the disease were excluded from the analysis. The mean standardised and normative PODCI scores for transfer and mobility were 98.23 and 48.03, respectively. The mean standardised and normative PODCI scores for sports and physical were 93.15 and 49.76, respectively. Neither of the scores showed a statistically significant difference between the late and early stages of the disease (Transfer and Basic Mobility Scale: Standardised (p=0.273), Normative (p=0.268); Sports and Physical Functioning Scale: Standardised (p=0.618), Normative (p=0.631)). However, a higher mean PODCI score was noted for the early stages. There was no statistically significant difference between the median score and the duration since surgery. However, there was a moderate negative correlation between the time scores and the times since surgery for the late stages of the disease, viz. Stage IIB and IIIA (Transfer and Basic Mobility Scale: Standardised (-0.445), Normative (-0.450); Sports and Physical Functioning Scale: Standardised (-0.228), Normative (-0.228)). This correlation, however, did not reach a statistical significance. CONCLUSION: VDRO can be regarded as a functionally rewarding option for femoral head containment in late-presenting LCPD across the evolutionary stages of the disease.

Intramyocardial hemorrhage drives fatty degeneration of infarcted myocardium.

Sudden blockage of arteries supplying the heart muscle contributes to millions of heart attacks (myocardial infarction, MI) around the world. Although re-opening these arteries (reperfusion) saves MI patients from immediate death, approximately 50% of these patients go on to develop chronic heart failure (CHF) and die within a 5-year period; however, why some patients accelerate towards CHF while others do not remains unclear. Here we show, using large animal models of reperfused MI, that intramyocardial hemorrhage - the most damaging form of reperfusion injury (evident in nearly 40% of reperfused ST-elevation MI patients) - drives delayed infarct healing and is centrally responsible for continuous fatty degeneration of the infarcted myocardium contributing to adverse remodeling of the heart. Specifically, we show that the fatty degeneration of the hemorrhagic MI zone stems from iron-induced macrophage activation, lipid peroxidation, foam cell formation, ceroid production, foam cell apoptosis and iron recycling. We also demonstrate that timely reduction of iron within the hemorrhagic MI zone reduces fatty infiltration and directs the heart towards favorable remodeling. Collectively, our findings elucidate why some, but not all, MIs are destined to CHF and help define a potential therapeutic strategy to mitigate post-MI CHF independent of MI size.

Improved Grip Force Prediction Using a Loss Function that Penalizes Reward Related Neural Information.

Neural activity in the sensorimotor cortices has been previously shown to correlate with kinematics, kinetics, and non-sensorimotor variables, such as reward. In this work, we compare the grip force offline Brain Machine Interface (BMI) prediction performance, of a simple artificial neural network (ANN), under two loss functions: the standard mean squared error (MSE) and a modified reward penalized mean squared error (RP_MSE), which penalizes for correlation between reward and grip force. Our results show that the ANN performs significantly better under the RP_MSE loss function in three brain regions: dorsal premotor cortex (PMd), primary motor cortex (M1) and the primary somatosensory cortex (S1) by approximately 6%.

Reward-dependent Graded Suppression of Sensorimotor Beta-band Local Field Potentials During an Arm Reaching Task in NHP.

A better understanding of reward signaling in the sensorimotor cortices can aid in developing Reinforcement Learning-based Brain-Computer Interfaces (RLBCI) for restoration of movement functions with fewer implants. Brain-computer interfaces (BCIs) using local field potentials (LFPs) have recently achieved performance comparable to spike-BCIs [1]. With superior stability over time, LFPs may be the preferred signal for BCIs. We show that sensorimotor LFPs can provide reward level information (R1 - R3) like spikes[2]. We used a cued reward-level reaching task in which reward information was temporally dissociated from movement information. This allowed the study of reward- and movement-related modulations in LFPs. We recorded simultaneously from contralateral primary -somatosensory (S1), -motor (M1), and the dorsal premotor (PMd) cortices in a female Macaca Mulatta. We found that all three cortices' average beta band (14-30 Hz) amplitude showed robust modulation with reward levels during the cue presentation period. Such modulation was consistently observed after controlling for cue color, differences in behavioral variables, and electromyogram (EMG) activity. Statistical amplitude analysis showed that reward level could be extracted from the simple LFP feature of beta band amplitude, even before a reaching target appeared, and no specific reach plan could be developed. Clinical Relevance - The availability of reward-related signals in the sensorimotor cortical (S1, M1,and PMd) LFPs' prior to movement planning opens new avenues to build RLBCIs with fewer implants recording fewer sites among different cortices Reward and motivational representations derived from LFPs compared to spikes allow the development of long-term clinical applications given LFP's stability and ease of recording over long periods.

High Classification Accuracy of Touch Locations from S1 LFPs Using CNNs and Fastai.

The primary somatosensory cortex (S1) is a region often targeted for input via somatosensory neuroprosthesis as tactile and proprioception are represented in S1. How this information is represented is an ongoing area of research. Neural signals are high-dimensional, making accurate models for decoding a significant challenge. Artificial neural networks (ANNs) have proven efficient at classification tasks in multiple fields. Moreover, ANNs allow for transfer learning, which exploits feature extraction trained on a large and more general dataset than may be available for a particular problem. In this work, convolutional neural networks (CNN), used for image recognition, were fine-tuned with somatosensory cortical recordings during experiments with naturalistic touch stimuli. We created a highly accurate ( correct) classifier for cutaneous stimulation locations as part of a somatosensory neuroprosthesis pipeline. Here we present the classifier results. Clinical Relevance- Our work provides a method for classifying cortical activity in brain-machine interface applications, specifically towards somatosensory neuroprosthetics.

Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis.

Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid oxidative and homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.