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Abstract Background The universal common ancestry (UCA) of all known life is a fundamental component of modern evolutionary theory, supported by a wide range of qualitative molecular evidence. Nevertheless, recently both the status and nature of UCA has been questioned. In earlier work I presented a formal, quantitative test of UCA in which model selection criteria overwhelmingly choose common ancestry over independent ancestry, based on a dataset of universally conserved proteins. These model-based tests are founded in likelihoodist and Bayesian probability theory, in opposition to classical frequentist null hypothesis tests such as Karlin-Altschul E-values for sequence similarity. In a recent comment, Koonin and Wolf (K&W) claim that the model preference for UCA is "a trivial consequence of significant sequence similarity". They support this claim with a computational simulation, derived from universally conserved proteins, which produces similar sequences lacking phylogenetic structure. The model selection tests prefer common ancestry for this artificial data set. Results For the real universal protein sequences, hierarchical phylogenetic structure (induced by genealogical history) is the overriding reason for why the tests choose UCA; sequence similarity is a relatively minor factor. First, for cases of conflicting phylogenetic structure, the tests choose independent ancestry even with highly similar sequences. Second, certain models, like star trees and K&W's profile model (corresponding to their simulation), readily explain sequence similarity yet lack phylogenetic structure. However, these are extremely poor models for the real proteins, even worse than independent ancestry models, though they explain K&W's artificial data well. Finally, K&W's simulation is an implementation of a well-known phylogenetic model, and it produces sequences that mimic homologous proteins. Therefore the model selection tests work appropriately with the artificial data. Conclusions For K&W's artificial protein data, sequence similarity is the predominant factor influencing the preference for common ancestry. In contrast, for the real proteins, model selection tests show that phylogenetic structure is much more important than sequence similarity. Hence, the model selection tests demonstrate that real universally conserved proteins are homologous, a conclusion based primarily on the specific nested patterns of correlations induced in genetically related protein sequences. Reviewers This article was reviewed by Rob Knight, Robert Beiko (nominated by Peter Gogarten), and Michael Gilchrist.

Abstract Background There is a growing awareness among providers of the symptom burden experienced by cancer patients. Systematic symptom screening is difficult. Our plan was to evaluate a technology-based symptom screening process using touch-tone telephone and Internet in our rural outreach cancer program in Indiana. Would rural patients have adequate access to technologies for home-based symptom reporting? Objectives 1) To determine access to touch-tone telephone service and Internet for patients in urban and rural clinics; 2) to determine barriers to access; 3) to determine willingness to use technology for home-based symptom reporting. Methods Patients from representative clinics (seven rural and three urban) in our network were surveyed. Inclusion criteria were age greater than 18, able to read, and diagnosis of malignancy. Results The response rate was 97%. Of 416 patients completing the survey (230 rural, 186 urban), 95% had access to touch-tone telephone service, while 46% had Internet access (56% of urban patients, 38% of rural patients). Higher rates of Internet access were related to younger patient age, current employment, and higher education and income. The primary barrier to Internet access was lack of interest. Use of the Internet for health related activities was less than 50%. The preferred means of symptom reporting in patients with internet access were the touch-tone telephone (70%), compared to reporting by the Internet (28%). Conclusion Access to communication technologies appears adequate for home-based symptom reporting. The use of touch-tone telephone and Internet reporting, based upon patient preference, has the potential of enhancing symptom detection among cancer patients that is not dependent solely upon clinic visits and clinician inquiry.

Helping oncologists to identify and treat depression is an important step in improving the overall care of people with cancer. In previous work performed in our community-based, ambulatory oncology outreach network, we validated a depression screening tool, put into place depression screening programs, and taught oncologists how to follow up on screening with brief, reliable clinical interviews. Subsequently, we provided these oncologists with a fluoxetine-based antidepressant algorithm to follow for the treatment of their depressed patients. In this article, we report on the initial experience identifying and treating 35 ambulatory oncology patients who were screened with the Zung Self-rating Depression Scale (ZSDS). Structured follow-up interviews by their oncologist determined whether the patients qualified for a diagnosis of a major depressive episode. These patients then received 1 of 4 treatments based on the algorithm (no treatment, fluoxetine alone, fluoxetine plus bedtime doxepin, or fluoxetine plus methylphenidate). Patients were matched by their oncologist to a prototype patient for each treatment arm based on their symptomatic presentation (i.e., patients requiring a side effect minimization approach were to be placed on fluoxetine alone; patients who had significant insomnia, weight loss, or neuropathic pain were placed on the fluoxetine plus doxepin regimen; those with prominent fatigue were to receive fluoxetine plus methylphenidate). Patients were followed weekly for one month, and then every two weeks for two more months, with telephone assessments of their depression, associated symptoms and overall quality of life. Results suggested that oncologists most often chose the simplest regimen (fluoxetine alone) but that patients uniformly benefited in terms of improved mood and overall quality of life throughout the 12 weeks of follow-up. Our initial experience suggests that oncologists can be empowered to recognize and treat depression in their patients with a screen-and-intervene approach. Such an approach may benefit patients, and, if kept simple, can be incorporated into day-to-day care of people with cancer. [ABSTRACT FROM AUTHOR]

Fatigue is a highly prevalent and distressing symptom of cancer and its treatment. However, cancer patients often fail to communicate with their oncologists about fatigue. In this study, we attempted to identify the patient-related barriers to communication about fatigue, as cited by patients. Two hundred patients were sampled across the Community Cancer Care, Inc. (CCC) network of Indiana using the Cancer Behavior Inventory-Brief scale (CBI-B), the Zung Self-Rating Depression Scale (ZSDS), the Functional Assessment of Cancer Inventory-Fatigue scale (FACT-F), and the Fatigue Management Barriers Questionnaire (FMBQ), a questionnaire devised by experts in the field of cancer-related fatigue. There were no significant correlations between the instrument scores and demographic variables. Scores on the instruments did not differ significantly based on whether the patient was from a rural or urban site. One hundred thirty-two patients (66%) reported that they had never spoken to their doctor about fatigue. The most frequently reported reasons for this lack of patient communication about fatigue included the doctor's failure to offer interventions (47%), patients' lack of awareness of effective treatments for fatigue (43%), a desire on the patient's part to treat fatigue without medications (40%), and not wanting to complain to the doctor (28%). Patients reported that medical staff offered a mean of 11.63 recommendations for dealing with fatigue. The FMBQ was found to correlate significantly with self-efficacy (CBI-B, r = -0.20, P < 0.01) and correlate weakly with the number of recommendations made (r = -0.15, P < 0.05). The FMBQ was noted to have acceptable internal consistency (alpha = 0.88) and validity and may prove to be a useful instrument for understanding why patients do not communicate about fatigue. Multiple barriers contribute to why cancer patients do not comment about fatigue but may be overcome if physicians screen and assess for this symptom. [ABSTRACT FROM AUTHOR]

This open-label pilot study explored the antiemetic activity of olanzapine, an atypical antipsychotic, in patients with advanced cancer requiring opioid analgesics for pain. Fifteen patients received 2 days of a washout and placebo "run-in" followed by two day periods on each of three doses of olanzapine (2.5 mgs, 5 mgs, and 10 mgs). Patients completed a daily food journal as well as the Mini Mental State Exam, Simpson Angus Scale, Barnes Akathisia Scale, and the Functional Assessment of Cancer Therapy-General across four time periods, with special attention being placed on the nausea item. Eleven women and 4 men with varied primary cancer sites participated. The average age of the sample was 58 years (SD = 16.8). All three dose levels were associated with significant reductions in nausea compared to baseline. Diary entries recorded by the subjects suggested substantial benefits to overall well being and the 5mg condition was associated with statistically significant improvement in overall quality of life over baseline (F = 12.0, p < 0.005). No extrapyramidal symptoms were noted and mental status exams were not changed over the course of the eight days. These results suggest an antiemetic effect for olanzapine and indicate the need for a controlled trial. [ABSTRACT FROM AUTHOR]

Phenotypic transformation of vascular smooth muscle (VSM) from a contractile state to a synthetic, proliferative state is a hallmark of cardiovascular disease (CVD). In CVD, diseased tissue often becomes acidic from altered cellular metabolism secondary to compromised blood flow, yet the contribution of local acid/base imbalance to the disease process has been historically overlooked. In this study, we examined the regulatory impact of the pH-sensing G protein-coupled receptor GPR68 on vascular smooth muscle (VSM) proliferation in vivo and in vitro in wild-type (WT) and GPR68 knockout (KO) male and female mice. Arterial injury reduced GPR68 expression in WT vessels and exaggerated medial wall remodeling in GPR68 KO vessels. In vitro, KO VSM cells showed increased cell-cycle progression and proliferation compared with WT VSM cells, and GPR68-inducing acidic exposure reduced proliferation in WT cells. mRNA and protein expression analyses revealed increased Rap1A in KO cells compared with WT cells, and RNA silencing of Rap1A reduced KO VSM cell proliferation. In sum, these findings support a growth-inhibitory capacity of pH-sensing GPR68 and suggest a mechanistic role for the small GTPase Rap1A in GPR68-mediated VSM growth control. These results shed light on GPR68 and its effector Rap1A as potential targets to combat pathological phenotypic switching and proliferation in VSM. NEW & NOTEWORTHY Extracellular acidosis remains an understudied feature of many pathologies. We examined a potential regulatory role for pH-sensing GPR68 in vascular smooth muscle (VSM) growth in the context of CVD. With in vivo and in vitro growth models with GPR68-deficient mice and GPR68 induction strategies, novel findings revealed capacity of GPR68 to attenuate growth through the small GTPase Rap1A. These observations highlight GPR68 and its effector Rap1A as possible therapeutic targets to combat pathological VSM growth.

Evidence suggests that patients with long COVID can experience neuropsychiatric, neurologic, and cognitive symptoms. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent symptoms are unknown. Here we establish an animal model of long-lasting effects on the brain by eliciting mild disease in K18-hACE2 mice. Male and female K18-hACE2 mice were infected with 4 × 10 3 TCID50 of SARS-CoV-2 and, following recovery from acute infection, were tested in the open field, zero maze, and Y maze, starting 30 days post infection. Following recovery from SARS-CoV-2 infection, K18-hACE2 mice showed the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also had elevated expression of B1R and inflammatory markers in the brain and exhibited behavioral alterations such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential for using this model of high sensitivity to SARS-CoV-2 to investigate mechanisms contributing to long COVID symptoms in at-risk populations. These results further suggest that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Theobald, Nair, Sriramula and Francis.)

Axillary dissection is a standard surgical procedure for stage III skin and soft tissue tumors and is usually performed under general anesthesia. This study aimed to investigate the feasibility of performing axillary dissection with Serratus muscle plane block plus intravenous sedation. Fifteen patients undergoing axillary dissection were prospectively recruited. The patients were evaluated during their pre-operative anesthetic appointment, during their procedure, and at post-operative days 1 and 30. The blockade was performed superficial to the Serratus muscle at the level of fourth rib. Sedation was performed using propofol, fentanyl, dexmedetomidine, and S-ketamine. None of the patients required conversion to general anesthesia. Surgeons showed a highly positive response when asked about the anesthetic technique, and most of them found the technique "indistinguishable" from general anesthesia. The median (interquartile range) pain scores at rest over all time frames was 0 (0-0). Furthermore, no patients developed nausea, hemodynamic instability, or any complications associated with the technique. The Serratus plane block associated with intravenous sedation proved feasible for axillary lymphadenectomy, however, further clinical trials should evaluate potential advantages compared to other techniques.

Hypertension is associated with increased expression of kinin B1 receptors (B1R) and increased levels of pro-inflammatory cytokines within the neurons. We previously reported that angiotensin II (Ang II) upregulates B1R expression and can induce neuroinflammation and oxidative stress in primary hypothalamic neurons. However, the order in which B1R activation, neuroinflammation, and oxidative stress occur has not yet been studied. Using primary hypothalamic neurons from neonatal mice, we show that tumor necrosis factor (TNF), lipopolysaccharides (LPS), and hydrogen peroxide (H 2 O 2 ) can upregulate B1R expression and increase oxidative stress. Furthermore, our study shows that B1R blockade with R715, a specific B1R antagonist, can attenuate these effects. To further confirm our findings, we used a deoxycorticosterone acetate (DOCA)-salt model of hypertension to show that oxidative stress is upregulated in the hypothalamic paraventricular nucleus (PVN) of the brain. Together, these data provide novel evidence that relationship between oxidative stress, neuroinflammation, and B1R upregulation in the brain is bidirectional, and that B1R antagonism may have beneficial effects on neuroinflammation and oxidative stress in various disease pathologies.

Violence against women is a form of gender violence, and the lethal aspect of it, defined as femicide, is a global health and human rights problem.This study looked at 330 cases of femicide that occurred in North West Italy, between 1970 and 2020, committed by 303 male perpetrators. The victims included women who were prostitutes and those who were not.Findings show that only a small proportion of femicide occurs within an anonymous setting: Victims were mostly killed by a man they knew. The type and intensity of the relationship was likely to affect how the violence occurred. In those cases in which victims and perpetrators had an intimate relationship, the risk of overkill, that is, an excessive use of violence that goes further than what is necessary to cause death, was four times higher in comparison with the murder of unknown victims. As with non-prostitutes, the risk of overkill was almost fourfold for those prostitutes who knew their perpetrators. Furthermore, when comparing prostitutes with any unknown victims, the risk of being overkilled was almost five times higher for the former, suggesting that prostitutes are more at risk of being murdered with excessive violence. In addition, prostitutes were more likely to be victims of sexual murder, postmortem mutilation, and being killed by men who had previous criminal records.Women who are victims of violence are not a homogeneous group, although some of the psychosocial correlates are the same and relevance should be given to the features behind the type, intensity, and nature of the relationship between prostitutes and non-prostitutes and their perpetrators. These variables are what make violence against women a preventable problem.

Intimate partner violence (IPV) is a continuum of abuse that is associated with a number of negative outcomes including substance misuse, depression, and suicidal ideation. This study aims to investigate the intergenerational transmission of IPV perpetration and the mechanisms involved. Intergenerational transmission was investigated using information from two generations of the Cambridge Study in Delinquent Development which is a prospective longitudinal study of 411 males from an inner London area in the UK who have been followed up over a period of 50 years. Information with regard to IPV perpetration, specifically physical violence, was garnered from self-reports by the male at age 32, from their female partner at age 48, and from their male and female children in early adulthood. Regression analyses were used to investigate intergenerational transmission and examine whether psychosocial risk factors could be identified as potential intergenerational pathways. Having a father who was a perpetrator of IPV significantly increased the odds of daughters being perpetrators by 2 times. It did not significantly increase the odds for sons. The intergenerational transmission of IPV perpetration remains between fathers and their daughters over and above a series of psychosocial factors such as accommodation problems and alcohol misuse. Identification of factors associated with the intergenerational transmission of IPV perpetration will inform practitioners and policymakers. Information garnered from studies such as this may contribute to the development of prevention and intervention strategies for those at risk.

The endoplasmic reticulum (ER) is a key organelle involved in homeostatic functions including protein synthesis and transport, and the storage of free calcium. ER stress potentiates neuroinflammation and neurodegeneration and is a key contributor to the pathogenesis of neurogenic hypertension. Recently, we showed that kinin B1 receptor (B1R) activation plays a vital role in modulating neuroinflammation and hypertension. However, whether B1R activation results in the progression and enhancement of ER stress has not yet been studied. In this brief research report, we tested the hypothesis that B1R activation in neurons contributes to unfolded protein response (UPR) and the development of ER stress. To test this hypothesis, we treated primary hypothalamic neuronal cultures with B1R specific agonist Lys-Des-Arg 9 -Bradykinin (LDABK) and measured the components of UPR and ER stress. Our data show that B1R stimulation via LDABK, induced the upregulation of GRP78, a molecular chaperone of ER stress. B1R stimulation was associated with an increased expression and activation of transmembrane ER stress sensors, ATF6, IRE1α, and PERK, the critical components of UPR. In the presence of overwhelming ER stress, activated ER stress sensors can lead to oxidative stress, autophagy, or apoptosis. To determine whether B1R activation induces apoptosis we measured intracellular Ca 2+ and extracellular ATP levels, caspases 3/7 activity, and cell viability. Our data show that LDABK treatment does increase Ca 2+ and ATP levels but does not alter caspase activity or cell viability. These findings suggest that B1R activation initiates the UPR and is a key factor in the ER stress pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 White, Parekh, Theobald, Pakala, Myers, Van Dross and Sriramula.)

Optimal superposition of protein structures or other biological molecules is crucial for understanding their structure, function, dynamics and evolution. Here, we investigate the use of probabilistic programming to superimpose protein structures guided by a Bayesian model. Our model THESEUS-PP is based on the THESEUS model, a probabilistic model of protein superposition based on rotation, translation and perturbation of an underlying, latent mean structure. The model was implemented in the probabilistic programming language Pyro. Unlike conventional methods that minimize the sum of the squared distances, THESEUS takes into account correlated atom positions and heteroscedasticity (ie. atom positions can feature different variances). THESEUS performs maximum likelihood estimation using iterative expectation-maximization. In contrast, THESEUS-PP allows automated maximum a-posteriori (MAP) estimation using suitable priors over rotation, translation, variances and latent mean structure. The results indicate that probabilistic programming is a powerful new paradigm for the formulation of Bayesian probabilistic models concerning biomolecular structure. Specifically, we envision the use of the THESEUS-PP model as a suitable error model or likelihood in Bayesian protein structure prediction using deep probabilistic programming.

Powerful innovations can occur when a concept is taken from one field and used to solve a problem in an unrelated field. In fact, it has been shown that as the distance between a problem solver's field of technical expertise and the focal field of a problem increase, so does the probability of success. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Background: Evidence regarding the association between cannabis use and depression remain conflicting, especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression., Method: Males from the Cambridge Study in Delinquent Development (CSDD) (N = 285) were assessed seven times from age 8 to 48 years to prospectively investigate the association between cannabis use and risk of major depressive disorder (MDD). A combination of multiple analyses (logistic regression, Cox regression, fixed-effects analysis) was employed to explore the strength and direction of effect within different developmental stages., Results: Multiple regression analyses revealed that early-onset cannabis use (before age 18) but not late-onset cannabis use (after age 27) was associated with a higher risk and shorter time until a subsequent MDD diagnosis. This effect was present in high-frequency [(odds ratio (OR) 8.83, 95% confidence interval (CI) 1.29-70.79]; [hazard ratio (HR) 8.69, 95% CI 2.07-36.52)] and low-frequency early-onset users (OR 2.41, 95% CI 1.22-4.76; HR 2.09, 95% CI 1.16-3.74). Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence (age 14-18) but not at later life stages, while controlling for observed and non-unobserved time-invariant factors. Conversely, MDD in adulthood (age 18-32) was linked to a reduction in subsequent cannabis use (age 32-48)., Conclusions: The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression. Future studies should further examine causality of effects in larger samples.

Information about the location and magnitudes of natural gas (NG) leaks from urban distribution pipelines is important for minimizing greenhouse gas emissions and optimizing investment in pipeline management. To enable rapid collection of such data, we developed a relatively simple method using high-precision methane analyzers in Google Street View cars. Our data indicate that this automated leak survey system can document patterns in leak location and magnitude within and among cities, even without wind data. We found that urban areas with prevalent corrosion-prone distribution lines (Boston, MA, Staten Island, NY, and Syracuse, NY), leaked approximately 25-fold more methane than cities with more modern pipeline materials (Burlington, VT, and Indianapolis, IN). Although this mobile monitoring method produces conservative estimates of leak rates and leak counts, it can still help prioritize both leak repairs and replacement of leak-prone sections of distribution lines, thus minimizing methane emissions over short and long terms.

Using data from the Cambridge Study in Delinquent Development, a prospective longitudinal survey of more than 400 males in the United Kingdom followed from age 8 years to age 48 years, we investigated the role of Cluster B personality traits and the association with violent offending groups based on a typology theory of male intimate partner violence (IPV) perpetrators: those who committed family-only violence and the generally violent offender. We also considered whether offending/violent groups could be predicted using risk factors measured in childhood, adolescence, and adulthood. Our findings suggest that those men who are violent both within and outside the home (the generally violent men) are distinguished from those who are involved in IPV within the home only. The differences appear to be more in degree than in kind. We discuss these findings in relation to the idea of specific interventions and policy.