Blocking activation of CD4-CD8- T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors.

CD4-CD8- (double negative - DN) T cells represent a small fraction of circulating T lymphocytes but are a major source of pro-inflammatory cytokines in patients with infectious diseases, including chronic Chagas cardiomyopathy (CCC), one of the deadliest cardiopathies known. Chagas disease is caused by an infection with the protozoan parasite Trypanosoma cruzi and can lead to either an asymptomatic form or a high-mortality cardiac disease. While circulating DN T cells represent a major inflammatory cytokine-expressing cell population in Chagas disease, their potential to be recruited to the heart and to perform cytotoxicity has not been determined. Our previous studies showed that blocking DN T cell activation decreases the expression of IFN-gamma, a cytokine involved in the severity of CCC. Here, studying a well-characterized cohort of Chagas patients with CCC or the asymptomatic form of Chagas disease (indeterminate form, IND), we evaluated the expression of cytotoxic molecules, cytokine and chemokine receptors in γδ+ and αß+ DN T cells by multiparameter flow cytometry, and investigated whether blocking the activation of DN T cells influences the expression of these molecules. We observed that DN T cells from CCC display a higher expression of granzyme A, perforin, inflammatory molecules, and inflammatory chemokine receptors than cells from IND. Messenger RNA coding for these molecules is also upregulated in the heart of CCC patients. Importantly, blocking the activation of DN T cells from CCC modulates their cytotoxic potential and the expression of inflammatory and of chemokine receptors, suggesting that targeting DN T cell activation may be a valid strategy to reduce recruitment to the heart, inflammation, cytotoxicity and, thereby diminish CCC progression and severity.

Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies.

Heart disease is a major cause of death worldwide. Chronic Chagas cardiomyopathy (CCC) caused by infection with Trypanosoma cruzi leading to high mortality in adults, and rheumatic heart disease (RHD), resulting from infection by Streptococcus pyogenes affecting mainly children and young adults, are amongst the deadliest heart diseases in low-middle income countries. Despite distinct etiology, the pathology associated with both diseases is a consequence of inflammation. Here we compare systemic immune profile in patients with these cardiopathies, to identify particular and common characteristics in these infectious heart diseases. We evaluated the expression of 27 soluble factors, employing single and multivariate analysis combined with machine-learning approaches. We observed that, while RHD and CCC display higher levels of circulating mediators than healthy individuals, CCC is associated with stronger immune activation as compared to RHD. Despite distinct etiologies, univariate analysis showed that expression of TNF, IL-17, IFN-gamma, IL-4, CCL4, CCL3, CXCL8, CCL11, CCL2, PDGF-BB were similar between CCC and RHD, consistent with their inflammatory nature. Network analysis revealed common inflammatory pathways between CCC and RHD, while highlighting the broader reach of the inflammatory response in CCC. The final multivariate model showed a 100% discrimination power for the combination of the cytokines IL-12p70, IL-1Ra, IL-4, and IL-7 between CCC and RHD groups. Thus, while clear immunological distinctions were identified between CCC and RHD, similarities indicate shared inflammatory pathways in these infectious heart diseases. These results contribute to understanding the pathogenesis of CCC and RHD and may impact the design of immune-based therapies for these and other inflammatory cardiopathies that may also share immunological characteristics.

A computational framework for studying energetics and resource management in sea turtle migration and autonomous systems.

Sea turtles complete migrations across vast distances, covering entire ocean basins. To track these migrations, satellite tracking tags are attached to their shells. The impact of these tags must be considered to ensure that turtles' natural behavior is not artificially and adversely impacted through tag-related drag, and that the data collected by a small sample of sea turtles accurately represents the larger population. Additionally, it can be difficult to study animal energetics in the field over large migration distances. In this work, we modify a computational behavior model to study how satellite tracking tags affect turtle migration behavior. Our agent based model contains synthetic magnetic field environments that are used for navigation cues, an ocean current, resource distributions that represent locations of food, and an agent that attempts to migrate to several different goals. The agent loses energy as it progresses, and searches for the resource distributions to replenish itself. Our novel simulation framework demonstrates the relationship between an agent's available energy capacity, its energy consumption based on mechanical power expended, and its ability to navigate to all migratory goal points. This study can be utilized to (1) probe the impacts of an animal's energy capacity and foraging behavior on its resulting navigation and ecology, (2) guide future satellite tag designs, and (3) develop usage recommendations for a suitable tracking tag based on the type of experiment being conducted. Our model can be expanded beyond sea turtles to study other marine species (e.g., sharks, whales). Additionally, this model could be expanded to other domains within the marine environment. For example, it could be modified to examine design trade-offs in remotely operated vehicles (ROVs), which share many of the same operational constraints as sea turtles and other migratory species.

CD14 genotype and functional dichotomy of CD14+ and CD14- cells are associated with activated immune response and development of Chagas dilated cardiomyopathy.

We aimed to investigate the association of CD14 -260C/T (rs2569190) polymorphism and Chagas cardiomyopathy and the functional characteristics of CD14+ and CD14- monocytes upon infection with Trypanosoma cruzi. We observed an association between the T- genotype (absence of allele -260T) related to low CD14 expression and the dilated cardiomyopathy type of Chagas disease. Furthermore, we observed that CD14- monocytes showed a more activated profile upon in vitro infection with T. cruzi than CD14+ monocytes. Our findings suggest that T- genotype is associated with susceptibility to develop Chagas dilated cardiomyopathy, likely linked to the T. cruzi-induced inflammatory profile of CD14- monocytes.

Loss of STI1-mediated neuronal survival and differentiation in disease-associated mutations of prion protein.

Cellular prion protein (PrPC ) is widely expressed and displays a variety of well-described functions in the central nervous system (CNS). Mutations of the PRNP gene are known to promote genetic human spongiform encephalopathies, but the components of gain- or loss-of-function mutations to PrPC remain a matter for debate. Among the proteins described to interact with PrPC is Stress-inducible protein 1 (STI1), a co-chaperonin that is secreted from astrocytes and triggers neuroprotection and neuritogenesis through its interaction with PrPC . In this work, we evaluated the impact of different PrPC pathogenic point mutations on signaling pathways induced by the STI1-PrPC interaction. We found that some of the pathogenic mutations evaluated herein induce partial or total disruption of neuritogenesis and neuroprotection mediated by mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase A (PKA) signaling triggered by STI1-PrPC engagement. A pathogenic mutant PrPC that lacked both neuroprotection and neuritogenesis activities fail to promote negative dominance upon wild-type PrPC . Also, a STI1-α7-nicotinic acetylcholine receptor-dependent cellular signaling was present in a PrPC mutant that maintained both neuroprotection and neuritogenesis activities similar to what has been previously observed by wild-type PrPC . These results point to a loss-of-function mechanism underlying the pathogenicity of PrPC mutations.

"If it looks like a duck " - why humans need to focus on different approaches than insects if we are to become efficiently and effectively ultrasocial.

The parallels between the agricultural successes of ultrasocial insects and those of humans are interesting and potentially important. There are a number of important caveats, however, including the relative complexities of insect reproduction, their more rigidly determined altricial patterns of social behaviour, the roles of post-reproductive group members, and differences in the known factors involved in ultrasocietal collapse.

Rifampin resistance and diabetes mellitus in a cross-sectional study of adult patients in rural South India.

BACKGROUND: Despite increasing reports of the linkage between diabetes and tuberculosis (TB), there is limited information regarding diabetes and TB drug resistance. METHODS: In this cross-sectional study, sputum and blood samples were collected from 304 adult patients in rural Andhra Pradesh. Rifampin resistance was assessed by Xpert MTB/RIF (Xpert), and diabetes status was based on self-report. Additionally, samples were assayed by acid-fast bacilli sputum smear microscopy (AFB) and QuantiFERON-TB Gold In-Tube (QFT-G), in order to compare relative diagnostic performances. RESULTS: Among patients with confirmed TB (n = 194), diabetes was associated with 3.0-fold higher risk of rifampin resistance (95 % CI 1.3-6.7). Considering Xpert MTB/RIF the gold standard, AFB had lower sensitivity (72.2 vs. 82.5 %) and higher specificity (96.4 vs. 37.0 %) compared to QFT-G for diagnosing TB. CONCLUSIONS: The increased risk of rifampin resistance in patients with diabetes highlights the need for integrated diabetes surveillance in TB programs, particularly in settings undergoing the epidemiological transition.

Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock.

INTRODUCTION: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis. METHODS: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer's solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na(+)-K(+)-2Cl(-) co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax). RESULTS: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group. CONCLUSIONS: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.

The sound of one hand clapping: overdetermination and the pansensory nature of communication.

Two substantive issues are relevant to discussions of the evolution of acoustic communication and merit further consideration here. The first is the importance of communicative ontogeny and the impact of the proximal social environment on the early development of communication and language. The second is the emerging evidence for a number of non-linguistic roles of FOXP2 and its orthologs.

Could Bertrand Russell's barber have bitten his own teeth? A problem of logic and definitions.

Guiding the positive evolution of behavior is an admirable goal. Wilson et al.'s arguments are based largely on studies of problem correction. The methodology is sound, but not the post hoc ergo procter hoc extrapolation. What is required is evidence that it can proactively generate positive change. The evolution of human behavior to date has been affected by many factors that include unmalleable and unpredicted environmental changes.

PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform (PD-CTT1298) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

It ain't what you do (it's the way that you do it).

Knowledge of the complexity of human communication comes from three main sources - (i) studies of the linguistics and neuropsychology of dysfunction after brain injury; (ii) studies of the development of social communication in infancy, and its dysfunction in developmental psychopathologies; and (iii) the evolutionary history of human communicative interaction. Together, these suggest the need for a broad, integrated theory of communication of which language forms a small but critical component.

Relating Design and Optoelectronic Properties of 1,4-Dihydropyrrolo[3,2-b]pyrroles Bearing Biphenyl Substituents.

Understanding the influence of peripheral functionality on optoelectronic properties of conjugated materials is an important task for the continued development of chromophores for myriad applications. Here, π-extended 1,4-dihydropyrrolo[3,2-b]pyrrole (DHPP) chromophores with varying electron-donating or electron-withdrawing capabilities were synthesized via Suzuki cross-coupling reactions, and the influence of functionality on optoelectronic properties was elucidated. First, chromophores display distinct differences in the UV-vis absorbance spectra measured via UV-vis absorbance spectroscopy in addition to changes in the onset of oxidation measured with cyclic voltammetry and differential pulse voltammetry. Solution oxidation studies found that variations in the electron-donating and -withdrawing capabilities result in different absorbance profiles of the radical cations that correspond to quantifiably different colors. In addition to fundamental insights into the molecular design of DHPP chromophores and their optoelectronic properties, two chromophores display high-contrast electrochromism, which makes them potentially compelling in electronic devices. Overall, this study represents the ability to fine-tune the optoelectronic properties of DHPP chromophores in their neutral and oxidized states and expands the understanding of structure-property relationships that will guide the continued development of DHPP-based materials.

Host biomarkers of clinical relevance in tuberculosis: review of gene and protein expression studies.

CONTEXT: Identification of clinically relevant biomarkers is required for better diagnosis, prevention and treatment of tuberculosis. OBJECTIVE: In this review, potential host biomarkers in blood or blood cells in tuberculosis were identified by a systematic approach. METHODS: A total of 55 articles were selected from PubMed and Google Scholar that analyzed gene and or protein expression in humans in active and or latent TB. Articles were scored according to certain criteria and categorized as strong or weak studies. Biomarkers reported by more than one article or by a single strong article were identified as potential biomarkers. RESULTS: Six most promising markers (IP-10, IL-6, IL-10, IL-4, FOXP3 and IL-12) were identified based on their presence in both mycobacterial antigen-stimulated and -unstimulated samples. CONCLUSIONS: With this review we hope to provide a reliable guideline for biomarker studies in tuberculosis.

Biplanar proximal phalanx closing wedge osteotomy for hallux rigidus.

BACKGROUND: Many procedures have been described for surgical treatment of symptomatic hallux rigidus. Dorsal cheilectomy of the metatarsophalangeal joint combined with a dorsal-based closing wedge osteotomy of the proximal phalanx (i.e., Moberg procedure) has been described as an effective procedure. For patients with hallux rigidus and clinically significant hallux valgus interphalangeus, the authors previously described a dorsal cheilectomy combined with a biplanar closing wedge osteotomy of the proximal phalanx, combining a Moberg osteotomy with an Akin osteotomy. The purpose of this study was to describe the clinical results of this procedure. METHODS: This article is a retrospective review of prospectively gathered data that reports the clinical and radiographic results of dorsal cheilectomy combined with a biplanar oblique closing wedge proximal phalanx osteotomy (i.e., Moberg-Akin procedure) for patients with symptomatic hallux rigidus and hallux valgus interphalangeus. Consecutive patients were followed and evaluated for clinical and radiographic healing, satisfaction, and ultimate need for additional procedure(s). Thirty-five feet in 34 patients underwent the procedure. RESULTS: All osteotomies healed. At an average of 22.5 months of follow-up, 90% of patients reported good or excellent results, with pain relief, improved function, and fewer shoe wear limitations following this procedure. Hallux valgus and hallux interphalangeal angles were radiographically improved. Other than one patient who requested hardware removal, no patients required additional surgical procedures. CONCLUSIONS: Dorsal cheilectomy combined with a Moberg-Akin procedure was an effective and durable procedure with minimal morbidity in patients with hallux rigidus combined with hallux valgus interphalangeus.

Clinicians learn less and less about more and more until they know nothing about everything; researchers learn more and more about less and less until they know everything about nothing: discuss.

A number of recent developments in our understanding of the biology of heritability question commonly held views on the immutability of genetic factors. These have numerous potential implications for improving understanding and practice in pre- and postconceptional care and for infant and child mental health, and they carry a cautionary message against overgeneralization.

The role of hemodynamic shear stress in healing chronic wounds.

Wounds continue to pose significant challenges to clinicians. Data based on randomized controlled trials from the US Wound Registry showed that less than 50% of wounds heal in an unpredictable period of time. Chronic wounds are difficult to heal, with multiple barriers to healing that include inadequate nutrient flow, an inflammatory-coagulation vicious cycle, redox imbalance, and anatomical, physiological, and biochemical dysfunction in the endothelium. In clinical practice, wounds that fail to heal within an appropriate time are at higher risk for deterioration as well as development of infection that further complicates the pathology. Wounds complicated by deep abscess and osteomyelitis often result in amputation. Higher level amputations, below the knee and above the knee, are associated with increased morbidity and mortality rates. However, the most consequential barrier to healing is the prolonged inflammatory phase, which prevents progression to the proliferation phase of wound healing. Diabetic foot ulcers are especially difficult to heal because of angiopathy, hypoxia and ischemia, AGEs, and other factors related to impaired hemodynamics. Restoration of physiological levels of blood flow to DFUs will concomitantly bring about normalization of laminar SS on the endothelium. These multifaceted healing mechanisms, specifically related to the effects of vascular SS on the endothelium, are reviewed here. Such mechanisms involve anti-inflammation, anticoagulation, antioxidation, vasodilation, and angiogenesis. A concluding inference is made that if normalized SS could be produced in the vasculature serving chronic wounds, the sequential healing processes would be enhanced.

Mask-Ed™: Let's Get Real With Simulation.

BACKGROUND: With the increasing shortage of clinical placement sites, nurse educators must be creative in providing alternative learning modalities that prepare students for nursing practice. Mask-Ed™ simulation may help address this challenge. PURPOSE: The purpose of this study was to describe junior-year undergraduate nursing students' experiences with Mask-Ed™ simulation in the context of caring for older adults. METHODS: Using a qualitative descriptive design, focus groups were conducted with 18 students who experienced Mask-Ed™ during 1 semester. RESULTS: Six themes emerged: (1) seeing the older adult as a person, not just a patient; (2) seeing the older adult in a new light; (3) authenticity of the experience and realistic scenarios; (4) ability to give myself to it; (5) safe space to practice; and (6) dress rehearsal for the RN role. CONCLUSIONS: Mask-Ed™ changed participants' perceptions of older adults and their consideration of pursuing a nursing career with this patient population. Participants also expressed Mask-Ed™ was a safe and authentic simulation to help prepare for nursing practice.