Characteristics and anatomic location of PD-1+TCF1+ stem-like CD8 T cells in chronic viral infection and cancer.

CD8 T cells play an essential role in antitumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in accordance with the progenitor-progeny relationship of TCF1+ stem-like and Tim-3+TCF1- more differentiated T cells. Here, we investigated the characteristics of stem-like and differentiated CD8 T cells isolated from several murine tumor models and human lung cancer samples in terms of phenotypic and transcriptional features as well as their location compared to virus-specific CD8 T cells in the chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. We found that CD8 tumor-infiltrating lymphocytes (TILs) in both murine and human tumors exhibited overall similar phenotypic and transcriptional characteristics compared to corresponding subsets in the spleen of chronically infected mice. Moreover, stem-like CD8 TILs exclusively responded and produced effector-like progeny CD8 T cells in vivo after antigenic restimulation, confirming their lineage relationship and the proliferative potential of stem-like CD8 TILs. Most importantly, similar to the preferential localization of PD-1+ stem-like CD8 T cells in T cell zones of the spleen during chronic LCMV infection, we found that the PD-1+ stem-like CD8 TILs in lung cancer samples are preferentially located not in the tumor parenchyma but in tertiary lymphoid structures (TLSs). The stem-like CD8 T cells are present in TLSs located within and at the periphery of the tumor, as well as in TLSs closely adjacent to the tumor parenchyma. These findings suggest that TLSs provide a protective niche to support the quiescence and maintenance of stem-like CD8 T cells in the tumor.

Cutting Edge: Polycomb Repressive Complex 1 Subunit Cbx4 Positively Regulates Effector Responses in CD8 T Cells.

CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.

An elderly patient's pancreatobiliary puzzle: unraveling diagnosis and treatment challenges.

Pancreatobiliary fistulas associated withntraductal Papillary Mucinous Neoplasm (IPMN) are rare and present therapeutic challenges. The authors describe the clinical course of an 81-year-old woman presenting with acute cholangitis, ultimately diagnosed with IPMN involving secondary ducts with focal high-grade dysplasia. Initial manifestations included elevated inflammatory markers, cholestasis, and imaging findings of a pancreatic lesion. Endoscopic retrograde cholangiopancreatography revealed dilation of both intrahepatic and extrahepatic bile ducts, along a cystic cluster originating from the pancreas, fistulizing into the common bile duct. Despite initial endoscopic interventions, recurrent cholestasis persisted. Subsequent multidisciplinary evaluation led to a cephalic duodenopancreatectomy. This case underscores the rarity of pancreatobiliary fistulas associated with IPMNs and the subsequent therapeutic challenges. The absence of standardized treatment algorithms for such intricate cases emphasizes the importance of individualized approaches. The fluoroscopy image displaying a cystic cluster originating from the pancreas and showing fistulization into the common bile duct is a rare image presented in our report, unique to this case.

Transcriptome analysis of six tissues obtained post-mortem from sepsis patients.

Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.

Kdm6b Regulates the Generation of Effector CD8+ T Cells by Inducing Chromatin Accessibility in Effector-Associated Genes.

The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs, respectively. In this study, we demonstrate that the lysine demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific knockout mice or knockdown using short hairpin RNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.

Cross-cultural investigation from nine countries on the associations of antisocial traits and the WHO's containment measures for the COVID-19 pandemic.

Personality traits play a role in prosocial behavior in relation to containment measures intended to tackle the COVID-19 pandemic. Empirical findings indicated that individuals high in socially aversive traits such as callousness are less compliant with containment measures. This study aimed to add cross-cultural data on the relationship between antisocial traits and adherence to COVID-19 containment measures. The sample consisted of 4,538 adults recruited by convenience in nine countries (Australia, Brazil, England, Iraq, Iran, Italy, Jordan, Saudi Arabia, and the United States). Statistical analyses indicated two latent profiles from our sample, empathic and antisocial, and six COVID-19 containment-measure-related factors using measures covering antisocial traits (PID-5), empathy (ACME), global personality pathology (LPFS-BF), and COVID-19 behaviors and beliefs. Through MANCOVA, the antisocial profile consistently showed less compliance and concern about the COVID-19 containment measures, even when controlling for demographics and local pandemic covariables. The network analysis indicated a lack of empathy and callousness as crucial traits of the predisposition to non-compliant behavior. In elaborating on prosocial campaigns in community emergencies, our cross-cultural findings would need to consider personality traits that focus on antisociality, anticipating similar associations and potential impacts in future disease outbreaks.

Gastric heterotopia in the rectum: a rare entity with potential pitfalls.

Gastric heterotopia (GHT) is a medical condition where the gastric mucosa is found at a non-phyysiological part of the body. GHT can present itself anywhere in the gastrointestinal tract from the mouth to the anorectal area, as well as in the hepatobiliary system. However, it is relatively rare to find GHT in the rectum, with only around 50 documented cases reported in medical literature. We present the case of a 51-year-old man who underwent average-risk screening colonoscopy. He had no clinically significant comorbidities and was otherwise asymptomatic, with no family history. Notable findings included a pseudopolypoid lesion in the distal rectum, adjacent to the dentate line, measuring approximately 15 mm with regular-appearing mucosa under narrow-band-imaging. Biopsy specimens showed histological characteristics of oxyntic-type gastric mucosa without inflammation or dysplasia. GHT has the potential to progress to malignancy, although the rate of malignancy is currently unknown. Awareness of this entity is important given its frequency and potential for misdiagnosis.

Hilar cholangiocarcinoma presenting with hematochezia due to metastases to the rectum.

An 84-year-old female, with history of endometrial and gallbladder adenocarcinomas, both submitted to curative surgeries, was admitted to the emergency room with obstructive jaundice. Computed tomography and subsequent magnetic resonance cholangiopancreatography revealed a common hepatic duct stenosis with intrahepatic biliary dilatation. She underwent percutaneous transhepatic cholangiography with successful biliary drainage. During the same admission, the patient experienced episodes of hematochezia. Rectosigmoidoscopy showed a 20 mm ulcer in the distal rectum and congestion of the rectal mucosa. Computed tomography revealed rectal wall circumferential thickening. Ulcer biopsies were compatible with a neoplasia of biliary origin.

Severe hepatitis E in an immunocompetent young female treated with ribavirin.

A healthy 24-year-old woman was admitted to the emergency department with acute hepatitis. She denied traveling, consumption of drugs, herbs, alcohol or medication other than the same oral contraceptive for years. The etiological work-up revealed positive Herpes Simplex Virus (HSV) 1+2 serology (IgG and IgM). Other viral serologies were negative, while Hepatitis E Virus (HEV) serology and viraemia were pending. Liver biopsy showed portal and lobular necroinflammatory activity without specific etiological findings. The remaining work-up was unremarkable. The patient developed jaundice. Acyclovir was started, considering a possible herpetic hepatitis, while waiting for HSV viraemia and immunohistochemistry in the liver biopsy, which later revealed to be negative. Despite therapy, hyperbilirubinemia and liver cytolysis worsened. At this point, HEV serology and viraemia came back positive. Ribavirin was started with rapid clinical and biochemical improvement. Liver enzymes were normal and HEV viraemia was negative after 12 weeks of ribavirin, remaining undetectable 3 months later.

Non-invasive liver fibrosis assessment: is transient elastography mandatory?

Real-time elastography (RTE) is a conventional ultrasonography-based liver stiffness assessment technique developed in chronic viral hepatitis. Evidence of its applicability in other aetiologies is lacking. This study aims to determine RTE diagnostic accuracy for advanced fibrosis in compensated chronic liver disease (cCLD) and to compare it with the biochemical scores FIB-4 and APRI, using transient elastography (TE) as the gold standard. A single center cross-sectional study including cCLD patients was conducted. RTE with assessment of Liver Fibrosis Index and TE were performed in the same day by different operators blind to the other technique result. The scores FIB-4 and APRI were calculated. Fibrosis cut-off values were inferred from previous evidence.

Preliminary findings on the associations between personality traits and engagement behavior to the COVID-19 containment measures.

In March 2020, the World Health Organization (WHO) had declared the coronavirus disease 2019 (COVID-19) pandemic. Three weeks after WHO's declaration, almost 900,000 cases of COVID-19 were confirmed, with more than 43,000 deaths worldwide. Containment measures were recommended, such as social distancing and hand hygiene. Although they are known to be helpful to slow down the spread of the COVID-19, the efficiency of these measures depends on people's adherence. We explore whether personality traits account for variations in the commitment to the COVID-19 containment measures. The sample consisted of 814 Brazilian adults who answered a questionnaire about adherence to COVID-19 containment measures (COVID-19 questionnaire), factors of the Personality Inventory for DSM-5 (PID-5), and the affective resonance factor of the Affective and Cognitive Measure of Empathy (ACME). We conducted a network analysis. All connections observed in the network analysis were significant (p < .05). Empathy was the personality trait to present more connections to the COVID-19 questionnaire variables. The strongest positive connection was observed for emotional lability (PID-5) and the tendency to be concern about others getting the COVID-19 (COVID-19 questionnaire). Our findings indicated that empathy and emotional lability might be key traits directly associated with the propensity to adhere to the COVID-19 containment measures.

Systems analysis of subjects acutely infected with the Chikungunya virus.

The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.

Effects of acute sleep deprivation on H reflex and V wave.

The impact of sleep deprivation on muscular strength and power remains poorly understood. We aimed to determine the acute effects of 24 hr of sleep deprivation on H-reflex and V-wave excitability. Fourteen healthy young adults (eight men, six women) were included. Participants visited the laboratory on two different occasions, without and with 24 hr of sleep deprivation. In each session, participants were tested for maximal voluntary contraction (MVC) of the plantar flexors and dorsiflexors, soleus H- and M-recruitment curves, and evoked V wave, as well as tibialis anterior/soleus electromyographic co-activation. Twenty-four hours of sleep deprivation did not affect either plantarflexion MVC or soleus electromyographic normalized amplitude (p > .05). Moreover, H-reflex and V-wave peak-to-peak normalized amplitude did not change with sleep deprivation (p > .05). Conversely, we obtained a significant increase in antagonist/agonist level of co-activation during MVC post-sleep deprivation (6.2 ± 5.2%, p < .01). In conclusion, we found that H-reflex and V-wave responses are well preserved after 24 hr of sleep deprivation, revealing that descending neural drive and/or modulation in Ia afferent input remains largely unaffected under these circumstances. Yet, sleep deprivation affects motor control by exacerbating the magnitude of antagonist/agonist co-activation during forceful muscle contractions and this is novel.

Contralateral training effects of low-intensity blood-flow restricted and high-intensity unilateral resistance training.

PURPOSE: Determine whether unilateral low-intensity blood-flow restricted (LIBFR) exercise is as effective as high-intensity (HI) resistance training for improving contralateral muscle strength. METHODS: Thirty healthy adults (20-30 years) were randomly allocated to the following dynamic plantar-flexion training interventions: HI [75% of one-repetition maximum (1RM), 4 sets, 10 reps] and LIBFR [20% of 1RM, 4 sets, 30 + 15 + 15 + 15 reps]. Evoked V-wave and H-reflex recruitment curves, as well as maximal voluntary contraction (MVC) and panoramic ultrasound assessments of the trained and untrained soleus muscles were obtained pre-training, post-4 weeks of training and post-4 weeks of detraining. RESULTS: Both interventions failed to increase contralateral MVC and muscle cross-sectional area (CSA). Yet, contralateral rate of torque development (RTD) was enhanced by both regimens (12-26%) and this was accompanied by heightened soleus EMG within the first milliseconds of the rising torque-time curve (14-22%; p < 0.05). These improvements were dissipated after detraining. Contralateral adaptations were not accompanied by changes in V-wave or H-reflex excitability. Conversely, LIBFR and HI elicited a similar magnitude of ipsilateral increase in MVC, RTD and CSA post-training (10-18%). Improvements in V-wave amplitude and soleus EMG were limited to the trained leg assigned to LIBFR training (p < 0.05). While gains in strength and CSA remained preserved post-4 weeks of detraining, this did not occur with RTD. CONCLUSION: Since gains in RTD were similar between interventions, our findings indicate that both training regimens can be used interchangeably for improving contralateral rapid torque production. Ultimately, this may be beneficial in circumstances of limb immobilization after injury or surgery.

Hybrid power generation for increasing water and energy securities during drought: Exploring local and regional effects in a semi-arid basin.

Reservoirs of hydropower plants (HPP) can amend water, energy, and food security in semi-arid regions. However, during severe droughts, the priority of energy demand leads to critical conditions of water availability. To reduce water use for energy, one possible measure is the adoption of solar power, an abundant energy source in semi-arid regions. This study assessed the influence of adding floating photovoltaic power (PV) in the large-scale reservoir of Sobradinho HPP, located in the São Francisco River (SFR), in Brazil, from 2009 to 2018. The simulated scenarios varied the installed PV power capacity from 50 to 1000 MW. For each scenario, water allocation was modified based on the solar-hydro equivalence that restrained the historical outflow of Sobradinho to maintain water in the reservoir. Besides, a diverse operation rule for the reservoirs in cascade of SFR was adopted to avoid ecological impacts of low streamflow. The scenarios were assessed in water security, solar-hydro electricity output, capacity factor of the powerplant, water and energy losses by evaporation and spilled water. Results show that a PV system starting from 250 MW was necessary to improve water security during the severe drought, reserving 0.7-2.3 of the annual water demand. In addition, the capacity factor was optimized from 29% to 34-47%. However, as the HPPs installed at SFR work as one system, the constrain of the river flow reduced the hydroelectricity by 4.4% for 750 MW. We concluded that PV significantly influenced water security and ecological conditions of SFR, with benefits in the range of 250-750 MW. The research provides assessment on substituting hydro for solar power on the operation of reservoirs in cascade and identifies the correlated benefits in social and ecological aspects. This information can support decisions of water and energy supply system operators and public policies focused on integrated resources management in semi-arid regions.

ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19.

Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.

Sex differences in soleus muscle H-reflex and V-wave excitability.

NEW FINDINGS: What is the central question of this study? How do H-reflex and V-wave excitability compare between men and women engaging in similar levels of physical activity?  What is the main finding and its importance? H-reflex excitability is lower in women than in men because of their greater level of antagonist co-activation during sustained plantar flexion isometric exercise. In addition, supraspinal drive is similar between men and women independently of their differences in H-reflex excitability and antagonist muscle co-activation. ABSTRACT: We compared H-reflex and V-wave excitability between men and women engaging in similar levels of physical activity. We also explored whether differences in antagonist muscle co-activation between sexes might partially explain sexual dimorphism in the excitability of the H-reflex and V-wave. Fifty-seven young participants were included (29 men: 21.7 ± 2.3 years; 28 women: 22.4 ± 3.3 years). Soleus M- and H-recruitment curves were constructed on a tonic background muscle activation. V-waves were elicited during maximal voluntary contraction (MVC). Besides being stronger than women, men achieved greater Hmax /Mmax values and presented a steeper slope of the ascending limb of the H-reflex recruitment curve (P < 0.05). The current intensity required to elicit Hmax was lower for men (P < 0.05). The co-activation of the tibialis anterior muscle during the sustained plantar flexions was greater in women (ratio between tibialis and soleus normalized EMG: 20.5 vs. 8.3%, P < 0.05). Covariance analysis showed that sexual dimorphism in H-reflex excitability was dissipated when controlling for antagonist co-activation. V-wave normalized amplitude was similar between sexes even after controlling for the effects of Hmax /Mmax and antagonist co-activation as covariates. Thus, women exhibit lower H-reflex excitability than men and this is dependent on their higher level of antagonist muscle co-activation. While sex differences in antagonist co-activation persist during MVCs, this is not the case for V-wave normalized amplitude. Thus, although the efficacy of the transmission between Ia afferent fibres to α-motoneurons is lower in women because of a greater level of antagonist co-activation, our findings are consistent with similar supraspinal drive between sexes.

Generation and evaluation of synthetic patient data.

BACKGROUND: Machine learning (ML) has made a significant impact in medicine and cancer research; however, its impact in these areas has been undeniably slower and more limited than in other application domains. A major reason for this has been the lack of availability of patient data to the broader ML research community, in large part due to patient privacy protection concerns. High-quality, realistic, synthetic datasets can be leveraged to accelerate methodological developments in medicine. By and large, medical data is high dimensional and often categorical. These characteristics pose multiple modeling challenges. METHODS: In this paper, we evaluate three classes of synthetic data generation approaches; probabilistic models, classification-based imputation models, and generative adversarial neural networks. Metrics for evaluating the quality of the generated synthetic datasets are presented and discussed. RESULTS: While the results and discussions are broadly applicable to medical data, for demonstration purposes we generate synthetic datasets for cancer based on the publicly available cancer registry data from the Surveillance Epidemiology and End Results (SEER) program. Specifically, our cohort consists of breast, respiratory, and non-solid cancer cases diagnosed between 2010 and 2015, which includes over 360,000 individual cases. CONCLUSIONS: We discuss the trade-offs of the different methods and metrics, providing guidance on considerations for the generation and usage of medical synthetic data.

Comparison of modified alpha functions of the PR-EoS for volume and enthalpy prediction of natural gases.

Proper simulation of processes of the natural gas industry such as dehydration, liquefaction and regasification require accurate prediction of thermodynamic properties of the working fluids. For such processes, cubic equations of state are the calculation methods most frequently employed. Among them, the Peng-Robinson equation is usually the one recommended for gas, refinery and petrochemical applications in many simulators. Numerous works have been proposed in order to improve the temperature dependence relation of the attraction parameter of the equation - the so called alpha function. In this work, five currently available alpha functions are evaluated for the prediction of molar volumes and enthalpies of natural gas samples. Additionally, parameters of one of the models are readjusted to volumetric data of methane, in order to represent its supercritical behavior more accurately. Experimental data of 44 mixtures are compared with calculated results. Van der Waals mixing rules are used, with binary interaction parameters set as zero. In the case of the original alpha function, it is also tested how the inclusion of non-zero binary parameters affects the predictions. The extended Saffari-Zahedi model presents the smallest average deviation for the molar volumes (1.35%). For the enthalpy calculation, the inclusion of the binary parameters results in deviation values of 2.62% for gas-gas transitions and 4.44% for gas-liquid transitions.