Miracle-dz/UniFAR-FTUs huggingface dataset:
All-Optical Interrogation of Neural Circuits

There have been two recent revolutionary advances in neuroscience: First, genetically encoded activity sensors have brought the goal of optical detection of single action potentials in vivo within reach. Second, optogenetic actuators now allow the activity of neurons to be controlled with millisecond precision. These revolutions have now been combined, together with advanced microscopies, to allow “all-optical” readout and manipulation of activity in neural circuits with single-spike and single-neuron precision. This is a transformational advance that will open new frontiers in neuroscience research. Harnessing the power of light in the all-optical approach requires coexpression of genetically encoded activity sensors and optogenetic probes in the same neurons, as well as the ability to simultaneously target and record the light from the selected neurons. It has recently become possible to combine sensors and optical strategies that are sufficiently sensitive and cross talk free to enable single-action-potential sensitivity and precision for both readout and manipulation in the intact brain. The combination of simultaneous readout and manipulation from the same genetically defined cells will enable a wide range of new experiments as well as inspire new technologies for interacting with the brain. The advances described in this review herald a future where the traditional tools used for generations by physiologists to study and interact with the brain—stimulation and recording electrodes—can largely be replaced by light. We outline potential future developments in this field and discuss how the all-optical strategy can be applied to solve fundamental problems in neuroscience. SIGNIFICANCE STATEMENT This review describes the nexus of dramatic recent developments in optogenetic probes, genetically encoded activity sensors, and novel microscopies, which together allow the activity of neural circuits to be recorded and manipulated entirely using light. The optical and protein engineering strategies that form the basis of this “all-optical” approach are now sufficiently advanced to enable single-neuron and single-action potential precision for simultaneous readout and manipulation from the same functionally defined neurons in the intact brain. These advances promise to illuminate many fundamental challenges in neuroscience, including transforming our search for the neural code and the links between neural circuit activity and behavior.
West Nile Virus in the United States — A Historical Perspective

Prior to 1999, West Nile virus (WNV) was a bit player in the screenplay of global vector-borne viral diseases. First discovered in the West Nile District of Uganda in 1937, this Culex sp. -transmitted virus was known for causing small human febrile outbreaks in Africa and the Middle East. Prior to 1995, the last major human WNV outbreak was in the 1950s in Israel. The epidemiology and ecology of WNV began to change in the mid-1990s when an epidemic of human encephalitis occurred in Romania. The introduction of WNV into Eastern Europe was readily explained by bird migration between Africa and Europe. The movement of WNV from Africa to Europe could not, however, predict its surprising jump across the Atlantic Ocean to New York City and the surrounding areas of the United States (U.S.). This movement of WNV from the Eastern to Western Hemisphere in 1999, and its subsequent dissemination throughout two continents in less than ten years is widely recognized as one of the most significant events in arbovirology during the last two centuries. This paper documents the early events of the introduction into and the spread of WNV in the Western Hemisphere.
Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: a meta‐analysis

This meta‐analysis quantified the risk of type 2 diabetes mellitus (T2DM) preceded by body weight (BW) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight‐gain, which was defined as BW gain from early adulthood (18–24 years of age) to cohort entry (≥25 years of age), and late weight‐gain, which was defined as BW gain from cohort entry. The pooled relative risk (RR; 95% confidence interval [CI]) of T2DM for an increment of BW gain standardized into a 5‐kg m−2 increment in the body mass index (BMI) was 3.07 (2.49–2.79) for early weight‐gain and 2.12 (1.74–2.58) for late weight‐gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight‐gain compared with current BMI (RR [95% CI], 3.38 [2.20–5.18] vs. 2.39 [1.58–3.62]), while there was little difference between late weight‐gain (RR [95% CI], 2.21 [1.91–2.56]) and current BMI (RR [95% CI], 2.47 [1.97–3.30]). The meta‐analysis suggested that BW gain was a quantifiable predictor of T2DM, as well as current obesity in adults. Particularly, BW gain in early rather than middle‐to‐late adulthood played an important role in developing T2DM.
Increased neutrophil membrane expression and plasma level of proteinase 3 in systemic vasculitis are not a consequence of the − 564 A/G promotor polymorphism

Several findings link proteinase 3 (PR3) to small vessel vasculitis. Besides being a major target of anti‐neutrophil cytoplasm antibodies (ANCA), previous findings have shown increased circulating levels of PR3 in vasculitis patients, increased levels of neutrophil membrane‐PR3 (mPR3) expression and a skewed distribution of the − 564 A/G polymorphism in the promotor region of the PR3 gene. In this study we elucidate how these three findings relate to each other. The plasma concentration of PR3 was measured by enzyme‐linked immunosorbent assay (ELISA), mPR3 expression by fluorescence activated cell sorter (FACS) and the gene polymorphism by real‐time polymerase chain reaction (PCR). We compared results from 63 patients with ANCA‐associated systemic vasculitis (AASV) with 107 healthy blood donors. In accordance with previous reports, AASV patients had increased plasma concentrations of PR3 compared to healthy controls (mean 224 µg/l versus 155 µg/l, P < 0·0001). They also showed an increased number of mPR3‐positive neutrophils (60%versus 42%, P < 0·001). However, contrary to a previous report, we found no skewed distribution of the polymorphism in PR3 gene. There was a weak correlation between mPR3 mean fluorescence intensity (MFI) and plasma PR3 among healthy controls and myeloperoxidase–ANCA (MPO–ANCA)‐positive patients (r = 0·24, P = 0·015 and r = 0·52, P = 0·011, respectively). In conclusion, increased plasma PR3 and high expression of mPR3 are associated with small vessel vasculitis, but neither of them is a consequence of the − 564 A/G polymorphism of the PR3 gene promotor.
Managed care in the genomics era: assessing the cost effectiveness of genetic tests.

BACKGROUND Despite the fact that the Human Genome Project was completed only recently, genetic tests already have entered the marketplace, some with few or no long-term data to support their use. Managed care organizations will face reimbursement decisions for genetic tests on a growing scale, and they should have a framework in place to evaluate the clinical and economic outcomes of this new class of diagnostics. OBJECTIVE To develop a set of criteria that could assist decision makers in evaluating the cost effectiveness of genetic testing. METHODS A literature review was conducted of marketed genetic tests and criteria used to evaluate the clinical and economic benefits of genetic testing. Criteria were developed and pilot-tested on currently available genetic tests in colon cancer, periodontitis, acute lymphoblastic leukemia, and anticoagulation. RESULTS A robust cost-effectiveness analysis requires data demonstrating (1) genotype-phenotype association; (2) genetic variant prevalence; (3) clinical outcome severity and incidence; (4) interventions for the variant group; and (5) sensitivity, specificity, and timing of the assay result. In addition, calculating the number of patients who need to be screened based on the above factors is useful for evaluating genetic tests. CONCLUSIONS When evaluating a genetic test for reimbursement, these criteria can help to: (1) quantify the potential clinical benefit and economic savings; (2) assess the robustness of a cost-effectiveness analysis; and (3) clarify areas where data are deficient. These criteria should be used to inform the decision-making process in the context of ethical, legal, and social issues related to genetic testing.
Cerebral Venous and Sinus Thrombosis and Thrombophilic Mutations in Western Iran: Association With Factor V Leiden

The present study aimed at investigating the prevalence of factor V Leiden G1691A, prothrombin G20210A, and MTHFR C677T in cerebral venous and sinus thrombosis (CVST) patients and their possible association with CVST in Western Iran. A total of 24 CVST patients with the mean age of 37.1 ± 11.7 years and 100 sex- and age-matched healthy individuals from Kermanshah Province of Iran with ethnic background of Kurd were studied for factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T by PCR-RFLP method using Mnl I, Hind III, and Hinf I restriction enzymes, respectively. Prevalence of factor V Leiden was 16.7% in patients and 2% in control group. A significant association was found between factor V Leiden mutation and CVST with odds ratio (OR) of 9.8 (95% confidence intervals [CI] 1.68-57.2, P = .01). No prothrombin G20210A was found among patients. In patients, MTHFR C677T tended to be higher (58.3%) compared to control (44%), OR of 1.8 (95% CI 0.73-4.5, P = .2). Our study for the first time has determined the prevalence of inherited thrombophilia in a homogenous ethnic group of CVST patients and suggests that factor V Leiden, and not the prothrombin gene mutation is a risk factor for CVST in Western Iran.
The Conformational Changes Induced by Ubiquinone Binding in the Na+-pumping NADH:Ubiquinone Oxidoreductase (Na+-NQR) Are Kinetically Controlled by Conserved Glycines 140 and 141 of the NqrB Subunit*

Background: Na+-pumping NADH:ubiquinone oxidoreductase (Na+-NQR) is a respiratory enzyme which reduces ubiquinone. Results: Two ubiquinone binding sites were found of which only one is catalytically relevant. Conclusion: Gly-140/Gly-141 residues in the NqrB subunit control entry to the catalytic binding site. Significance: Learning how conformational changes are linked to ubiquinone reduction is directly relevant to a large number of respiratory enzymes. Na+-pumping NADH:ubiquinone oxidoreductase (Na+-NQR) is responsible for maintaining a sodium gradient across the inner bacterial membrane. This respiratory enzyme, which couples sodium pumping to the electron transfer between NADH and ubiquinone, is not present in eukaryotes and as such could be a target for antibiotics. In this paper it is shown that the site of ubiquinone reduction is conformationally coupled to the NqrB subunit, which also hosts the final cofactor in the electron transport chain, riboflavin. Previous work showed that mutations in conserved NqrB glycine residues 140 and 141 affect ubiquinone reduction and the proper functioning of the sodium pump. Surprisingly, these mutants did not affect the dissociation constant of ubiquinone or its analog HQNO (2-n-heptyl-4-hydroxyquinoline N-oxide) from Na+-NQR, which indicates that these residues do not participate directly in the ubiquinone binding site but probably control its accessibility. Indeed, redox-induced difference spectroscopy showed that these mutations prevented the conformational change involved in ubiquinone binding but did not modify the signals corresponding to bound ubiquinone. Moreover, data are presented that demonstrate the NqrA subunit is able to bind ubiquinone but with a low non-catalytically relevant affinity. It is also suggested that Na+-NQR contains a single catalytic ubiquinone binding site and a second site that can bind ubiquinone but is not active.
Termination of pregnancy due to fetal abnormalities performed after 32 weeks’ gestation: survey of 57 fetuses from a single medical center

Abstract Objective: To assess fetal abnormalities leading to very late termination of pregnancy (VLTOP) performed after 32 weeks’ gestation. Method: The study population included all pregnant women with singleton pregnancy that underwent VLTOP in our institute because of fetal indications between the years 1998 and 2015. Results: Fifty-seven cases (2.0%) were at ≥32 weeks’ gestation and are the subjects of the current study. Our VLTOP cases were subdivided into four categories according to the sequence of events that led to the decision for VLTOP: (1) No routine prenatal screening with an incidental fetal finding discovered after 32 weeks’ gestation (9 fetuses ∼16%); (2) Routine early prenatal care raised suspicion of abnormalities, and the final diagnosis was established by additional tests (8 fetuses, ∼14%); (3) Developmental findings detected during the third trimester (21 fetuses; ∼37%), and (4) fetal abnormalities that could have been detected earlier during pregnancy (19 fetuses; ∼33%). Conclusions: The two categories in which the pregnant women did not underwent any fetal evaluation (i.e. group 1) or those that could have been detected earlier (i.e. group 4) consists ∼49% from our cohort in which VLTOP could have been avoided.
Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

Costimulatory blockade can induce long‐term allograft survival in naïve animals, but may not be as effective in animals with previously primed immune repertoires. We attempted to induce long‐term graft survival in B10.D2 recipients of B10.A cardiac allografts using donor‐specific transfusion (DST) plus anti‐CD40 ligand antibody (αCD40L). Recipients were either naïve mice, or mice previously primed to B10.A or third party alloantigens through engraftment and rejection of skin transplants. Untreated naïve mice rejected cardiac transplants by day 15 and contained a high frequency of primed, donor‐reactive T cells. Donor‐specific transfusion/αCD40L treatment of naïve animals induced long‐term graft survival associated with low frequencies of donor‐reactive T cells. Previous priming of donor‐specific T cells through rejection of B10.A, but not third party, skin grafts prevented the effects of DST/αCD40L on prolonging survival of B10.A hearts. Moreover, adoptive transfer of CD3+, CD4+ or CD8+ T cells from B10.A skin‐graft‐primed animals prevented the effects of DST/αCD40L. The data demonstrate that animals with immune repertoires containing previously primed, donor‐reactive T cells are resistant to the effects of costimulatory blockade. The findings have important implications for ongoing, costimulatory blockade‐based trials in humans, whose T‐cell repertoires are known to contain memory alloreactive T cells.
A comparison of anthropometric and training characteristics among recreational male Ironman triathletes and ultra-endurance cyclists.

"The physique of Ironman triathletes was considered to be similar to that of cyclists. We intended to investigate differences and similarities in anthropometry and training between 83 Ironman triathletes competing in a qualifier for 'Ironman Hawaii' and 84 ultra-endurance cyclists competing in a qualifier for the 'Race across America'. The anthropometric and training characteristics were compared between these two groups of athletes; associations of anthropometric and training characteristics with race time were investigated using bi- and multi-variate analysis. The Ironman triathletes had shorter legs, lower circumferences of upper arm, thigh and calf and a lower skeletal muscle mass compared to the ultra- cyclists. The Ironman triathletes invested more weekly training hours but fewer weekly cycling hours than the ultra-cyclists; the ultra-cyclists completed more cycling kilometres per week. In the multi- variate analysis, the skin-fold thicknesses at abdominal (P = 0.02) and iliacal site (P = 0.02) as well as percent body fat (P = 0.0008) were associated with race time for the Ironman triathletes. The abdominal (P = 0.003) and the iliacal (P = 0.02) skin-fold thicknesses, percent body fat (P = 0.001) and cycling speed during training (P = 0.01) were related to cycling split time in the Ironman race. For the ultra-cyclists, percent body fat (P = 0.04) was related to race time. We concluded that anthropometry and training of Ironman triathletes were different when compared to ultra-endurance cyclists. "
A prospective comparative study of narrow-band imaging, chromoendoscopy, and conventional colonoscopy in the diagnosis of colorectal neoplasia

Background: Discrimination between neoplastic and non-neoplastic lesions is crucial in colorectal cancer screening. Application of narrow-band imaging (NBI) in colonoscopy visualises mucosal vascular networks in neoplastic lesions and may improve diagnostic accuracy. Aim: To compare the diagnostic efficacy of NBI in differentiating neoplastic from non-neoplastic colorectal lesions with diagnostic efficacies of standard modalities, conventional colonoscopy, and chromoendoscopy. Methods: In this prospective study, 180 colorectal lesions from 133 patients were observed with conventional colonoscopy, and under low-magnification and high-magnification NBI and chromoendoscopy. Lesions were resected for histopathological analysis. Endoscopic images were stored electronically and randomly allocated to two readers for evaluation. Sensitivity, specificity and diagnostic accuracy of each endoscopic modality were assessed by reference to histopathology. Results: NBI and chromoendoscopy scored better under high magnification than under low magnification in comparison with conventional colonoscopy. The diagnostic accuracy of NBI with low or high magnification was significantly higher than that of conventional colonoscopy (low magnification: p = 0.0434 for reader 1 and p = 0.004 for reader 2; high magnification: p<0.001 for both readers) and was comparable to that of chromoendoscopy. Conclusion: Both low-magnification and high-magnification NBI were capable of distinguishing neoplastic from non-neoplastic colorectal lesions; the diagnostic accuracy of NBI was better than that of conventional colonoscopy and equivalent to that of chromoendoscopy. The role of NBI in screening colonoscopy needs further evaluation.
Signaling Crosstalk during Sequential TLR4 and TLR9 Activation Amplifies the Inflammatory Response of Mouse Macrophages1

The TLR family of pattern recognition receptors is largely responsible for meditating the activation of macrophages by pathogens. Because macrophages may encounter multiple TLR ligands during an infection, signaling crosstalk between TLR pathways is likely to be important for the tailoring of inflammatory reactions to pathogens. Here, we show that rather than inducing tolerance, LPS pretreatment primed the inflammatory response (e.g., TNF production) of mouse bone marrow-derived macrophages (BMM) to the TLR9 ligand, CpG DNA. The priming effects of LPS, which correlated with enhanced Erk1/2, JNK, and p38 MAPK activation, appeared to be mediated via both c-Fms-dependent and -independent mechanisms. LPS pretreatment and inhibition of the M-CSF receptor, c-Fms, with GW2580 had comparable effects on CpG DNA-induced Erk1/2 and p38 MAPK activation. However, c-Fms inhibition did not enhance CpG DNA-induced JNK activation; also, the levels of TNF produced were significantly lower than those from LPS-primed BMM. Thus, the priming effects of LPS on TLR9 responses appear to be largely mediated via the c-Fms-independent potentiation of JNK activity. Indeed, inhibition of JNK abrogated the enhanced production of TNF by LPS-pretreated BMM. The c-Fms-dependent priming effects of LPS are unlikely to be a consequence of the inhibitory constraints of M-CSF signaling on TLR9 expression being relieved by LPS; instead, LPS may exert its priming effects via signaling molecules downstream of TLR9. In summary, our findings highlight the importance of signaling crosstalk between TLRs, as well as between TLRs and c-Fms, in regulating the inflammatory reaction to pathogens.
Differences between the thermal stabilities of the three triple-helical domains of type IX collagen.

Fibre-forming collagens in dilute solution show highly co-operative helix-coil transitions at temperatures that are remarkably close to the body temperature of the animal from which the collagen was extracted. This close correlation holds across animal Phyla and the transition temperatures, which range from 5 degrees C to 40 degrees C, are adjusted to suit by changing the primary structure, especially the concentration of the water-bridge-enhancing hydroxyproline residue. Fibril-forming collagens are thermally stabilised by fibrillogenesis, which causes a loss of random coil configurational entropy by intermolecular and intramolecular cross-linking and by spacial confinement of the molecule within the lattice of the fibre. But this mechanism cannot apply to the full length of the type IX collagen molecule, since its COL3 arm, according to current models, projects out from the stabilising influence of the type II fibre. In this paper we examine the thermal stability of the type IX collagen molecule and its three triple-helical domains, thereby demonstrating that the COL3 arm is much more stable than the rest of the molecule. At a scanning rate of 60 deg. C/h COL3 exhibited an unfolding endotherm with a tmax at 49.0 degrees C, well above body temperature. Corresponding peak maxima for COL1 and COL2 were seen at 40.6 degrees C and 39.6 degrees C, respectively. The sizes of the thermally labile units of COL1, COL2 and COL3, calculated from the measured activation enthalpies, were 24, 28 and 28 residues, respectively, much smaller than type I (65 residues) because of the relatively short lengths of triple helix to be unfolded. However, unlike type I collagen, no regions of the required size were found completely devoid of hydroxyproline. Consequently, the intrinsic stabilities of these thermally labile units were higher than that of type I with DeltaH updownarrow DeltaS updownarrow for COL1, COL2 and COL3 being, respectively, 385 K, 371 K and 384 K, contrasting with the much lower 349 K of type I collagen. We therefore speculate that the increased thermal stability of the thermally labile units was caused by the presence of the water-bridge-enhancing residue, hydroxyproline. Finally the stabilisation of type IX collagen tissue is considered and an alternative structural organisation of the type IX molecule on the type II fibre is proposed.