cssi/SciSciGPT-SciSciNet huggingface dataset:
Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons.

Objectives Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding of the disorder. With the advancement of induced pluripotent stem (iPS) cell technology, in vitro models based on patient samples are now available that inherently incorporate the complex genetic variants that largely are the basis for this disorder. A number of groups are starting to apply iPS technology to the study of bipolar disorder. Methods We selectively reviewed the literature related to understanding bipolar disorder based on using neurons derived from iPS cells. Results So far, most work has used the prototypical iPS cells. However, others have been able to transdifferentiate fibroblasts directly to neurons. Others still have utilized olfactory epithelium tissue as a source of neural-like cells that do not need reprogramming. In general, iPS and related cells can be used for studies of disease pathology, drug discovery, or stem cell therapy. Conclusions Published studies have primarily focused on understanding bipolar disorder pathology, but initial work is also being done to use iPS technology for drug discovery. In terms of disease pathology, some evidence is pointing toward a differentiation defect with more ventral cell types being prominent. Additionally, there is evidence for a calcium signaling defect, a finding that builds on the genome-wide association study results. Continued work with iPS cells will certainly help us understand bipolar disorder and provide a way forward for improved treatments.
Raman spectrometer for field determination of H2O in natural gas pipelines

Abstract Spontaneous Raman spectroscopy was used to measure changes in the ratio of water vapor to molecular nitrogen gas in laboratory air sample with relative uncertainty of 5 × 10−4 during 100 s observations. Experimental data were collected during 100 s-runs in order to obtain sufficient signal-to-noise ratios. Estimated detection limit of water vapor at signal-to-noise ratio equal to 1 was determined to be equal to 1.4 × 1013 molecules per cm3, which is equivalent to molar concentration of 7.4 × 10−7 at Standard Temperature and Pressure (STP). The achieved sensitivities make our Raman spectrometer suitable for noninvasive, rapid monitoring of gaseous species with very broad applications, for example in natural gas pipe-lines. An inexpensive, 70 mW power, multi-mode, diode-pumped solid-state laser operating near 532 nm served as an excitation source. The high sensitivity was achieved using a multi-pass cell built out of high reflectivity concave mirrors.
Characteristics of Medicaid recipients in Methadone Maintenance Treatment: A comparison across the lifespan.

Abstract Methadone Maintenance Treatment (MMT) is utilized by an increasingly broad age-range of individuals with opioid use disorders. The present study aims to (1) describe health, behavioral, and psychosocial characteristics among adults aged 50 years and older compared with younger adults enrolled in MMT, (2) describe socioeconomic and clinical characteristics by age and time in MMT and (3) investigate whether age influences the associations between duration of MMT and health and psychosocial characteristics. Our sample consisted of 1364 recipients from four MMT programs (age ranged from 18 to 77 years; mean: 38 years: standard deviation: 11.1 years) in Southern New England Using descriptive analysis and logistic regression, we determined that one-third (33%) of adults 50 years of age and older had been admitted or readmitted into MMT within the previous 6 months, 27% had been in treatment for 7–47 months, while 40% had been in treatment for at least 4 years. Psychosocial problems and smoking were both common (>80%) at the time of MMT enrollment but declined with longer duration of MMT for all age groups. The prevalence of metabolic conditions was associated with increased duration of MMT for younger adults for both age (1.03; CI 1.02–1.05; p
Test characteristics of a drug CAGE questionnaire for the detection of non-alcohol substance use disorders in trauma inpatients.

Abstract Background Non-alcohol substance use disorders (drug use disorders [DUDs]) are common in trauma patients. Objective To determine the test characteristics of a 4-item drug CAGE questionnaire to detect DUDs in a cohort of adult trauma inpatients. Methods Observational cross-sectional cohort of 1,115 adult patients admitted directly to a level-one trauma center between September, 1994 and November, 1996. All participants underwent both a 4-item drug CAGE questionnaire and the substance use disorder section of a structured psychiatric diagnostic clinical interview (SCID) (DSM-IIIR criteria), administered by staff unaware of their clinical status. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV), positive (LR+) and negative likelihood ratios (LR-), and the area under the receiver operating curve (AUC) were calculated for each individual question and the overall questionnaire, using SCID-generated DUD diagnoses as the standard. Performance characteristics of the screen were also compared across selected sociodemographic, injury mechanism, and diagnostic sub-groups. Results Subjects with DUDs were common (n = 349, 31.3%), including cannabis (n = 203, 18.2%), cocaine (n = 199, 17.8%), and opioids (n = 156, 14.0%). The screen performed well overall (AUC = 0.90, 95% CI: 0.88–0.91) and across subgroups based on age, sex, race, marriage status, income, education, employment status, mechanism of injury, and current/past DUD status (AUCs 0.75–1.00). Answering any one question in the affirmative had a sensitivity = 83.4% (95% CI: 79.1–87.1), specificity = 92.3% (95% CI: 90.2–94.1), PPV = 83.1%, LR+ = 10.8. Conclusions The 4-item drug CAGE and its individual questions had good–to–excellent ability to detect DUDs in this adult trauma inpatient population, suggesting its usefulness as a screening tool.
Drawing the line of ineligibility.

In this issue of Blood , Statler et al report the incidence and outcomes of patients who were treated on leukemia clinical trials conducted by Southwest Oncology Group (SWOG) from 2005 to 2015, but who were retrospectively deemed ineligible. The primary finding is that patients labeled as ineligible for the included clinical trials have similar outcomes as eligible patients. 1
Attacks on Ecstasy: Theology—We Don’t Want It Either

Modern Theology has also rejected ecstasy. In Judaism, this is associated with the ending of the era of prophecy, for Torah study and rabbinical law have come to replace the direct encounter between the person and God. In Islam, there are to be no more prophets after Muhammad, the seal of the prophets. For mainstream Christians, the canonization of the Bible meant that the time of “signs and wonders” was over. This “closing of the canon,” or Cessationism, was partially rejected by Catholicism, which emphasized the rarity of supernatural events. Reformation theologians followed total Cessationism, associating ecstatic states with Catholic myth and superstition. We still see these concerns in groups like the Deliverance Movement, and in the analysis of the ecstatic states of the children of Medjugorje.
Challenging the imbalances of power in feminist oral history

Synopsis For decades, feminists have been arguing that oral histories of women are empowering for all those involved. They provide a voice for women whose stories would otherwise go unrecorded and offer readers personal stories of and insights about groups of women they might not otherwise meet. They provide feminist researchers with a way to uncover significant information about women and to further political causes by weaving women's stories into a narrative. Recently, however, practitioners have begun to question the ethics of oral history work. Arguably, researchers have far more to gain in this process than respondents do. This article explores several ethical issues and suggests that any oral history project should begin by asking what the researcher will do to compensate respondents for the information they provide, in an effort to acknowledge, address, and minimize the inherent imbalances of power and of benefits.
The Problem of Other Minds Is Not a Problem: Mirror Neurons and Intersubjectivity

This chapter discusses evidence from single unit recordings in monkeys and brain imaging in humans suggesting that neural mechanisms of mirroring allow the sharing of mental states between individuals. Such sharing solves the old philosophical problem of other minds. Correlations between mirroring and empathy also suggest that relatively simple neurobiological mechanisms of mirroring maybe at the basis of a secular morality which is built upon biological predispositions we have inherited from our evolutionary ancestors.
Comments on “Sterilization, Privacy, and the Value of Reproduction”

Joseph Ellin has written a provocative paper on the matter of procreation and sterilization. Although he concludes that involuntary sterilization violates a basic right to privacy, not many will be satisfied with his argument that this is unrelated to a right to procreate, and that the latter interest in procreation is not an “important” interest to individuals. As he notes, having robbed procreation of both the strong status of a right, and the weaker status of an important interest, the road is cleared for an unfavorable comparison with truly important and most likely public interests. Although the cleanup tasks are left for another occasion, Ellin himself assumes that from the perspective of public policy procreation is quite important, and thus as a matter of public policy, it will require legislation and control. The remaining safeguard against control is based upon the fact that effecting control requires an “intrusion into the body.” Therefore it is a matter of violating that sense of privacy which protects the use of our body. He seems to think that to the degree that actual physical intrusion is not necessary, to that degree privacy will not be violated. Therefore, since there is no other reason for banning the effecting of control through sterilization, such sterilization would be legitimate.
Risk of Developing Postoperative Deficits Based on Tumor Location after Surgical Resection of an Intracranial Meningioma.

Object Meningiomas occur in various intracranial locations. Each location is associated with a unique set of surgical nuances and risk profiles. The incidence and risk factors that predispose patients to certain deficits based on tumor locations are unclear. This study aimed to determine which preoperative factors increase the risk of patients having new deficits after surgery based on tumor location for patients undergoing intracranial meningioma surgery. Methods Adult patients who underwent primary, nonbiopsy resection of a meningioma at a tertiary care institution between 2007 and 2015 were retrospectively reviewed. Stepwise multivariate logistic regression analyses were used to identify associations with postoperative deficits based on tumor location. Results Postoperatively, from the 761 included patients, there were 39 motor deficits (5.1%), 23 vision deficits (3.0%), 19 language deficits (2.5%), 27 seizures (3.5%), and 26 cognitive deficits (3.4%). The factors independently associated with any postoperative deficits were preoperative radiation (hazard ratio [HR] [95% confidence interval, CI] 3.000 [1.346–6.338], p = 0.008), cerebellopontine angle tumors (HR [95% CI] 2.126 [1.094–3.947], p = 0.03), Simpson grade 4 resections (HR [95% CI] 2.000 [1.271–3.127], p = 0.003), preoperative motor deficits (HR [95% CI] 1.738 [1.005–2.923], p = 0.048), preoperative cognitive deficits (HR [95% CI] 2.033 [1.144–3.504], p = 0.02), and perioperative pulmonary embolisms (HR [95% CI] 11.741 [2.803–59.314], p = 0.0009). Conclusion Consideration of the factors associated with postoperative deficits in this study may help guide treatment strategies for patients with meningiomas.
Research in the archival multiverse

Where to start? The first comment I received from anyone seeing me reading this book was about its size. This is a blockbuster of a book at over 1000 pages. So how to review it? The standard approa...
The transition from steady frictional sliding to inertia-dominated instability with rate and state friction

Abstract Unstable frictional slip motions are investigated with a rate and state friction law across the transitions from stable, quasi–static slip to dynamic, stick–slip motion, and finally to, inertia dominated quasi–harmonic vibration. We use a novel numerical method to capture the full dynamics and investigate the roles of inertial and quasistatic factors of the critical stiffness defining the transition to instability, Kc. Our simulations confirm theoretical estimates of Kc, which is dependent on mass and velocity. Furthermore, we show that unstable slip motion has two distinct dynamic regimes with characteristic limit cycles: (i) stick–slip motions in the quasi–static (slowly loaded) regime and (ii) quasi–harmonic oscillations in the dynamic (rapidly loaded) regime. Simulation results show that the regimes are divided by the dynamic frictional instability coefficient, η = MV2/σaDc and stiffness of the system K. The quasi–static regime is governed by the ratio K/Kc and both the period and magnitude of stick–slip cycles decrease with increasing loading rate. In the dynamic regime, slip occurs in harmonic limit cycles, the frequency of which increases with loading velocity to a limit set by the natural frequency of the system. Our results illuminate the origin of the broad spectrum of slip behaviors observed for systems ranging from manufacturing equipment to automobiles and tectonic faults, with particular focus on the role of elasto–frictional coupling in dictating the transition from slow slip to dynamic instability. We highlight distinct characteristics of friction–induced slip motions (stick–slip and friction–induced vibration) and show that the dynamic frictional instability coefficient (η) is a key parameter that both defines the potential for instability and determines the dynamic characteristics of instability.
Leading Edge Learning in Network Science

This article focuses on teaching and learning network science—the emerging science of studying complex networks by modeling its actors as nodes and their relationship as edges—through discovery-based techniques. The outline presented in this article is for a graduate level course, in this case in the applied mathematics department, which can easily be mimicked at other educational levels.
Kuchu activism, queer sex-work and “lavender marriages,” in Uganda’s virtual LGBT safe(r) spaces

This article builds on Michael Warner’s theory of “damaged publicness” to examine virtual queer counterpublics in Uganda. Online spaces have become a viable platform for LGBT Ugandans, locally know...
Campuses: Overvalued, Underused, and Very Costly

Campus-based higher education is finding new competition in on-line learning leaving public universities with tough questions about the future of the campus. A growing body of research is showing that the brick and mortar campus is “starting to lose its monopoly as a place of learning.” Construction costs, low utilization, high maintenance expenditures, a growing backlog of deferred maintenance, and obsolete facilities have led increasing numbers of higher education policy makers to argue that “we must rethink the American university campus.” All these costs are contributing to the high cost of tuition with only a portion directly related to education. Governing boards of our public universities are issuing long-term bonds in the billions of dollars to pay for deferred maintenance and often extravagant facilities to aid in student recruitment. Some observers call this an “arms race.” This chapter looks at the future of the university campus and sees another important, costly aspect of American higher education calling for reform.
Biomarkers for platinum sensitivity in bladder cancer: are we there yet?

The current standard of care for treating patients with newly diagnosed muscle-invasive bladder cancer (MIBC) is the administration of neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) in surgical candidates. This recommendation is based on level 1 evidence demonstrating improved overall survival for NAC followed by RC compared to RC alone (1,2). The survival benefit from the use of NAC is largely attributable to pathologic downstaging of the primary tumor (3) and the potential eradication of micrometastatic disease.
Introducing Edge Controlling to Software Defined Networking to Reduce Processing Time

Edge computing enables computational services to be performed at the edge of a network on behalf of the main cloud services. The rationale of edge computing is applicable to any centralized system where the service should be provided at the proximity of the end-systems. Software-Defined Networking (SDN) is an evolving network model that runs a single-centralized controller to handle all network functions which may lead to limited performance capabilities with the recent growth of data communication. In this paper, we introduce a novel SDN Edge Controlling model that overcomes the performance-limitations by leveraging edge computing capabilities. It aims to bring the computing and storage resources close to network devices so that the load on the main SDN controller can be eased, and the delay between the forward plane and the control plane is minimized. We develop a simulation program to assess the effectiveness of our model. Experimental results show that the bandwidth usage is reduced by about 45% and the total processing time of the main controller is reduced by almost 62% for 10,000 requests. Therefore, the proposed model handles a higher network load and maintains lower latency when compared with a traditional SDN.
Parent Roles and Facilitation Strategies as Influenced by a Mobile-Based Technology During a Family Nature Hike

AbstractFamilies use mobile technologies in many educational spaces, such as museums or other informal learning venues to support their social learning experience. This trend encourages parents to ...
Voicing the Silenced Through African Tongues: An Examination of Moolaadé and Tumaini

This paper proposes to comparatively analyze two works written in African languages, namely Sembene’s movie Moolaade (2004) and Momanyi’s novel Tumaini (2007), to examine the functional use of African languages in the expression and production of a feminist discourse in African creative arts. I argue that the utilization of Bambara in Moolaade and Swahili in Tumaini opens up African women’s cultural worlds and employ African heritage knowledge to provide an African insider perspective and active involvement in the ongoing campaign to eradicate female circumcision. By portraying ordinary women as agents of transformation, the authors counter stereotypes of African womanhood as victims, showing their great potential in engendering change within their societies.
A Critique of Pandemic Catastrophe Modeling

Catastrophe modeling is a popular risk assessment tool for the insurance industry and has been applied to a variety of natural disaster events. More recently, catastrophe modeling techniques have been extended to events, such as pandemics, where the range of possible scenarios is less understood due to the complexity of the hazard and the dependence of event magnitude to human response. Some general limitations of catastrophe modeling are discussed in the context of pandemics—such as the failure to distinguish natural variability from incertitude and the difficulty of ensuring a representative model—along with recommendations for minimizing surprises.
Triple therapy with intralesional 5-fluorouracil, chemowraps, and acitretin: A well-tolerated option for treatment of widespread cutaneous squamous cell carcinomas on the legs

Neither patient experienced myelosuppression. Acitretin was briefly withheld when the latter patient had hypercholesterolemia until pravastatin was started and cholesterol normalized. Both patients tapered down to acitretin, 10 mg/d after 4 months. After 3 additional months, they tapered to 10 mg every other day for prevention for up to 10 months. At 1-year follow-up, both patients remained without clinical recurrence (Figs 1, D and ​and2,2, D)
Building preparedness in response to active shooter incidents: Results of focus group interviews

Abstract Active shooter incidents present an increasing threat to the American society. Many of these incidents occur in building environments, therefore, it is important to consider design and security elements in buildings to decrease the risk of active shooter incidents. This study aims to assess current security countermeasures and identify varying considerations associated with implementing these countermeasures. Fifteen participants, with expertise and experience in a diverse collection of operational and organizational backgrounds, including security, engineering, law enforcement, emergency management and policy making, participated in three focus group interviews. The participants identified a list of countermeasures that have been used for active shooter incidents. Important determinants for the effectiveness of countermeasures include their influence on occupants' behavior during active shooter incidents, and occupants' and administrators' awareness of how to use them effectively. The nature of incidents (e.g., internal vs. external threats), building type (e.g., office buildings vs. school buildings), and occupants (e.g., students of different ages) were also recognized to affect the selection of appropriate countermeasures. The nexus between emergency preparedness and normal operations, and the importance of tradeoffs such as the ones between cost, aesthetics, maintenance needs and the influence on occupants' daily activities were also discussed. To ensure the effectiveness of countermeasures and improve safety, the participants highlighted the importance of both training and practice, for occupants and administrators (e.g., first responder teams). The interview results suggested that further study of the relationship between security countermeasures and occupants' and administrators’ responses, as well as efficient training approaches are needed.
Cardiac ischemia/reperfusion stress reduces inner mitochondrial membrane protein (mitofilin) levels during early reperfusion.

Abstract Mitochondrial inner membrane protein (Mitofilin or Mic60) is a mitochondria-shaping protein that plays a key role in maintaining mitochondrial cristae structure and remodeling. We recently showed that Mitofilin knockdown in H9c2 myoblasts induces mitochondrial structural damage resulting in mitochondrial dysfunction that is responsible for cell death via apoptosis. Here, we investigated the role of Mitofilin regulation in ischemia/reperfusion (I/R) injury and studied the relationship between Mitofilin and Cyclophilin (CypD), a key regulator of mitochondrial permeability transition pore (mPTP) opening. C57Bl6 male mice hearts were subjected to different ischemia times (15, 30, or 45 min) followed by a 2 h reperfusion period, or 45 min ischemia followed by 0, 15, 30, 60, or 120 min reperfusion to determine the impact of ischemia or reperfusion times on Mitofilin levels and its interaction with CypD. We found that the increase in myocardial infarct size and the reduction of mitochondrial calcium retention capacity were concomitant with Mitofilin reduction as a function of ischemic duration. We also found that 15 min reperfusion after 45 min ischemia was sufficient to cause a reduction of Mitofilin levels compared to sham, while 45 min ischemia alone was not enough to cause a significant decrease of Mitofilin. We revealed that the c-terminus coiled-coiled domain of Mitofilin is important for its interaction with CypD and the deletion of this identified sequence resulted in a loss of Mitofilin-CypD link, dissipation of mitochondrial membrane potential and increase in cell death. A decrease of the levels of Mitofilin was also associated with mitochondrial structural integrity damage, increased reactive oxygen species (ROS) production, and calpain activity. Our results indicate that Mitofilin physically binds to CypD in the inner mitochondrial membrane and the disruption of this interaction may play a critical role in the increase of mitochondrial dysfunction and initiation of myocytes’ death after I/R injury.
Distinct roles for calcium signaling in apoptosis of prostate and cervical cancer cells exposed to diindolylmethane

1739 Diindolylmethane (DIM), a dietary phytochemical derived from indole-3-carbinol (I3C) in cruciferous vegetables, causes growth arrest and apoptosis of cancer cells in vitro. At micromolar concentrations, DIM induces endoplasmic reticulum (ER) stress1,2, and pre-treatment of cancer cells with thapsigargin (TG), a specific inhibitor of the sarcoplasmic/ER calcium-dependent ATPase and itself an inducer of ER stress, enhances DIM cytotoxicity. Increased intracellular calcium [Ca2+]i has been implicated as an apoptotic signal in several experimental and pathophysiologic models, including ER-stress; however, increased [Ca2+ ]i was not required to produce apoptosis after exposure of LnCaP prostate cancer cells to I3C3. We asked whether elevated [Ca2+]i is required for cytotoxicity of DIM and TG in two cancer cells lines, C33A (cervical), and DU145, (prostate). DIM, like TG, rapidly mobilized ER Ca2+ (measured by real-time Fura2 fluorescence). We tested the ability of DIM, TG, and DIM + TG to cause apoptosis under conditions that prevented elevation of [Ca2+ ]i (“clamp”)3. In unclamped C33A cells, 25μM DIM alone caused no detectable increase in basal levels of apoptosis (measured by nucleosome-release ELISA) after 24h, whereas thapsigargin alone increased apoptosis 3-fold, and the combination of 25μM DIM + TG caused a further, 4-fold, increase. Clamping C33A cells slightly increased basal apoptosis, but did not interfere with apoptosis induced by TG or by TG + DIM. In contrast to C33A, Ca2+ clamping significantly reduced apoptosis of DU145 cells induced by all treatments; the combination of TG + DIM acted synergistically to cause a 16-fold increase in nucleosome release in DU145 that was attenuated >50% by Ca2+ clamping. Inhibitor studies appear to rule out CaM kinase II and protein phosphatase 2A as potential mediators of the Ca2+-dependent apoptotic signal in DU145. The different responses of C33A and DU145 to perturbations in calcium homeostasis suggest either that DIM induces apoptosis by different mechanisms in these two cell lines, or that calcium mobilization activated survival pathways in C33A, but not in DU145. Apoptosis of C33A appeared to be independent of increased [Ca2+]i , suggesting that depletion of ER Ca2+ stores may be sufficient for killing by TG and DIM, whereas induction of apoptosis in DU145 requires elevated [Ca2+]i for full response. Further work is ongoing to define these different mechanisms, and to determine the role(s) of calcium-dependent apoptotic signaling in the cytotoxic effects of DIM on tumor cells. Supported in part by grants CA73850 and CA100967. 1. Carter, TH, Liu, K, Ralph, WJ, Jr. et al., (2002) J. Nutrition 132, 3314-3324. 2. Sun, S-S, Han, J, Ralph, WJ, Jr, et al., (2003) Cell Stress and Chap. 9, 1355-8145. 3. Wertz, IE and Dixit, VM, (2000) J. Biol. Chem. 275, 11470-11477.
Correcting the sex disparity in MELD-Na.

MELD-Na appears to disadvantage women awaiting liver transplant by underestimating their mortality rate. Fixing this problem involves: (1) estimating the magnitude of this disadvantage separately for each MELD-Na, (2) designing a correction for each MELD-Na, and (3) evaluating corrections to MELD-Na using simulated allocation. Using Kaplan-Meier modeling, we calculated 90-day without-transplant survival for men and women, separately at each MELD-Na. For most scores between 15 and 35, without-transplant survival was higher for men by 0-5 percentage points. We tested two proposed corrections to MELD-Na (MELD-Na-MDRD and MELD-GRAIL-Na), and one correction we developed (MELD-Na-Shift) to target the differences we quantified in survival across the MELD-Na spectrum. In terms of without-transplant survival, MELD-Na-MDRD overcorrected sex differences while MELD-GRAIL-Na and MELD-Na-Shift eliminated them. Estimating the impact of implementing these corrections with the liver simulated allocation model, we found that MELD-Na-Shift alone eliminated sex disparity in transplant rates (p = 0.4044) and mortality rates (p = 0.7070); transplant rates and mortality rates were overcorrected by MELD-Na-MDRD (p = 0.0025, p = 0.0006) and MELD-GRAIL-Na (p = 0.0079, p = 0.0005). We designed a corrected MELD-Na that eliminates sex disparities in without-transplant survival, but allocation changes directing smaller livers to shorter candidates may also be needed to equalize women's access to liver transplant.
Small Airway Disease as long-term Sequela of COVID-19: Use of Expiratory CT despite Improvement in Pulmonary Function test

BackgroundIt is important to understand the spectrum of pulmonary diseases that patients are presenting after recovery from initial SARS-CoV-2 infection. We aim to study small airway disease and changes in Computed Tomography (CT)and pulmonary function tests (PFTs) with time. MethodsThis is retrospective observation study including adult patients with confirmed SARS-CoV-2 infection with at-least two CT scans either during acute (defined as 3months) phase after positive test. Radiological features and follow up PFTs were obtained. Results22 patients met the inclusion criteria with mean age 57.6 years (range 36-83). Out of these,18 (81.81%) were hospitalized. Mean duration of diagnosis to CT and PFT was 192.68(112-385) days and 161.54(31-259) days respectively. On PFTs, restrictive pulmonary physiology was predominant finding during subacute 56.25% (9/16) and chronic phases 47% (7/15). PFTs improved significantly with time {FEV1((p=0.0361), FVC (p=0.0341), FEF 25%-75% (p=0.0259) and DLCO (p=0.0019)}, but there was persistent air trapping in the expiratory chronic phase CT. There was resolution of ground glass opacity, consolidation, and bronchiectasis however air trapping increased with time in 41.61% (10/21) of subacute CTs compared to 81.25% (13/16) in chronic CTs. ConclusionOur study shows evidence of airway as well as parenchymal disease as relatively long-term sequel of SARS-CoV-2 infection. It also highlights the natural course and spontaneous recovery of some radiological and pulmonary function test abnormalities over time with evidence of persistent small airway disease (air trapping) on expiratory CT imaging months after infection. HighlightsO_LILong term pulmonary complication of SARS-CoV-2 infection include small airway disease C_LIO_LIThere is role of inspiratory and expiratory Computed tomography (CT) scan to identify air trapping in patients with persistent respiratory symptoms after SARS-CoV-2 infection C_LIO_LINormal spirometry and normal routine CT may not be sufficient to characterize and identify cause of persistent respiratory complains in patients after COVID-19 C_LIO_LIThis study highlights persistent parenchymal and physiological airway abnormalities more than six months after recovery from initial SARS-CoV-2 infection C_LI
Camptothecin binding to topoisomerase I-DNA complexes impedes DNA uncoiling and induces the accumulation of positive supercoils

5735 DNA topoisomerase I (Top1) catalyzes the relaxation of positively or negatively supercoiled DNA via the formation of a transient Top1-DNA covalent intermediate, which acts as a swivel to allows DNA uncoiling or rewinding, respectively. Camptothecin targets Top1 by reversibly stabilizing this covalent complex. During S-phase, the collision of advancing replication forks with Top1-DNA-drug complexes are thought to induce the formation of potentially lethal DNA lesions that cause cell death. Several camptothecin analogs, including irinotecan and topotecan have significant activity against adult and pediatric solid tumors. A detailed understanding of Top1-drug interactions is critical for the optimal clinical development of these chemotherapeutics; however, the dynamic interactions underlying Top1 poisoning by camptothecins and their biological ramifications remain largely unknown. Employing a single-molecule technique allowed us to monitor the binding and unbinding of an individual topotecan molecule in real-time and quantify the drug-induced trapping of Top1 on DNA. In these experiments, a single double-stranded DNA molecule is anchored between a glass surface and a paramagnetic bead. A pair of magnets generates an upward stretching force, while rotating the magnets about their axis mechanically injects positive or negative supercoils. By continuously monitoring bead height (DNA extension), the degree of DNA supercoiling is determined in real-time. Our studies show that a bound topotecan molecule alters the Top1 swivel in two ways. First, we conclude that an individual topotecan traps Top1 for at least 2 minutes, an increase of roughly a factor of 100 in comparison to when topotecan is absent. Second, our findings also show that topotecan significantly hinders DNA rotation within the covalent complex. Unexpectedly, however, this effect was more pronounced on the removal of positive (overwound) rather than negative supercoils. These single-molecule observations led us to posit that this bias towards negative supercoil removal would also be induced by camptothecin in vivo, during cellular processes such as transcription and replication that induce DNA supercoiling. Indeed, yeast as a model system, we show that camptothecin poisoning of Top1 induces the accumulation of positive supercoils in G1 and S-phases of the cell cycle, independent of Topoisomerase II. These findings suggest a novel mechanism for drug-induced cell death. Instead of the covalent complex presenting a physical barrier to the advancing fork, the local domain of positive supercoils generated ahead of the fork, which is not efficiently removed by the drug-bound Top1, may itself hamper fork progression. The resultant stalling of the replication machinery would result in fork collapse and the formation of potentially lethal DNA lesions that ultimately induce cell death.
Relevance of soil microbiology to search for life on other planets.

Publisher Summary The initial phases of the search for extraterrestrial life apparently concentrates on detecting some form of microscopic life in the surface layers of other planets. The reason why this happens lies with the fact that the particulate surface layer of the soil is the repository for and source of the widest diversity and greatest density of microbial life on our planet, and so the surfaces of other planets probably consist of some sort of particulate layers. Soil, as an environment for microorganisms, possesses certain unique features, which, although probably not changing the genotypic biochemical potentialities of microorganisms, probably influence their phenotypic expression. Many of the environmental parameters that influence microorganisms in soil also influence microorganisms in other habitats. Microbial life in soil exists in discrete microhabitats, while the chemical, physical, mineralogical, and microbiological compositions of which undoubtedly differ.
Technical Note: The LDC TRIPS Transition Extension and the Question of Rollback

When the WTO TRIPS Agreement entered into force on January 1, 1995, least developed countries (LDCs) were given until January 1, 2006 to bring their legislation into conformity with the agreement (subject to compliance with national treatment and most favored nation (MFN) treatment obligations). Pursuant to Article 66.1, upon presentation of a duly motivated request, the TRIPS Council is obligated to provide extensions of the transition period “In view of the special needs and requirements of least-developed country Members, their economic, financial and administrative constraints, and their need for flexibility to create a viable technological base.” The first LDC extension was granted in 2002 further to Paragraph 7 of the Doha Declaration on the TRIPS Agreement and Public Health in respect to pharmaceutical patents and regulatory data requirements, and included authority to disapply existing protections. That public health-related extension expires on January 1, 2016. A general extension of the LDC transition was adopted by the TRIPS Council in 2005, and is set to expire on July 1, 2013. The 2005 extension included a clause that has become known as the “no-rollback” provision, providing that “Least-developed country Members will ensure that any changes in their laws, regulations and practice made during the additional transitional period do not result in a lesser degree of consistency with the provisions of the TRIPS Agreement”. LDCs have presented a request for an additional extension of the transition arrangement. In this context, they have objected to the inclusion of a “no-rollback” clause. This paper examines whether the WTO TRIPS Council has the authority to establish a no-rollback requirement as a condition of further LDC transition extensions. It considers the terms of the TRIPS Agreement, the negotiating history of the transition arrangements, other WTO Agreement language regarding waivers, ambiguity of terms, prospective options should there not be an agreement, and policies underlying the LDC request and certain objections. This paper was presented and discussed at a meeting organized by ICTSD at the WTO on May 24, 2013.
Lysis of Yeast Cell Walls Induced by 2-Deoxyglucose at Their Sites of Glucan Synthesis

Abstract Six sites of 2-deoxyglucose (2DG)–induced lysis on three yeasts (Schizosaccharomyces pombe, Pichia farinosa, and Saccharomyces cerevisiae) coincided with the regions of growth of their glucan layers. Identification of the glucan layer as the site of lysis suggests a mechanism of attack by 2DG or by its derivatives. It is proposed that the glucan layer grows by addition of glucose into internal breaks of polysaccharide molecules. 2DG inhibited resynthesis (insertion of glucose) of the broken glycosidic linkage.
Optimal Plan Search in a Rule-Based Query Optimizer

This paper describes an optimal plan search strategy adopted in a rule-based query optimizer. Instead of attempting to search for the optimal plan directly, an initial plan is first generated based upon a set of heuristic rules. Depending upon the application, the initial plan may be used either as the final plan or as a base in a subsequent search. A new concept — clustering degree of an index — is introduced to better model the I/O costs of index scans. This new statistical information facilitates the formulation of the rules. An exhaustive search based upon the A* algorithm is then invoked to guarantee the optimal property of the plan. A lower bound value is derived and used as the estimation of ”remaining distance” required in the A* algorithm. Noteworthy features of our approach include the capability for dynamic control of exhaustive search for an optimal plan, and on-line performance monitoring/tuning. The preliminary results lead us to believe that the rule-based approach is a promising one to face the new challenges of the optimizer, as created by the requirements of supporting diversified applications.
Epigenetics and lupus

Lupus develops when genetically predisposed people encounter environmental agents that initiate flares. Current evidence indicates that the environmental contribution is mediated by T-cell DNA demethylation. DNA methylation patterns are established during differentiation, and silence inappropriate or unnecessary genes by promoting a condensed chromatin configuration that is inaccessible to transcription factors. The methylation patterns are then replicated each time a cell divides by DNA methyltransferase 1 (Dnmt1). Dnmt1 is upregulated during mitosis, binds the replication fork, and catalyzes transfer of the methyl group from S-adenosylmethionine (SAM) to dC bases in the daughter DNA strand only where the parent strand is methylated. Environmental agents that block ERK pathway signaling prevent Dnmt1 upregulation, and low Dnmt1 levels synergize with dietary micronutrient deficiencies that decrease SAM pools to impair methylation of the daughter strand. This activates genes silenced only by DNA methylation. Inhibiting T-cell DNA methylation converts helper CD4+ T cells into autoreactive, cytotoxic, proinflammatory cells that cause lupus-like autoimmunity in mice. Similar changes in CD4+ T-cell DNA methylation and gene expression are found in patients with active lupus. Procainamide and hydralazine, which cause ANAs in a majority of patients and lupus in a genetically predisposed subset, also inhibit T-cell DNA methylation. The lupus T-cell DNA methylation defect has been traced to low Dnmt1 levels caused by decreased ERK pathway signaling, and the signaling defect has now been traced to PKCδ inactivation caused by oxidative damage. The importance of decreased ERK pathway signaling was confirmed by generating a transgenic mouse with an inducible dominant negative MEK. Inducing the signaling defect selectively in T cells decreases Dnmt1, causing anti-DNA antibodies in mice without lupus genes, and higher anti-DNA antibody levels and an immune complex glomerulonephritis in mice with lupus genes. Autoantibody levels and kidney disease are suppressed by dietary transmethylation micronutrient supplementation in these mice. Epigenetic mechanisms also contribute to the gender dimorphism in lupus. Immune genes on the normally silenced X chromosome demethylate in women with active lupus, contributing to flare severity. In contrast, men with only one X chromosome require a greater genetic predisposition and/or greater degree of DNA demethylation to develop a lupus flare equal in severity to women. Together, these studies indicate that environmental agents including oxidative stress and diet combine to inhibit T-cell DNA methylation, and that the epigenetically modified cells cause lupus-like autoimmunity in genetically predisposed people and mice.
Abstract P030: Use of Skilled Nursing Facilities in Heart Failure: Role of Multimorbidity in the Community

Background: As the population ages, it has been reported that discharges to skilled nursing facilities (SNF) have increased. Yet, data on SNF utilization in HF are sparse and predictors are not well defined. Objectives: In a community cohort of incident hospitalized HF patients, we evaluated trends in use of SNF from 1987 through 2006 and described predictors of discharge to SNF. Methods: All Olmsted County, MN residents hospitalized with first ever (incident) HF (ICD-9 code 428) from 1987 through 2006 were identified. HF was validated by Framingham criteria. Patients residing in a SNF prior to hospitalization were excluded from the analysis. Using logistic regression, we determined whether referral to SNF had increased over time and identified predictors of referral to SNF. Results: Among 952 patients (mean age 75±13, 47% male), 185 (19%) were referred to a SNF. After adjustment for age and sex, referral of HF patients to SNF did not change from 1987 to 2006 (p=0.849). Patients with a Charlson comorbidity index of 3 or higher were twice as likely to be referred to a SNF (odds ratio: 1.91, 95% CI: 1.36-2.69, adjusted for age and sex). Individual characteristics associated with referral to a SNF are tabulated. After adjustment, the strongest predictor was dementia, followed by older age, anemia, hypertension and diabetes. Conclusion: In the community, approximately one-fifth of hospitalized HF patients are referred to a SNF and this did not change from 1987 to 2006. While older age and cardiovascular-related factors (hypertension, diabetes) were associated with referral to SNF, non-cardiovascular factors (particularly dementia) were strong predictors of referral. These findings underscore the impact of multimorbidity on HF outcomes.
T cell help controls the speed of the cell cycle in germinal center B cells

The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression, while preserving the relative order of replication origin activation. Thus, high-affinity GC B cells are selected by a mechanism that involves prolonged dwell time in the DZ where selected cells undergo accelerated cell cycles.
Protein metabolism and beta-myosin heavy-chain mRNA in unweighted soleus muscle

To investigate the relative influence of protein synthetic and degradative control mechanisms in vivo during skeletal muscle atrophy, we measured myofibril and total mixed protein synthesis rates in muscles of rats prevented from hindlimb weight-bearing for 5 h and 7 days. Protein synthesis rates were determined by infusing the animals with [3H]Leu for 5 h and measuring the specific activity of [3H]Leu in the aminoacyl-tRNA precursor and protein product fractions of the muscles. In the soleus muscle, myofibril protein synthesis rates decreased from a control value of 5.9 to 4.6%/day during 5 h of hindlimb unweighting and to 2.4%/day after 7 days of hindlimb unweighting. The relatively more phasic muscles (plantaris, medial gastrocnemius, quadriceps) showed a tendency for increased myofibril protein synthesis rates (117-127% of control) during the first 5 h followed by a decrease (46-62% of control) at 7 days of hindlimb unweighting. A predicted time course of soleus muscle myofibril protein degradation rate was obtained from a numerical model of the decrease in soleus myofibril protein synthesis rate as a first-order process [half-time (t1/2) = 0.3 day by least-squares fit] and the time course of soleus muscle myofibril protein previously observed with hindlimb unweighting (Thomason et al., J. Appl. Physiol. 63: 130-137, 1987). The degradation rate model makes specific, testable predictions for the mechanism of myofibril protein degradation during soleus muscle atrophy: 1) the first-order degradation rate constant does not obtain a fixed value over a 24-day period but is continuously changing throughout atrophy, and 2) the first-order degradation rate constant changes on a time scale slower than protein synthesis rate.(ABSTRACT TRUNCATED AT 250 WORDS)