Miracle-dz/UniFAR-FTUs huggingface dataset:
A 3.48ps jitter @ 1.45GHz fully differential dual band DCO with a new reconfigurable delay cell

In this paper a dual band differential Digital-Controlled-Oscillator (DCO) with a reconfigurable delay cell in each four stages of digitally controlled ring Oscillator is proposed. The bands switching will done by a digital mode select bit. Each band will controls by 6 bit codes and varies in a 50MHz band width. Band variations occurs by changing the sizing of the current tails of Source-Coupled-Logic (SCL) based delay cells. A new SCL based delay cell is used which has a reconfigurable structure. The structure transformation influence on power and delay path. But in each band the power consumption profile has a monotonic changes. Fully differential oriented structure ensures low jitter design, 6.04ps @505.1MHz in lower band and for upper band 3.48ps @1.45MHz. The simulations are in 180nm CMOS technology. First band with select bit 0 has frequency range [455.2-505.1] MHz and consumes power 1.98mW @455MHz. Upper band in select bit 1 position with frequency range of [1.39-1.45] MHz has power consumption, 9.7mW @1.39GHz. Small signal model for delay calculation and circuit analysis are done for validity of results. Also, Monte Carlo and central frequency disturbance are shown the acceptable operation of the proposed circuit.
Procedural pain management in the treatment of scleroderma digital ulcers.

OBJECTIVES Digital ulcers (DU) may develop in half of systemic sclerosis (SSc) patients; they are often resistant to treatments. Deep wound debridement is crucial for DU healing, but very difficult to carry out without adequate procedural pain management. Here, we report the results of our experience on procedural pain management in scleroderma DU. METHODS The study included 51 DU observed in 32 consecutive SSc patients; procedural pain was treated following a definite schedule: local lidocaine and prilocaine (25 mg of either agent per gram of cream, EMLA 5%) were initially used in all cases, followed by local and oral morphine, according to the severity of pain scored on a 10 cm visual analogue scale (VAS). RESULTS At baseline, higher pain VAS was recorded in more severe (p=0.0001) and/or infected DU (p=0.0001). Good compliance to DU debridement was observed in patients with mild pain (VAS ≤4) treated with only EMLA, and in 5 cases with moderate-severe pain (VAS >4) at baseline. While, the majority of DU with moderate-severe pain (34/39) needed a combined therapy with EMLA and local morphine (8/34) or with EMLA, local and oral morphine (26/34). On the whole, pain management during DU debridement required only EMLA application in 33% of cases, EMLA plus local morphine in 16%, while combined EMLA, local and oral morphine were necessary in 51%, generally with more severe and/or infected lesions. CONCLUSIONS The present study showed valuable control of procedural pain during DU debridement with sequential, combined analgesic treatment.
Use of Anidulafungin as a Surrogate Marker To Predict Susceptibility and Resistance to Caspofungin among 4,290 Clinical Isolates of Candida by Using CLSI Methods and Interpretive Criteria

ABSTRACT This study addressed the application of anidulafungin as a surrogate marker to predict the susceptibility of Candida to caspofungin due to unacceptably high interlaboratory variation of caspofungin MIC values. CLSI reference broth microdilution methods and species-specific interpretive criteria were used to test 4,290 strains of Candida (eight species), including 71 strains with documented fks mutations. Caspofungin MIC values were compared with those of anidulafungin to determine the percentage of categorical agreement (CA) and very major (VME), major (ME), and minor error rates, as well as the ability to detect fks mutants. For all 4,290 isolates the CA was 97.1% (0.2% VME and ME, 2.5% minor errors) using anidulafungin as the surrogate. Among the 62 isolates of Candida albicans (4 isolates), C. tropicalis (5 isolates), C. krusei (4 isolates), C. kefyr (2 isolates), and C. glabrata (47 isolates) that were nonsusceptible (NS; either intermediate [I] or resistant [R]) to both caspofungin and anidulafungin, 52 (83.8%) contained a mutation in fks1 or fks2. Eight mutants of C. glabrata, two of C. albicans, and one each of C. tropicalis and C. krusei were classified as susceptible (S) to both antifungal agents. The remaining 7 mutants (2 C. albicans and 5 C. glabrata) were susceptible to one of the agents and either intermediate or resistant to the other. Using the epidemiological cutoff value (ECV) of 0.12 μg/ml for both caspofungin and anidulafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 42 of the 55 (76.4%) C. glabrata mutants were non-WT and 8 of the 55 (14.5%) were WT for both agents (90.9% concordance). Anidulafungin can accurately serve as a surrogate marker to predict S and R of Candida to caspofungin.
Factors influencing bowel function after low anterior resection and sigmoid colectomy.

BACKGROUND/AIMS The aim of this study was to evaluate the subjective bowel function after low anterior resection and sigmoid colectomy and to clarify the clinicopathologic factors influencing postoperative bowel habits. METHODOLOGY Eighty-six patients who underwent low anterior resection and sigmoid colectomy replied to the questionnaire which consisted of 8 categories of bowel symptoms. The patients were divided into 2 groups: good bowel function showing less than half of symptoms (< 4) and poor bowel function showing more than half of symptoms (> or = 4). RESULTS After low anterior resection, patients were often complicated with incomplete evacuation (75%), bowel movement at night (60%), defecation more than twice a day (46%), and soiling (27%). The mean number of defecation/day and frequency of patients with night stools was significantly higher after low anterior resection than sigmoid colectomy (2.81 vs. 2.18, P < 0.05; and 60% vs. 29%, P < 0.05). Poor bowel function after low anterior resection was frequent in patients with high ligation of the inferior mesenteric artery (82%, P < 0.05), injury to the pelvic autonomic nerve (82%, P < 0.05), and blood transfusion; while poor bowel function after sigmoid colectomy was frequent in patients with resected colon measuring 25 cm or more (81%, P < 0.05). CONCLUSIONS These results indicate that poor bowel function after low anterior resection is associated with high ligation of the inferior mesenteric artery and injury to the pelvic autonomic nerve; while poor bowel function after sigmoid colectomy correlates with length of the resected colon. Less aggressive surgery is needed to preserve good bowel function.
Allosteric Modulation by Tertiary Structure in Mammalian Hemoglobins

Bovine erythrocytes do not contain 2,3-diphosphoglycerate, the principal allosteric effector of human hemoglobin. Bovine hemoglobin has a lower oxygen affinity than human hemoglobin and is regulated by physiological concentrations of chloride (Fronticelli, C., Bucci, E., and Razynska, A.(1988) J. Mol. Biol. 202, 343-348). It has been proposed that the chloride regulation in bovine hemoglobin is introduced by particular amino acid residues located in the amino-terminal region of the A helix and in the E helix of the β subunits (Fronticelli, C.(1990) Biophys. Chem. 37, 141-146). In accordance with this proposal we have constructed two mutant human hemoglobins, β(V1M+H2deleted+T4I+P5A) and β(V1M+H2deleted+T4I+P5A+A76K). These are the residues present at the proposed locations in bovine hemoglobin except for isoleucine at position 4. Oxygen binding studies demonstrate that these mutations have introduced into human hemoglobin the low oxygen affinity and chloride sensitivity of bovine hemoglobin and reveal the presence of a previously unrecognized allosteric mechanism of oxygen affinity regulation where all the interactions responsible for the lowered affinity and chloride binding appear to be confined to individual β subunits.
Quantitative analysis of gene expression in human articular cartilage from normal and osteoarthritic joints.

OBJECTIVE To quantify the expression of genes encoding extracellular matrix (ECM) proteins in human cartilage from normal and osteoarthritic (OA) joints. DESIGN Human cartilage samples were classified as control (CTR) or OA according to clinical evaluation and assessed histologically and biochemically to confirm the diagnosis. mRNAs encoding collagen types I, II and X, aggrecan, versican, osteopontin and osteocalcin were quantified by real-time reverse transcription-PCR assays and normalized to a reference mRNA (GAPDH). RESULTS RNA from native cartilage could be reproducibly and efficiently amplified by real-time PCR only if isolated using purification membranes. Primers and fluorescent probes for real-time PCR, endowed with comparable (<6% difference from GAPDH) and high (>91%) amplification efficiencies, were designed and validated for the selected ECM genes. The expression of most genes under investigation displayed large variations and was not significantly different in CTR and OA cartilage. Only osteopontin mRNA levels were significantly higher in OA than CTR specimens. mRNA ratios of collagen type II to I and of aggrecan to versican, defined as indexes of chondrocyte differentiation, were less variable within each population than the single genes and markedly higher (27.0 and 7.6-fold, respectively) in CTR than OA cartilage, with high statistical significance (P = 0.00013 and P = 0.00007, respectively). CONCLUSIONS Our results provide evidence that gene patterns related to chondrocyte differentiation discriminate between CTR and OA human cartilage with higher sensitivity than single ECM genes. The method described here has the potential to improve understanding of the progression of OA and could become a valuable diagnostic tool.
Changes in knee kinematics following total knee arthroplasty

Total knee arthroplasty (TKA) changes the knee joint in both intentional and unintentional, known and unknown, ways. Patellofemoral and tibiofemoral kinematics play an important role in postoperative pain, function, satisfaction and revision, yet are largely unknown. Preoperative kinematics, postoperative kinematics or changes in kinematics may help identify causes of poor clinical outcome. Patellofemoral kinematics are challenging to record since the patella is obscured by the metal femoral component in X-ray and moves under the skin. The purpose of this study was to determine the kinematic degrees of freedom having significant changes and to evaluate the variability in individual changes to allow future study of patients with poor clinical outcomes. We prospectively studied the 6 degrees of freedom patellofemoral and tibiofemoral weightbearing kinematics, tibiofemoral contact points and helical axes of rotation of nine subjects before and at least 1 year after total knee arthroplasty using clinically available computed tomography and radiographic imaging systems. Normal kinematics for healthy individuals were identified from the literature. Significant differences existed between pre–TKA and post–TKA kinematics, with the post-TKA kinematics being closer to normal. While on average the pre–total knee arthroplasty knees in this group displayed no pivoting (only translation), individually only five knees displayed this behaviour (of these, two showed lateral pivoting, one showed medial pivoting and one showed central pivoting). There was considerable variability postoperatively as well (five central, two lateral and two medial pivoting). Both preop and postop, flexion behaviour was more hinge-like medially and more rolling laterally. Helical axes were more consistent postop for this group. An inclusive understanding of the pre–TKA and post–TKA kinematics and changes in kinematics due to total knee arthroplasty could improve implant design, patient diagnosis and surgical technique.
Signaling pathways perturbing muscle mass

Purpose of reviewTo discuss the mechanisms of muscle loss during cachexia. Recent findingsCachexia can be defined as a wasting of lean body mass that cannot be reversed nutrionally, indicating a dysregulation in the pathways maintaining body composition. In skeletal muscle, during cachexia, there is an upregulation of protein degradation. A search for transcriptional markers of muscle atrophy led to the discovery of the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1). These genes are upregulated in multiple models of atrophy and cachexia. They target particular protein substrates for degradation via the ubiquitin/proteasome pathway. The insulin-like growth factor-1 can block the transcriptional upregulation of MuRF1 and MAFbx via the phosphatidylinositol-3 kinase/Akt/Foxo pathway. MuRF1's substrates include several components of the sarcomeric thick filament, including myosin heavy chain. Thus, by blocking MuRF1, insulin-like growth factor-1 prevents the breakdown of the thick filament, particularly myosin heavy chain, which is asymmetrically lost in settings of cortisol-linked skeletal muscle atrophy.Insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt signaling also dominantly inhibits the effects of myostatin, which is a member of the transforming growth factor-β family of proteins. Deletion or inhibition of myostatin causes a significant increase in skeletal muscle size. Recently, myostatin has been shown to act both by inhibiting gene activation associated with differentiation, even when applied to postdifferentiated myotubes, and by blocking the phosphatidylinositol-3 kinase/Akt pathway. SummaryThese findings will help to define strategies to treat cachexia.
Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly

The incidence of serious and severe multisystem adverse events (AEs) following yellow fever (YF) 17D vaccine is higher in persons of advanced age. One hypothesis for the occurrence of these AEs in the elderly is immunological senescence and a reduced ability to clear the vaccine virus infection. We determined age-specific rates of serious and nonserious AEs in two large clinical trials of two YF 17D vaccines from different manufacturers. In addition, we analyzed AEs reported in a large general practice data base in the United Kingdom. Neutralizing antibody responses were compared in young and elderly subjects. In the clinical trials, involving a total of 4,532 subjects, there were no neurological and viscerotropic AEs; interestingly, the incidence of common injection site and systemic AEs was significantly lower in elderly than in younger subjects. The neutralizing antibody categorical and quantitative responses were equivalent across younger and elderly subjects. In contrast, the larger retrospective analysis of 43,555 persons receiving YF 17D in the UK general practice database revealed a higher incidence of significant neurologic and multisystem AEs with advancing age. The age-specific reporting rate ratio (RRR) was approximately twice that in the 25-44 year-old reference group for subjects in the 45-64 year age group (RRR 1.82; 95% CI 0.88,3.77) and 3-fold higher for the 65-74 year-old age group (RRR 2.82; 95% CI 0.81, 9.81). These results are consistent with previous reports on YF vaccine safety in the US (Martin M, et al. Emerg Infect Dis 2001;6:945-951; Khromova et al., Vaccine 2005;23:3256-3263). In elderly persons, YF 17D vaccine is associated with a higher frequency of significant AEs in the elderly but a lower incidence of common non-serious side-effects. The neutralizing antibody response, which is the mediator of protective immunity to YF, is not diminished in healthy, elderly persons.
Interaction design for female-oriented games

Recently, more and more game designers begin to develop games for a wide range player group to meet the increasing competition. The attention female players attracted to game designers is growing day by day. This essay discusses the characteristic of female-oriented games from the aspect of instinct, thinking mode and so on, and proposes some principles of the interaction design for the female-oriented computer games.
Afferent and efferent interfaces of lymph nodes are distinguished by expression of lymphatic endothelial markers and chemokines.

BACKGROUND Lymph nodes (LNs) are important sites of connection between the sampled peripheral tissues, the many cells of the immune system, and the blood. The organization of the interface between the afferent and efferent lymphatic vasculature and LN parenchyma is incompletely understood, and obtaining a better understanding of these tissue microenvironments will contribute to an improved understanding of overall lymphatic function. METHODS AND RESULTS We used histologic approaches to define the distributions of cells expressing lymphatic endothelial cell (LEC) markers in LNs from healthy, simian immunodeficiency virus (SIV) infected, or Mycobacterium tuberculosis infected cynomolgus macaques. Cells at the afferent and efferent interfaces of LNs from all animals showed differential expression of LEC markers, with podoplanin, Prox-1, and VEGFR3 expressed in both microenvironments, but with LYVE-1 expressed only at the efferent interface. The chemokine CCL20 was uniquely expressed at the afferent interface by cells co-expressing podoplanin, and this expression was increased during SIV or M. tuberculosis infection. In contrast, only a small proportion of cells expressing the CCR7 ligand CCL21 co-expressed podoplanin. Treatment of model LECs with the TLR3 ligand poly(I:C) or gamma-irradiated M. tuberculosis increased production of CCL20 without altering CCL21 or LEC marker expression. CONCLUSIONS This study provides a comprehensive mapping of the organization of the lymphatic endothelial network entering and exiting LNs in health and in chronic infectious diseases in a nonhuman primate model. The differences we have defined between the afferent and efferent interfaces of LNs could inform the future design of vaccines and immunotherapies.
Transfer of R388 Derivatives by a Pathogenesis-Associated Type IV Secretion System into both Bacteria and Human Cells

ABSTRACT Bacterial type IV secretion systems (T4SSs) are involved in processes such as bacterial conjugation and protein translocation to animal cells. In this work, we have switched the substrates of T4SSs involved in pathogenicity for DNA transfer. Plasmids containing part of the conjugative machinery of plasmid R388 were transferred by the T4SS of human facultative intracellular pathogen Bartonella henselae to both recipient bacteria and human vascular endothelial cells. About 2% of the human cells expressed a green fluorescent protein (GFP) gene from the plasmid. Plasmids of different sizes were transferred with similar efficiencies. B. henselae codes for two T4SSs: VirB/VirD4 and Trw. A ΔvirB mutant strain was transfer deficient, while a ΔtrwE mutant was only slightly impaired in DNA transfer. DNA transfer was in all cases dependent on protein TrwC of R388, the conjugative relaxase, implying that it occurs by a conjugation-like mechanism. A DNA helicase-deficient mutant of TrwC could not promote DNA transfer. In the absence of TrwB, the coupling protein of R388, DNA transfer efficiency dropped 1 log. The same low efficiency was obtained with a TrwB point mutation in the region involved in interaction with the T4SS. TrwB interacted with VirB10 in a bacterial two-hybrid assay, suggesting that it may act as the recruiter of the R388 substrate for the VirB/VirD4 T4SS. A TrwB ATPase mutant behaved as dominant negative, dropping DNA transfer efficiency to almost null levels. B. henselae bacteria recovered from infected human cells could transfer the mobilizable plasmid into recipient Escherichia coli under certain conditions, underscoring the versatility of T4SSs.
Identification of capacitation-associated phosphoproteins in porcine sperm electroporated with ATP-gamma-(32)P.

Our objectives were to incorporate ATP-gamma-(32)P into boar sperm to radiolabel endogenous phosphoproteins and compare phosphorylation patterns from sperm incubated in capacitating (CM) and non-capacitating conditions (NCM). Sperm were electroporated (1000 V/cm, 125 microF/cm, 65 Omega/cm, 0.3 msec) with ATP-gamma-(32)P which moderately decreased sperm viability (P < 0.01), but did not affect motility (P = 0.34) or the appearance of spontaneous acrosome reactions (P = 0.49). Sperm incubated in CM for 3 hr underwent capacitation, determined by the ability to undergo ionophore-induced acrosome reactions (P </= 0.05). Furthermore, more sperm in CM than in NCM exhibited chlortetracycline (CTC) pattern B (capacitated) fluorescence (P </= 0.01). SDS-PAGE, autoradiography and phosphoimagery of extracted, (32)P-labeled sperm proteins revealed a subset of phosphoproteins (Mr 28,000-60,000) from cells incubated in CM, whereas only two phosphorylated proteins were evident from sperm in NCM (44 and 57 kDa). The appearance of phosphoproteins increased concomitant with capacitation (P </= 0.05). In NCM, the 44 kDa protein was unaffected by time (P > 0.05) and the 57 kDa phosphoprotein increased after capacitation (P </= 0.05). Computer-assisted analysis revealed that the percentage of motile sperm in either medium decreased with time, and CM only transiently maintained motility over NCM (P >/= 0.02). ATP-gamma-(32)P can, therefore, be incorporated into porcine sperm to radiolabel endogenous phosphoproteins, and the different profiles from sperm incubated in NCM versus CM suggest that capacitation is mediated by signaling events involving protein phosphorylation.
Brain fMRI and craving response to heroin-related cues in patients on methadone maintenance treatment

Objective: To investigate the subjective craving and brain response to heroin-related cues in former heroin addicts on long-term methadone maintenance treatment. Methods: Fourteen participants completed an event-related functional magnetic resonance imaging task including heroin-related and nonheroin-related (neutral) cues. Craving self-reports were collected before and after the task. Results: Although no significant craving changes were associated with the task, blood oxygen-level dependence intensity was significantly greater during exposure to heroin-related cues, compared to neutral cues in brain areas studied. Conclusions and Scientific Significance: The results indicate that the learned brain response of former heroin addicts to drug-related stimuli may persist despite long-term methadone maintenance treatment.
Quality of cancer pain management: an update of a systematic review of undertreatment of patients with cancer.

PURPOSE Pain is a frequent symptom in patients with cancer, with substantial impact. Despite the availability of opioids and updated guidelines from reliable leading societies, undertreatment is still frequent. METHODS We updated a systematic review published in 2008, which showed that according to the Pain Management Index (PMI), 43.4% of patients with cancer were undertreated. This review included observational and experimental studies reporting negative PMI scores for adults with cancer and pain published from 2007 to 2013 and retrieved through MEDLINE, Embase, and Google Scholar. To detect any temporal trend and identify potential determinants of undertreatment, we compared articles published before and after 2007 with univariable, multivariable, and sensitivity analyses. RESULTS In the new set of 20 articles published from 2007 to 2013, there was a decrease in undertreatment of approximately 25% (from 43.4 to 31.8%). In the whole sample, the proportion of undertreated patients fell from 2007 to 2013, and an association was confirmed between negative PMI score, economic level, and nonspecific setting for cancer pain. Sensitivity analysis confirmed the robustness of results. CONCLUSION Analysis of 46 articles published from 1994 to 2013 using the PMI to assess the adequacy of analgesic therapy suggests the quality of pharmacologic pain management has improved. However, approximately one third of patients still do not receive pain medication proportional to their pain intensity.