Miracle-dz/UniFAR-FTUs huggingface dataset:
Co‐ and Post‐Translational Protein Folding in the ER

The biophysical rules that govern folding of small, single‐domain proteins in dilute solutions are now quite well understood. The mechanisms underlying co‐translational folding of multidomain and membrane‐spanning proteins in complex cellular environments are often less clear. The endoplasmic reticulum (ER) produces a plethora of membrane and secretory proteins, which must fold and assemble correctly before ER exit – if these processes fail, misfolded species accumulate in the ER or are degraded. The ER differs from other cellular organelles in terms of the physicochemical environment and the variety of ER‐specific protein modifications. Here, we review chaperone‐assisted co‐ and post‐translational folding and assembly in the ER and underline the influence of protein modifications on these processes. We emphasize how method development has helped advance the field by allowing researchers to monitor the progression of folding as it occurs inside living cells, while at the same time probing the intricate relationship between protein modifications during folding.
Adaptive equalization for co-channel interference in a multipath fading environment

The paper concerns the feasibility and achievable performance of adaptive filtering in an interference-limited multipath fading environment as encountered in indoor wireless communications. In a typical cellular radio application, the performance-limiting impairment is interference due to synchronous data streams from other co-channel and adjacent channel users (CCI and ACI). The receiver under consideration employs an adaptive fractionally spaced decision feedback equalizer (DFE) Which exploits the correlation of the cyclostationary interference to achieve superior performance relative to the worst case when the interference is stationary noise. The paper presents ideal calculations which confirm that significant DFE performance gains are potentially achievable by explicitly accounting for the cyclostationary CCI. Two adaptive DFE strategies are considered. One approach is to adapt the DFE directly using iterative algorithms such as least mean square (LMS) or recursive least squares (RLS). Another approach is to compute the minimum mean square error DFE using an RLS channel impulse response (CIR) estimate and a sample estimate of the CCI autocorrelation obtained from the CIR estimation error during training. The best approach for adaptive equalization, in terms of adaptation speed and system performance, is to employ an RLS DFE which does not explicitly estimate the CIR or the CCI autocorrelation. >
Effect of the numbers of slots and barriers on the optimal design of synchronous reluctance machines

This paper analyzes the impact of the numbers of stator slots and rotor layers on the optimal design of synchronous reluctance (SyR) machines. Eighteen SyR machine examples have been designed by means of a multi-objective optimization algorithm and finite element analysis so to maximize torque and minimize torque ripple. Twelve, twenty-four and forty-eight slot stators are considered, associated to rotors with four-poles and one to six flux barriers per pole. The results of the comparative analysis show that high numbers of slots and layers are beneficial for maximizing the torque and the power factor, and that torque ripple and iron loss minimization require precise matches between the slots and the layers, which are not necessarily the same for the two purposes. Finally, for some slot/layer combinations the optimization algorithm produces nonconventional barrier distributions, very promising is some cases. A fast finite element evaluation is used for the evaluation of thousands of candidate machines during the optimization, whereas an accurate transient with motion finite element analysis stage is used for the off-line characterization of the final designs.
Structure of Escherichia coli Hfq bound to polyriboadenylate RNA

Hfq is a small, highly abundant hexameric protein that is found in many bacteria and plays a critical role in mRNA expression and RNA stability. As an “RNA chaperone,” Hfq binds AU-rich sequences and facilitates the trans annealing of small RNAs (sRNAs) to their target mRNAs, typically resulting in the down-regulation of gene expression. Hfq also plays a key role in bacterial RNA decay by binding tightly to polyadenylate [poly(A)] tracts. The structural mechanism by which Hfq recognizes and binds poly(A) is unknown. Here, we report the crystal structure of Escherichia coli Hfq bound to the poly(A) RNA, A15. The structure reveals a unique RNA binding mechanism. Unlike uridine-containing sequences, which bind to the “proximal” face, the poly(A) tract binds to the “distal” face of Hfq using 6 tripartite binding motifs. Each motif consists of an adenosine specificity site (A site), which is effected by peptide backbone hydrogen bonds, a purine nucleotide selectivity site (R site), and a sequence-nondiscriminating RNA entrance/exit site (E site). The resulting implication that Hfq can bind poly(A-R-N) triplets, where R is a purine nucleotide and N is any nucleotide, was confirmed by binding studies. Indeed, Hfq bound to the oligoribonucleotides (AGG)8, (AGC)8, and the shorter (A-R-N)4 sequence, AACAACAAGAAG, with nanomolar affinities. The abundance of (A-R-N)4 and (A-R-N)5 triplet repeats in the E. coli genome suggests additional RNA targets for Hfq. Further, the structure provides insight into Hfq-mediated sRNA-mRNA annealing and the role of Hfq in RNA decay.
Growth factor control of pancreatic islet regeneration and function

Type 1 and type 2 diabetes mellitus together are predicted to affect over 300 million people worldwide by the year 2020. A relative or absolute paucity of functional β-cells is a central feature of both types of disease, and identifying the pathways that mediate the embryonic origin of new β-cells and mechanisms that underlie the proliferation of existing β-cells are major efforts in the fields of developmental and islet biology. A poor secretory response of existing β-cells to nutrients and hormones and the defects in hormone processing also contribute to the hyperglycemia observed in type 2 diabetes and has prompted studies aimed at enhancing β-cell function. The factors that contribute to a greater susceptibility in aging individuals to develop diabetes is currently unclear and may be linked to a poor turnover of β-cells and/or enhanced susceptibility of β-cells to apoptosis. This review is an update on the recent work in the areas of islet/β-cell regeneration and hormone processing that are relevant to the pathophysiology of the endocrine pancreas in type 1, type 2 and obesity-associated diabetes.
LeCPK1, a Calcium-Dependent Protein Kinase from Tomato. Plasma Membrane Targeting and Biochemical Characterization1

The cDNA of LeCPK1, a calcium-dependent protein kinase, was cloned from tomato (Lycopersicon esculentum Mill.). LeCPK1 was expressed in Escherichia coli and purified from bacterial extracts. The recombinant protein was shown to be a functional protein kinase using a synthetic peptide as the substrate (syntide-2,K m = 85 μm). Autophosphorylation of LeCPK1 was observed on threonine and serine residues, one of which was identified as serine-439. Kinase activity was shown to be Ca2+ dependent and required the C-terminal, calmodulin-like domain of LeCPK1. Two classes of high- and low-affinity Ca2+-binding sites were observed, exhibiting dissociation constants of 0.6 and 55 μm, respectively. LeCPK1 was found to phosphorylate the regulatory C-terminal domain of the plasma membrane H+-ATPase in vitro. A potential role in the regulation of proton pump activity is corroborated by the apparent colocalization of the plasma membrane H+-ATPase and LeCPK1 in vivo. Upon transient expression in suspension-cultured cells, a C-terminal fusion of LeCPK1 with the green fluorescent protein was targeted to the plasma membrane. Myristoylation of theLeCPK1 N terminus was found to be required for plasma membrane targeting.
Plasma-lead concentration: investigations into its usefulness for biological monitoring of occupational lead exposure.

BACKGROUND The lead concentration in plasma is correlated to that in whole blood with a two to fourfold variation. It has never been investigated if this variation is inter-individual. METHODS Lead and hemoglobin were determined in blood and plasma from 13 lead workers with a history of relatively high blood-lead concentrations, sampled three times during 1 day. The variation in the distribution of lead between cells and plasma was studied, but not the variation in the lead concentrations as such. RESULTS Blood hemoglobin decreased with rising plasma lead (0.9-3.0 microg/L). Regarding the distribution of lead, no effect of current exposure during the day or of recent meals appeared. As much as 84% of the overall variance of the distribution of lead between cells and plasma could be attributed to individual factors. After adjustment for erythrocyte volume fraction this decreased to 67%. Plasma samples with elevated hemoglobin concentrations (due to in vitro hemolysis) had somewhat elevated lead concentrations. CONCLUSIONS Plasma lead is not significantly altered by variation in a single day's exposure and, therefore, the choice of time of the day is not critical for sampling. However, plasma lead is negatively correlated to blood hemoglobin and mild hemolysis (not visible by the eye) in a sample may increase plasma lead with up to 30%. Finally, plasma provides lead exposure information that differs from whole blood, but it is not clear which one of these is the biomarker with the closest relation to exposure and/or effects.
Estradiol-17&bgr; Treatment Induces Intersexual Gonadal Development in the Pufferfish, Takifugu rubripes

Estrogens are responsible for most characteristics of the female sex of a species, such as metabolic, behavioral, and morphological changes during reproduction. Artificial estradiol-17&bgr; (E2) treatment induces sex reversal in some fish. The Japanese pufferfish (Takifugu rubripes) has the most compact genome among vertebrates and great pottial for comparative genome analysis. In this paper, we describe the influence of E2 treatment during gonadal development in the pufferfish. After hatching, fry were treated with no (control) or a 0.1, 1, 10, or 100 &mgr;g/g diet from 21 to 80 days after hatching (dah). Doublesex-mab3-related transcription factor (DMRT1) is involved in testicular development. VASA is responsible for germ cell development, and CYP19A plays a role in E2 biosynthesis during ovarian development across animal phyla as well as in gonadal morphology after E2 treatment. DMRT1, VASA, and CYP19A were investigated in the gonads of E2-treated pufferfish. Fish fed with the highest dose (E2 100 µg/g diet) developed intersexual gonads in the testis; the majority of germ cells were oocytes, but some spermatocytes were detected. RT-PCR results showed the expression of VASA and CYP19A in all intersexual gonads and DMRT1 in some. Furthermore, abnormalities in the epithelium-tunica layer were detected, and gonadal somatic cells (e.g., granulosa cells, theca cells, or germinal epithelium) proliferated extensively in the intersexual gonad. These results suggest that E2 treatment induces ovarian development in the bipotential gonads of genetic males by modification of gonadal somatic cells and E2 production, mediated by CYP19A.
OSTEOPOROSIS DRUGS MARKETED IN THE UNITED STATES: GENERIC COMPETITION, PRICING STRUCTURE, AND DISPERSION AMONG PAYERS

Background: Despite the cost of pharmaceuticals, studies assessing prices of osteoporosis drugs are lacking. This study examined trends in prices of osteoporosis drugs in the United States in the period 1988–2014, assessed pricing structure of osteoporosis drugs, and evaluated price trends before and after generic drugs market entry. Methods: Data were derived from the U.S. Food and Drug Administration, the RedBook, the Centers for Medicare & Medicaid Services, and the Federal Supply Schedule (FSS). Descriptive statistics and segmented linear regression analyses were performed. Results: In the period 1988–2014, osteoporosis drug prices increased faster than the inflation. The average wholesale price (AWP) of generic products at market entry represented 90 percent of the AWP for the corresponding brand. Prices of brand products continued to increase after generic entry. Drug prices showed a significant variation when compared with the brand AWP. The brand wholesale acquisition cost (WAC) was typically set at 83.3 percent of the AWP. Community pharmacies acquired osteoporosis brand drugs at a median of 80.5 percent of the brand AWP. Significant reductions in brand AWP were observed for Medicare Part B (78.5 percent of the brand AWP), generic National Average Drug Acquisition Cost (33.7 percent), and FSS (22.5 percent). Conclusions: There are significant differences in the manufacturer prices, pharmacy acquisition costs and reimbursement rates of osteoporosis drugs. Pharmaceutical companies listed prices are higher than the pharmacy actual estimated acquisitions costs, and the prices used for reimbursement to providers. Generic drugs entry significantly drives down prices; still, prices of branded drugs facing generic competition continued to increase after generic market entry.
Biological and chemical inhibitors of NF‐κB sensitize SiHa cells to cisplatin‐induced apoptosis

Cisplatin, a chemotherapeutic agent, is known to induce apoptosis of cancer cells. We examined the role of NF‐κB during cisplatin‐induced apoptosis in two human cervical cancer cell lines, HeLa and SiHa, known to differ in their response to cisplatin treatment. We found that SiHa cells were relatively more resistant than HeLa cells to the cytotoxic effects induced by cisplatin as measured by MTT assays. HeLa cells were more sensitive to the apoptotic effects induced by cisplatin as shown by increases in annexin staining, DNA fragmentation, and loss of mitochondrial membrane potential. Similarly the activities of caspases 3, 8, and 9 and cleavage of PARP induced by cisplatin were more in HeLa than SiHa cells. Cisplatin induced NF‐κB DNA binding activity in HeLa and SiHa cells but not in primary cervical cells and the active DNA binding complex in SiHa cells consists of p50 and RelA heterodimers. However, when NF‐κB DNA binding activity was blocked by chemical (curcumin, PDTC, or salicylic acid) or biological inhibitors (NIK‐KM or IKK‐β DN), the cell viability was less in SiHa cells with cisplatin treatment, but these effects were not observed in HeLa cells. Similarly upon treatment with cisplatin SiHa cells had more activation of caspases compared to that seen in HeLa cells under conditions of NF‐κB inhibition by biological or chemical inhibitors. These results suggest that NF‐κB may contribute to the resistance of human cervical cancer cells to cisplatin and highlight the potential use of combination therapy involving cisplatin and NF‐κB inhibitors. © 2005 Wiley‐Liss, Inc.
Infective Etiology Affects Outcomes of Late Open Conversion After Failed Endovascular Aneurysm Repair

Purpose: To retrospectively review all patients undergoing late open conversion (LOC) after endovascular aneurysm repair (EVAR) in order to identify any clinical or technical predictors of poor outcome. Methods: Twenty-six consecutive patients (24 men; mean age 74.7±8.3 years) underwent LOC between June 2006 and April 2013 at our institution. The mean interval from index EVAR to LOC was 40.4±29.2 months (range 5–93 months). The indication for LOC was endoleak in 14 (54%) patients and infection in 12 (46%): 2 (8%) patients with endoleak had a ruptured aneurysm and 6 (23%) patients with infection had a recurrent secondary aortoesophageal fistula (sAEF). Results: In all 12 cases of infection and in 12 of 14 endoleaks, the entire endograft was explanted. A rifampin-soaked Dacron silver graft was implanted in all patients with infection. Patients with any infection and with recurrent AEF required more blood units than patients with endoleak (6.40 vs. 1.86, p=0.045; 6.76 vs. 1.86, p=0.0036, respectively). Compared with endoleak, the duration of conversions in the setting of infection (274 vs. 316 minutes, p=0.42) and recurrent sAEF (274 vs. 396 minutes, p=0.021) was longer. All patients with recurrent sAEF died at a mean 3.0±2.5 days after LOC from proximal anastomosis disruption and hemorrhagic shock (n=2), myocardial infarction (n=2), acute stroke (n=1), or persistent sepsis (n=1). Perioperative mortality was significantly higher in patients with endograft infection (6/12, p=0.002) and in cases of supraceliac cross-clamping (4/6, p=0.003). The association of infection with supraceliac cross-clamping was a strong predictor for perioperative mortality (p<0.001). Conclusion: In our experience, endograft infection led to greater perioperative mortality after LOC. Recurrent aortoenteric fistula in association with supraceliac cross-clamping is a strong predictor of poor outcome. Patients surviving the perioperative period may have good chances of long-term survival.
Teaching psychodynamic formulation to psychiatric trainees. Part 2: Teaching methods

Teaching methods to help students appreciate the value of psychodynamic formulation and to become more skilled in producing formulations are described. These are closely related to the four levels of our model formulation, each level corresponding to a set of competencies through which students should normally progress. Accurate diagnosis of a student's current capabilities and needs is crucial to effective teaching. Teaching methods at each level are illustrated through detailed reference to a case example. The usefulness of small­group discussion for assimilating clinical material within a clear framework is emphasised throughout.
Evaluation of a three-dimensional educational computer model of the larynx: voicing a new direction.

OBJECTIVE To evaluate a novel method of teaching laryngeal anatomy. DESIGN Prospective, randomized, controlled trial. SETTING University educational program. METHODS Computer model development: A three-dimensional (3D) educational computer model of the larynx was created from high-resolution computed tomography and magnetic resonance images of cadaveric necks using segmentation software (Amira) (Visage Imaging, Inc., Carlsbad, CA). E-learning authoring software (Articulate, Articulate Global, Inc, New York, NY) then was used to make the model interactive and multimedia. The model was launched on a Web-based platform. Model evaluation: One hundred students (age 23.8 +/- 2.2 years; 55% male) were randomized to either the 3D computer model group (3D group) (n = 50) or the standard written instruction group (SWI group) (n = 50). MAIN OUTCOME MEASURES The primary outcome measure was the score on a 20-question laryngeal anatomy test; the secondary outcome measure was a student opinion questionnaire. RESULTS The mean score on the laryngeal anatomy test was 14.2 +/- 2.8 (72.0 +/- 15.1%). The mean score for the 3D group was 13.6 +/- 3.0 (67.0 +/- 16.1%) versus 14.8 +/- 2.5 (76.0 +/- 12.7%) for the SWI group (t = 2.194, df = 98, p < .031). A majority of students felt that the 3D model was effective, clear, user-friendly, and a preferred supplement to traditional methods of instruction. The 3D group rated the computer model more enjoyable than the SWI group. CONCLUSIONS A 3D educational computer model of the larynx was not shown to be superior to written lecture notes in its efficacy in teaching anatomy; however, it was judged to be a preferred and valuable supplement to traditional teaching methods.
General practitioners' knowledge, confidence and attitudes in the diagnosis and management of dementia.

OBJECTIVE To measure general practitioners' knowledge of, confidence with and attitudes to the diagnosis and management of dementia in primary care. SETTING 20 general practices of varying size and prior research experience in Central Scotland, and 16 similarly varied practices in north London. PARTICIPANTS 127 general practitioners who had volunteered to join a randomised controlled trial of educational interventions about dementia diagnosis and management. METHODS Self-completion questionnaires covering knowledge, confidence and attitudes were retrieved from practitioners prior to the educational interventions. RESULTS General practitioners' knowledge of dementia diagnosis and management is good, but poor awareness of its epidemiology leads to an over-estimate of caseload. Knowledge of local diagnostic and support services is less good, and one third of general practitioners expressed limited confidence in their diagnostic skills, whilst two-thirds lacked confidence in management of behaviour and other problems in dementia. The main difficulties identified by general practitioners were talking with patients about the diagnosis, responding to behaviour problems and coordinating support services. General practitioners perceived lack of time and lack of social services support as the major obstacles to good quality care more often than they identified their own unfamiliarity with current management or with local resources. Attitudes to the disclosure of the diagnosis, and to the potential for improving the quality of life of patients and carers varied, but a third of general practitioners believed that dementia care is within a specialist's domain, not that of general practice. More experienced and male general practitioners were more pessimistic about dementia care, as were general practitioners with lower knowledge about dementia. Those reporting greater difficulty with dementia diagnosis and management and those with lower knowledge scores were also less likely to express attitudes endorsing open communication with patient and carer. CONCLUSION Educational support for general practitioners should concentrate on epidemiological knowledge, disclosure of the diagnosis and management of behaviour problems in dementia. The availability and profile of support services, particularly social care, need to be enhanced, if earlier diagnosis is to be pursued as a policy objective in primary care.
External control of walking direction, using cross-wire mobile assist suit

In this paper, we control the walking direction of a subject using an assistive robotic device for the first time, using the internal/external rotation hip torque generated by our cross-wire assist suit to induce turning gait. The cross-wire assist device is a soft exosuit with four independently controllable actuators located around at hip joint, and selective actuation allows for the generation of internal/external rotational torque. Turning was most effectively induced using external rotation for the inside leg and internal rotation for the outside leg, which is a combination of human step turning strategy and ‘ipsilateral crossover’ spin turning strategy. The degree of turning increased with applied force level, and multi-subject testing showed that the walking direction all subjects were capable of being modified (average 16.2 degree/m for 80 N); however, there was large variation between subjects.