Miracle-dz/UniFAR-FTUs huggingface dataset:
Family history of Alzheimer's disease and hippocampal structure in healthy people.

OBJECTIVE Structural brain changes appear years before the onset of Alzheimer's disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer's disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment. METHOD High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N=13; noncarriers: N=13) with at least one first-degree relative with Alzheimer's disease and 25 subjects (APOE-4 carriers: N=12; noncarriers: N=13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38-86 years) were cognitively healthy. RESULTS Family history of Alzheimer's disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer's disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status. CONCLUSIONS APOE-4 carrier status and family history of Alzheimer's disease are independently associated with and contribute additively to hippocampal cortical thinning.
How many people are living with undiagnosed HIV infection? An estimate for Italy, based on surveillance data

Objective:To estimate the size and characteristics of the undiagnosed HIV population in Italy in 2012 applying a method that does not require surveillance data from the beginning of the HIV epidemic. Methods:We adapted the method known as ‘London method 2’; the undiagnosed population is estimated as the ratio between the estimated annual number of simultaneous HIV/clinical AIDS diagnoses and the expected annual progression rate to clinical AIDS in the undiagnosed HIV population; the latter is estimated using the CD4+ cell count distribution of asymptomatic patients reported to surveillance. Under-reporting/ascertainment of new diagnoses was also considered. Also, the total number of people living with HIV was estimated. Results:The undiagnosed HIV population in 2012 was 13 729 (95% confidence interval: 12 152–15 592), 15 102 (13 366–17 151) and 16 475 (14 581–18 710), assuming no under-reporting/ascertainment, 10 and 20% of under-reporting/ascertainment, respectively. The percentage of undiagnosed cases was higher among HIV people aged below 25 years (25–28%), MSM (16–19%) and people born abroad (16–19%), whereas it was small among injection drug users (3%). Conclusion:The estimate of people in Italy with undiagnosed HIV in 2012 was in a plausible range of 12 000–18 000 cases, corresponding to 11–13% of the overall prevalence. The method is straightforward to implement only requiring annual information from the HIV surveillance system about CD4+ cell count and clinical stage at HIV diagnosis. Thus, it could be used to monitor if a certain prevention initiative lead to the reduction of the undiagnosed HIV population over time. It can also be easily implemented in other countries collecting the same basic information from the HIV surveillance system.
Structure of human Mad1 C-terminal domain reveals its involvement in kinetochore targeting

The spindle checkpoint prevents aneuploidy by delaying anaphase onset until all sister chromatids achieve proper microtubule attachment. The kinetochore-bound checkpoint protein complex Mad1-Mad2 promotes the conformational activation of Mad2 and serves as a catalytic engine of checkpoint signaling. How Mad1 is targeted to kinetochores is not understood. Here, we report the crystal structure of the conserved C-terminal domain (CTD) of human Mad1. Mad1 CTD forms a homodimer and, unexpectedly, has a fold similar to those of the kinetochore-binding domains of Spc25 and Csm1. Nonoverlapping Mad1 fragments retain detectable kinetochore targeting. Deletion of the CTD diminishes, does not abolish, Mad1 kinetochore localization. Mutagenesis studies further map the functional interface of Mad1 CTD in kinetochore targeting and implicate Bub1 as its receptor. Our results indicate that CTD is a part of an extensive kinetochore-binding interface of Mad1, and rationalize graded kinetochore targeting of Mad1 during checkpoint signaling.
Glucose-Dependent Insulinotropic Polypeptide

OBJECTIVE To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m2, and HbA1c 5.5 ± 0.1%). RESEARCH DESIGN AND METHODS Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia. RESULTS During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. −11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (−461 ± 81 vs. −371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001). CONCLUSIONS In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.
Ventilation-perfusion relationships following experimental pulmonary contusion.

Ventilation-perfusion changes after right-sided pulmonary contusion (PC) in swine were investigated by means of the multiple inert gas elimination technique (MIGET). Anesthetized swine (injury, n = 8; control, n = 6) sustained a right-chest PC by a captive-bolt apparatus. This was followed by a 12-ml/kg hemorrhage, resuscitation, and reinfusion of shed blood. MIGET and thoracic computed tomography (CT) were performed before and 6 h after injury. Three-dimensional CT scan reconstruction enabled determination of the combined fractional volume of poorly aerated and non-aerated lung tissue (VOL), and the mean gray-scale density (MGSD). Six hours after PC in injured animals, Pa(O(2)) decreased from 234.9 +/- 5.1 to 113.9 +/- 13.0 mmHg. Shunt (Q(S)) increased (2.7 +/- 0.4 to 12.3 +/- 2.2%) at the expense of blood flow to normal ventilation/perfusion compartments (97.1 +/- 0.4 to 87.4 +/- 2.2%). Dead space ventilation (V(D)/V(T)) increased (58.7 +/- 1.7% to 67.2 +/- 1.2%). MGSD increased (-696.7 +/- 6.1 to -565.0 +/- 24.3 Hounsfield units), as did VOL (4.3 +/- 0.5 to 33.5 +/- 3.2%). Multivariate linear regression of MGSD, VOL, V(D)/V(T), and Q(S) vs. Pa(O(2)) retained VOL and Q(S) (r(2) = . 835) as independent covariates of Pa(O(2)). An increase in Q(S) characterizes lung failure 6 h after pulmonary contusion; Q(S) and VOL correlate independently with Pa(O(2)).
An update on anal neoplasia

Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high‐risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non‐surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry.
Neuropsychiatric Symptoms, Omega-3, and Mercury Exposure in Freshwater Fish-Eaters

Mercury is a neurotoxin, absorbed primarily through fish consumption. However, the nutritional benefit from omega-3 fatty acids (n-3 FA) may offset the deleterious effects of mercury. Increased n-3 FA have been associated with lower rates of mood disorders. The authors examined neuropsychiatric symptoms among 243 freshwater fish-eaters, with low serum n-3 FA (median = 0.11 mg/mL) and low mercury exposure (median in blood and hair = 2.22 and 0.54 μg/g). They assessed neuropsychiatric symptoms with the Brief Symptom Inventory. The results did not show the expected inverse association between serum n-3 FA and neuropsychiatric symptoms. For men who consumed more than 130 g of alcohol per week, the authors observed a positive association between serum n-3 FA and neuropsychiatric symptoms, possibly reflecting an alcohol-related release of n-3 FA from membranes into blood. They observed a positive relation between hair mercury and neuropsychiatric symptoms solely for women, suggesting that men may respond differently to mercury.
Characterizing fruit fly flight behavior using a microforce sensor with a new comb-drive configuration

This paper reports a MEMS microforce sensor with a novel configuration of bulk micromachined differential triplate comb drives that overcomes the difficulty of electrically isolating the two stationary capacitor comb sets in bulk micromachining. A high-yield fabrication process using deep-reactive ion etching (DRIE) on silicon-on-insulator (SOI) wafers and only three lithographic masks was utilized to construct the high aspect ratio devices. The process features dry release of both suspended structures and the entire device in order to protect fragile components. The sensor has a high sensitivity (1.35 mV//spl mu/N), good linearity (<4%), and a large bandwidth (7.8 kHz), and is therefore well suited for characterizing flight behavior of fruit flies (Drosophila melanogaster). The technique allows for the instantaneous measurement of flight forces, which result from a combination of aerodynamic forces and inertial forces generated by the wings, and demonstrates a novel experimental paradigm for exploring flight biomechanics in the fruit fly. The average lift force is determined to be 9.3 /spl mu/N (/spl plusmn/2.3 /spl mu/N), which is in the range of typical body weights of fruit flies. The potential impact of this research extends beyond gathering flight data on Drosophila melanogaster by demonstrating how MEMS technology can be used to provide valuable tools for biomechanical investigations.
Epicardial adipose tissue is an independent marker of cardiovascular risk in HIV-infected patients

Background:Epicardial adipose tissue (EAT) is increased in HIV-infected patients. The aim of this study was to evaluate the association between EAT and coronary artery calcium (CAC) a marker of atherosclerosis; furthermore, we investigated the association of EAT with HIV infection, antiretroviral therapy (ART), and lipodystrophy. Methods:This was a cross-sectional study of 876 consecutive HIV-infected ART experienced patients. Patients underwent CAC imaging with multidetector computed tomography (CT) for atherosclerosis screening and risk of cardiovascular events (CAC score >100); EAT was measured in the same CT images. Factors independently associated with EAT were explored in a multivariable backward stepwise linear regression analysis. Multivariable logistic regression was used to evaluate the association of EAT and CAC score greater than 100. Results:Patients' mean age was 47.2 ± 8 years, 68% were men. EAT was associated with central fat accumulation and mixed lipodystrophy phenotypes. Factors independently associated with EAT were: age [β = 0.6, confidence interval (CI) 0.2–1.0], male sex (β = 6.6, CI 0.5–12.7), visceral adipose tissue (β = 0.12, CI 0.08–0.17), waist circumference (β = 0.7, CI 0.04–1.3), current CD4+ (β = 0.6, CI 0.1–1.2, per 50 cells), total cholesterol (β = 0.1, CI 0.02–0.15), and cumulative exposure to ART (months) (β = 0.05, CI 0.00–0.11). EAT (per 10 cm3) was associated with CAC greater than 100 (odds ratio = 1.10, CI 1.02–1.19) after adjustment for age, male sex, and diabetes. Conclusion:We showed an association between EAT and central fat accumulation and mixed form lipodystrophy phenotypes as well as traditional risk factors for atherosclerosis. EAT may be a useful marker of cardiovascular risk as shown by its association with CAC greater than 100.
Clinical Utility of Cognistat in Multiprofessional Team Evaluations of Patients with Cognitive Impairment in Swedish Primary Care

Background. Diagnostic evaluations of dementia are often performed in primary health care (PHC). Cognitive evaluation requires validated instruments. Objective. To investigate the diagnostic accuracy and clinical utility of Cognistat in a primary care population. Methods. Participants were recruited from 4 PHC centres; 52 had cognitive symptoms and 29 were presumed cognitively healthy. Participants were tested using the Mini-Mental State Examination (MMSE), the Clock Drawing Test (CDT), and Cognistat. Clinical diagnoses, based on independent neuropsychological examination and a medical consensus discussion in secondary care, were used as criteria for diagnostic accuracy analyses. Results. The sensitivity, specificity, positive predictive value, and negative predictive value were 0.85, 0.79, 0.85, and 0.79, respectively, for Cognistat; 0.59, 0.91, 0.90, and 0.61 for MMSE; 0.26, 0.88, 0.75, and 0.46 for CDT; 0.70, 0.79, 0.82, and 0.65 for MMSE and CDT combined. The area under the receiver operating characteristic curve was 0.82 for Cognistat, 0.75 for MMSE, 0.57 for CDT, and 0.74 for MMSE and CDT combined. Conclusions. The diagnostic accuracy and clinical utility of Cognistat was better than the other tests alone or combined. Cognistat is well adapted for cognitive evaluations in PHC and can help the general practitioner to decide which patients should be referred to secondary care.
MCT 1 inhibitor AZD 3965 increases mitochondrial metabolism , facilitating combination therapy and non-invasive magnetic resonance spectroscopy

Financial support: M Beloueche-Babari, S Wantuch, T Casals Galobart, M Koniordou, HG Parkes, V Arunan, Y-L Chung, TR Eykyn and MO Leach are supported by a CRUK Centre for Cancer Imaging grant C1090/A16464. We also acknowledge grant C1060/A10334 from CRUK and EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England), NHS funding to the NIHR Biomedical Research Centre and the Clinical Research Facility in Imaging. MO Leach is a NIHR Emeritus Senior Investigator.
Transitioning from analog to digital audio recording in childhood speech sound disorders

Few empirical findings or technical guidelines are available on the current transition from analog to digital audio recording in childhood speech sound disorders. Of particular concern in the present context was whether a transition from analog‐ to digital‐based transcription and coding of prosody and voice features might require re‐standardizing a reference database for research in childhood speech sound disorders. Two research transcribers with different levels of experience glossed, transcribed, and prosody‐voice coded conversational speech samples from eight children with mild to severe speech disorders of unknown origin. The samples were recorded, stored, and played back using representative analog and digital audio systems. Effect sizes calculated for an array of analog versus digital comparisons ranged from negligible to medium, with a trend for participants' speech competency scores to be slightly lower for samples obtained and transcribed using the digital system. We discuss the implications of these and other findings for research and clinical practise.
Effect of a cylindrical refracting interface on ultrasound intensity and the CW Doppler spectrum

The insonation of axisymmetric flow in a tube by an ultrasound beam which is refracted at the tube surface is considered. A three-dimensional (3-D) model for refraction at a cylindrical interface is developed. The incident beam, which is planar but otherwise arbitrary, is refracted at a single acoustic impedance interface between the medium within the tube and the surrounding medium. A ray approximation is used as the ultrasonic wavelength is small compared to the radius of curvature of the tube. A parametric form for the ray paths is obtained and used to derive an expression for the intensity. The intensity depends on the specific position within the tube, as well as the ratio of sound speeds, N, and the Doppler angle /spl theta//sub D/. A diverging (N=1.2, /spl theta//sub D/=45/spl deg/) and a converging (N=0.8, /spl theta//sub D/=45/spl deg/) case are presented in detail. The converging interface results in more extreme intensity distortion. The regions of maximum and minimum intensity over a tube slice are immediately adjacent in both diverging and converging cases. Once the intensity distribution across a tube slice is known, the previously reported (Aldis and Thompson, 1992) volume integral method for the calculation of continuous wave (CW) Doppler spectral power density (spd) functions may be used. The effect of refraction of the incident beam on the spd function is shown for both an infinite beam and a circular beam with radius equal to the tube radius. A curved acoustic impedance interface, as may be encountered in vitro in flow phantoms or in vivo in vascular disease, leads to nonuniform insonation and spectral distortion which depends on transducer orientation.
Ageing and infertility: an overview

In many modern societies, the proportion of women who delay childbearing beyond the age of 35 years has increased greatly in recent decades. They are falsely reassured by popular beliefs that advances in new reproductive technologies can compensate for the age-realted decline in fertility, but science cannot beat the biological clock. Age is the single most important determinant of male and female fertility, either natural or treated. The consequences of advancing maternal age are not only for the risk of natural and assisted conception, but also for the outcome of pregnancy. Female fertility has a ‘best-before date’ of 35, and for men, it is probably before age 45–50.
One‐step affinity capture and precipitation for improved purification of an industrial monoclonal antibody using Z‐ELP functionalized nanocages

Protein A chromatography has been identified as a potential bottleneck in the monoclonal antibody production platform, leading to increased interest in non‐chromatographic capture technologies. Affinity precipitation using environmentally responsive, Z‐domain‐elastin‐like polypeptide (Z‐ELP) fusion proteins has been shown to be a promising alternative. However, elevated temperature and salt concentrations necessary for precipitation resulted in decreased antibody monomer content and reduced purification capacity. To improve upon the existing technology, we reported an enhanced affinity precipitation of antibodies by conjugating Z‐ELP to a 25 nm diameter, self‐assembled E2 protein nanocage (Z‐ELP‐E2). The enlarged scale of aggregate formation and IgG‐triggered crosslinking through multi‐valent binding significantly outperformed traditional Z‐ELP‐based methods. In the current work, we sought to develop an affinity precipitation process capable of purifying industrial monoclonal antibodies (mAbs) at ambient temperature with minimal added salt. We discovered that the mAb‐nanocage complex aggregated within 10 min at room temperature without the addition of salt due to the enhanced multi‐valent cross‐linking. After precipitating out of solution, the complex remained insoluble under all wash buffers tested, and only resolubilized after a low pH elution. Through optimization of key process steps, the affinity precipitation yield and impurity clearance met or exceeded protein A chromatography performance with 95% yield, 3.7 logs host cell protein reduction, and >5 logs of DNA reduction from mAb cell culture. Because of the operational flexibility afforded by this one‐step affinity capture and precipitation process, the Z‐ELP‐E2 based approach has the potential to be a viable alternative to platform mAb purification.
Correlated evolution between hearing sensitivity and social calls in bats

Echolocating bats are auditory specialists, with exquisite hearing that spans several octaves. In the ultrasonic range, bat audiograms typically show highest sensitivity in the spectral region of their species-specific echolocation calls. Well-developed hearing in the audible range has been commonly attributed to a need to detect sounds produced by prey. However, bat pups often emit isolation calls with low-frequency components that facilitate mother–young reunions. In this study, we examine whether low-frequency hearing in bats exhibits correlated evolution with (i) body size; (ii) high-frequency hearing sensitivity or (iii) pup isolation call frequency. Using published audiograms, we found that low-frequency hearing sensitivity is not dependent on body size but is related to high-frequency hearing. After controlling for high-frequency hearing, we found that low-frequency hearing exhibits correlated evolution with isolation call frequency. We infer that detection and discrimination of isolation calls have favoured enhanced low-frequency hearing because accurate parental investment is critical: bats have low reproductive rates, non-volant altricial young and must often identify their pups within large crèches.
Vaccination against Q fever for biodefense and public health indications

Coxiella burnetii is the etiological agent of Q fever, a disease that is often spread to humans via inhalational exposure to the bacteria from contaminated agricultural sources. Outbreaks have been observed all over the world with larger foci generating interest in vaccination programs, most notably in Australia and the Netherlands. Importantly, exposure rates among military personnel deployed to the Middle East can be relatively high as measured by seroconversion to C. burnetii-specific antibodies. Q fever has been of interest to the biodefense community over the years due to its low infectious dose and environmental stability. Recent advances in cell-free growth and genetics of C. burnetii also make this organism easier to culture and manipulate. While there is a vaccine that is licensed for use in Australia, the combination of biodefense- and public health-related issues associated with Q fever warrant the development of a safer and more effective vaccine against this disease.