Anisotropic proximity-induced superconductivity and edge supercurrent in Kagome metal, K1-xV3Sb5.

Materials with Kagome nets are of particular importance for their potential combination of strong correlation, exotic magnetism, and electronic topology. KV3Sb5 was discovered to be a layered topological metal with a Kagome net of vanadium. Here, we fabricated Josephson Junctions of K1-xV3Sb5 and induced superconductivity over long junction lengths. Through magnetoresistance and current versus phase measurements, we observed a magnetic field sweeping direction-dependent magnetoresistance and an anisotropic interference pattern with a Fraunhofer pattern for in-plane magnetic field but a suppression of critical current for out-of-plane magnetic field. These results indicate an anisotropic internal magnetic field in K1-xV3Sb5 that influences the superconducting coupling in the junction, possibly giving rise to spin-triplet superconductivity. In addition, the observation of long-lived fast oscillations shows evidence of spatially localized conducting channels arising from edge states. These observations pave the way for studying unconventional superconductivity and Josephson device based on Kagome metals with electron correlation and topology.

Trends in osteoporosis diagnosis and management in Australia.

Trends in bone mineral density monitoring, and drug treatment for osteoporosis, in Australia were examined. Rates of DEXA scanning have increased in response to changes to government policy affecting reimbursement. The drug denosumab is being utilised at an increasing rate, while bisphosphonate use has declined. Osteoporosis prevalence remained stable over the same timeframe, while rate of hip fractures declined, suggesting that introduction of osteoporosis screening was associated with a reduction in adverse osteoporosis outcomes, but may also have been associated with overutilisation. INTRODUCTION: Radiology interventions to diagnose and medications to manage osteoporosis in Australia are reimbursed under the Medicare benefits schedule (MBS) and Pharmaceutical Benefits Scheme (PBS). Monitoring of these databases enables changes in utilisation of these practices to be monitored over time. METHODS: This study examined rates of utilisation for bone mineral density (BMD) measurement and osteoporosis pharmacotherapy subsidised under the MBS. Rates of osteoporosis and hip fracture were estimated using data reported by the Australian Bureau of Statistics (ABS) and Australian Institute for Health and Welfare (AIHW). RESULTS: Rates of BMD measurement increased since the technology was first reimbursed, with changes to policy regarding reimbursement for screening for individuals over 70 leading to an increase in BMD measurement after 2007. Prescribing rates also increased over time, initially with the introduction of oral bisphosphonates and subsequently for denosumab, which has subsequently become the most commonly prescribed agent for osteoporosis management in Australia, while bisphosphonate use has declined. Osteoporosis prevalence in Australia has remained relatively static at 3-4% of the population since 2001 to 2017, while rates of minimal trauma hip fracture hospitalisations have declined from 195 per 100,000 to 174 per 100,000 in the same timeframe. CONCLUSION: Available data indicates that osteoporosis screening rates changed over time from 2001 to 2018 and that changes to government policy had a significant effect on the rates at which screening was performed. Over the same timeframe, there was a sustained reduction in hip fracture hospitalisation rates, with no change to reported osteoporosis prevalence. This suggests that policy changes permitting unlimited access to BMD measurement were associated with a reduction in osteoporotic fractures, but may also have been associated with overutilisation. Prospective studies to assess the efficacy of specific policies to ensure screening is performed in accordance with best-practice guidelines may be desirable.

Giant, unconventional anomalous Hall effect in the metallic frustrated magnet candidate, KV3Sb5.

The anomalous Hall effect (AHE) is one of the most fundamental phenomena in physics. In the highly conductive regime, ferromagnetic metals have been the focus of past research. Here, we report a giant extrinsic AHE in KV3Sb5, an exfoliable, highly conductive semimetal with Dirac quasiparticles and a vanadium Kagome net. Even without report of long range magnetic order, the anomalous Hall conductivity reaches 15,507 Ω-1 cm-1 with an anomalous Hall ratio of ≈ 1.8%; an order of magnitude larger than Fe. Defying theoretical expectations, KV3Sb5 shows enhanced skew scattering that scales quadratically, not linearly, with the longitudinal conductivity, possibly arising from the combination of highly conductive Dirac quasiparticles with a frustrated magnetic sublattice. This allows the possibility of reaching an anomalous Hall angle of 90° in metals. This observation raises fundamental questions about AHEs and opens new frontiers for AHE and spin Hall effect exploration, particularly in metallic frustrated magnets.

Categorical Encoding of Vowels in Primary Auditory Cortex.

Speech perception involves mapping from a continuous and variable acoustic speech signal to discrete, linguistically meaningful units. However, it is unclear where in the auditory processing stream speech sound representations cease to be veridical (faithfully encoding precise acoustic properties) and become categorical (encoding sounds as linguistic categories). In this study, we used functional magnetic resonance imaging and multivariate pattern analysis to determine whether tonotopic primary auditory cortex (PAC), defined as tonotopic voxels falling within Heschl's gyrus, represents one class of speech sounds-vowels-veridically or categorically. For each of 15 participants, 4 individualized synthetic vowel stimuli were generated such that the vowels were equidistant in acoustic space, yet straddled a categorical boundary (with the first 2 vowels perceived as [i] and the last 2 perceived as [i]). Each participant's 4 vowels were then presented in a block design with an irrelevant but attention-demanding level change detection task. We found that in PAC bilaterally, neural discrimination between pairs of vowels that crossed the categorical boundary was more accurate than neural discrimination between equivalently spaced vowel pairs that fell within a category. These findings suggest that PAC does not represent vowel sounds veridically, but that encoding of vowels is shaped by linguistically relevant phonemic categories.

CsV_{3}Sb_{5}: A Z_{2} Topological Kagome Metal with a Superconducting Ground State.

Recently discovered alongside its sister compounds KV_{3}Sb_{5} and RbV_{3}Sb_{5}, CsV_{3}Sb_{5} crystallizes with an ideal kagome network of vanadium and antimonene layers separated by alkali metal ions. This work presents the electronic properties of CsV_{3}Sb_{5}, demonstrating bulk superconductivity in single crystals with a T_{c}=2.5 K. The normal state electronic structure is studied via angle-resolved photoemission spectroscopy and density-functional theory, which categorize CsV_{3}Sb_{5} as a Z_{2} topological metal. Multiple protected Dirac crossings are predicted in close proximity to the Fermi level (E_{F}), and signatures of normal state correlation effects are also suggested by a high-temperature charge density wavelike instability. The implications for the formation of unconventional superconductivity in this material are discussed.

Neural representation of vowel formants in tonotopic auditory cortex.

Speech sounds are encoded by distributed patterns of activity in bilateral superior temporal cortex. However, it is unclear whether speech sounds are topographically represented in cortex, or which acoustic or phonetic dimensions might be spatially mapped. Here, using functional MRI, we investigated the potential spatial representation of vowels, which are largely distinguished from one another by the frequencies of their first and second formants, i.e. peaks in their frequency spectra. This allowed us to generate clear hypotheses about the representation of specific vowels in tonotopic regions of auditory cortex. We scanned participants as they listened to multiple natural tokens of the vowels [ɑ] and [i], which we selected because their first and second formants overlap minimally. Formant-based regions of interest were defined for each vowel based on spectral analysis of the vowel stimuli and independently acquired tonotopic maps for each participant. We found that perception of [ɑ] and [i] yielded differential activation of tonotopic regions corresponding to formants of [ɑ] and [i], such that each vowel was associated with increased signal in tonotopic regions corresponding to its own formants. This pattern was observed in Heschl's gyrus and the superior temporal gyrus, in both hemispheres, and for both the first and second formants. Using linear discriminant analysis of mean signal change in formant-based regions of interest, the identity of untrained vowels was predicted with ∼73% accuracy. Our findings show that cortical encoding of vowels is scaffolded on tonotopy, a fundamental organizing principle of auditory cortex that is not language-specific.

The neural substrates of improved phonological processing following successful treatment in a case of phonological alexia and agraphia.

Phonological deficits are common in aphasia after left-hemisphere stroke, and can have significant functional consequences for spoken and written language. While many individuals improve through treatment, the neural substrates supporting improvements are poorly understood. We measured brain activation during pseudoword reading in an individual through two treatment phases. Improvements were associated with greater activation in residual left dorsal language regions and bilateral regions supporting attention and effort. Gains were maintained, while activation returned to pre-treatment levels. This case demonstrates the neural support for improved phonology after damage to critical regions and that improvements may be maintained without markedly increased effort.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.

Inelastic x-ray scattering measurements of phonon dispersion and lifetimes in PbTe1-x Se x alloys.

PbTe1-x Se x alloys are of special interest to thermoelectric applications. Inelastic x-ray scattering determination of phonon dispersion and lifetimes along the high symmetry directions for PbTe1-x Se x alloys are presented. By comparing with calculated results based on the virtual crystal model calculations combined with ab initio density functional theory, the validity of virtual crystal model is evaluated. The results indicate that the virtual crystal model is overall a good assumption for phonon frequencies and group velocities despite the softening of transverse acoustic phonon modes along [1 1 1] direction, while the treatment of lifetimes warrants caution. In addition, phonons remain a good description of vibrational modes in PbTe1-x Se x alloys.

Nonclinical safety assessment of recombinant human acid sphingomyelinase (rhASM) for the treatment of acid sphingomyelinase deficiency:the utility of animal models of disease in the toxicological evaluation of potential therapeutics.

Recombinant human acid sphingomyelinase (rhASM) is being developed as an enzyme replacement therapy for patients with acid sphingomyelinase deficiency (Niemann-Pick disease types A and B), which causes sphingomyelin to accumulate in lysosomes. In the acid sphingomyelinase knock-out (ASMKO) mouse, intravenously administered rhASM reduced tissue sphingomyelin levels in a dose-dependent manner. When rhASM was administered to normal rats, mice, and dogs, no toxicity was observed up to a dose of 30mg/kg. However, high doses of rhASM≥10mg/kg administered to ASMKO mice resulted in unexpected toxicity characterized by cardiovascular shock, hepatic inflammation, adrenal hemorrhage, elevations in ceramide and cytokines (especially IL-6, G-CSF, and keratinocyte chemoattractant [KC]), and death. The toxicity could be completely prevented by the administration of several low doses (3mg/kg) of rhASM prior to single or repeated high doses (≥20mg/kg). These results suggest that the observed toxicity involves the rapid breakdown of large amounts of sphingomyelin into ceramide and/or other toxic downstream metabolites, which are known signaling molecules with cardiovascular and pro-inflammatory effects. Our results suggest that the nonclinical safety assessment of novel therapeutics should include the use of specific animal models of disease whenever feasible.

Delay discounting and the use of mindful attention versus distraction in the treatment of drug addiction: a conceptual review.

In recent decades, researchers have integrated measurements of delay discounting, how the subjective valuation of a reward changes as a function of time, into their study of addiction. Research has begun to explore the idea that delay discounting may serve as both a marker for the effectiveness of existing treatments for addiction and a potential target for novel intervention strategies. As this work is in its infancy, many potentially significant connections between the construct of delay discounting and the treatment of addiction have yet to be explored. Here, we present a conceptual review highlighting novel points of intersection between delay discounting and two approaches to treating addiction that have become increasingly popular in recent years: those that focus on the development of mindfulness skills and those that emphasize the use of distraction techniques. Viewing these two techniques through the lens of delay discounting is particularly intriguing because of the very different way that they address the experience of drug cravings in the present moment (nonjudgmentally attending to vs. shifting attention away from subjective cravings, respectively). We propose that these opposing strategies for dealing with cravings may interact with delay discounting in ways that have important implications for treatment effectiveness.

What role does the anterior temporal lobe play in sentence-level processing? Neural correlates of syntactic processing in semantic variant primary progressive aphasia.

Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA; also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the ATLs is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA to determine which regions normally involved in syntactic processing are damaged in semantic PPA and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural MRI and fMRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that, in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, whereas anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the ATLs but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left ATL did show abnormal functionality in semantic PPA patients; however, this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the ATL in sentence processing is less likely to relate to syntactic structure-building and more likely to relate to higher-level processes such as combinatorial semantic processing.

Duration of immunity of a multivalent (DHPPi/L4R) canine vaccine against four Leptospira serovars.

Despite effective vaccines against common Leptospira serovars, the development of new products with long duration of immunity is still important to protect dogs against leptospirosis. The results from four challenge studies performed one year after vaccination of dogs with a multivalent vaccine containing four Leptospira antigens are reported. Six week old dogs received two vaccinations, three weeks apart, and were challenged 367 days later. Clinical observations were recorded, while blood (culture, biochemistry and haematology), urine (culture) and liver and kidney (culture) samples were collected throughout the study or at necropsy. All control dogs remained seronegative until challenge, when they seroconverted. Antibody titres to Leptospira antigens were seen in vaccinated dogs 21 days after first vaccination and peaked three to six weeks after the second vaccination. Titres decreased in all studies over the following 12 months, until challenge when anamnestic responses were observed. In all studies control dogs demonstrated various abnormal clinical signs, while no vaccinated dogs were affected; differences between groups were only significant following L. bratislava challenge. Analysis of blood cultures showed all control and five of the 24 vaccinated dogs were Leptospira positive after challenge; all studies showed significant differences between treatment groups in mean number of days with positive cultures. Significant differences between vaccinated and control groups in mean number of days with positive urine cultures were also observed, with all non-vaccinated and one vaccinated dog Leptospira positive. The urine culture positive vaccinated dog also gave positive culture from kidney and liver samples. All except one control dog also showed positive Leptospira isolation from kidney or liver, with significant differences between vaccinated and control groups observed. The results demonstrate that administration of a new vaccine to six week old puppies induces immunity which is still effective up to one year later as demonstrated by challenge.

Cloning and developmental expression of zebrafish pdzrn3.

Pdzrn3, a member of the PDZRN/SEMCAP/LNX protein family containing a RING finger and two PDZ domains, has been implicated in myoblast and osteoblast differentiation. However, its spatio-temporal expression pattern during embryonic development has not been defined. Here, we describe the cloning and expression pattern of pdzrn3 during zebrafish development. We found that in addition to being expressed in several mesodermal structures, this gene displays specific expression in the central nervous system including rhombomere 1, ventral retina, thalamus and motor neurons, indicating a novel function during neural development. In particular, the absence of expression of pdzrn3 in the ventral retina of noi mutant fish suggests a possible role for this gene in regulating fasciculation and/or navigation of retinal ganglion cell axons.

How important is it to investigate the whole of the colon after initial assessment at a rapid access colorectal clinic?

BACKGROUND: The Stirling Royal Infirmary Rapid Access Colorectal Clinic (RACC) is a one-stop clinic that uses flexible sigmoidoscopy as the initial investigation to diagnose patients referred urgently with colorectal symptoms. This study aimed to examine the diagnoses and outcomes of patients who attended the RACC in 2006. PATIENTS AND METHODS: All patients who attended the RACC from 1 January 2006 to 31 December 2006 were identified and retrospectively reviewed from our prospectively collected unit database and case notes. RESULTS: Five hundred ninety-one patients attended the RACC in 2006. One hundred sixteen (19.6%) patients were discharged after the first clinic attendance, and the remaining 475 (80.4%) had further investigations or clinic review. There were 370 barium enemas requested with 92.4% compliance. The most common pathology identified by barium enemas was diverticular disease which only required reassurance and lifestyle changes. There were nine false-positive findings from barium enemas requiring further investigations. Of the 105 patients without barium enema, 49 had a colonoscopy. In total, 42 colorectal cancers were diagnosed with 34 (81.0%) distal to the splenic flexure and eight (19.0%) proximal. Of these, 32 (76%) were diagnosed by flexible sigmoidoscopy, three (7%) by barium enemas, three (7%) by colonoscopy, and four (10%) by computed tomography. CONCLUSIONS: A rapid access colorectal clinic using flexible sigmoidoscopy as the initial diagnostic test was safe and effective in investigating distal colonic pathologies. However, over two thirds of patients proceeded to imaging of the remaining colon, and most of them were found to have only benign pathologies. The cost effectiveness and acceptability of this were unclear.

Giving speech a hand: gesture modulates activity in auditory cortex during speech perception.

Viewing hand gestures during face-to-face communication affects speech perception and comprehension. Despite the visible role played by gesture in social interactions, relatively little is known about how the brain integrates hand gestures with co-occurring speech. Here we used functional magnetic resonance imaging (fMRI) and an ecologically valid paradigm to investigate how beat gesture-a fundamental type of hand gesture that marks speech prosody-might impact speech perception at the neural level. Subjects underwent fMRI while listening to spontaneously-produced speech accompanied by beat gesture, nonsense hand movement, or a still body; as additional control conditions, subjects also viewed beat gesture, nonsense hand movement, or a still body all presented without speech. Validating behavioral evidence that gesture affects speech perception, bilateral nonprimary auditory cortex showed greater activity when speech was accompanied by beat gesture than when speech was presented alone. Further, the left superior temporal gyrus/sulcus showed stronger activity when speech was accompanied by beat gesture than when speech was accompanied by nonsense hand movement. Finally, the right planum temporale was identified as a putative multisensory integration site for beat gesture and speech (i.e., here activity in response to speech accompanied by beat gesture was greater than the summed responses to speech alone and beat gesture alone), indicating that this area may be pivotally involved in synthesizing the rhythmic aspects of both speech and gesture. Taken together, these findings suggest a common neural substrate for processing speech and gesture, likely reflecting their joint communicative role in social interactions.

Neural organization of linguistic short-term memory is sensory modality-dependent: evidence from signed and spoken language.

Despite decades of research, there is still disagreement regarding the nature of the information that is maintained in linguistic short-term memory (STM). Some authors argue for abstract phonological codes, whereas others argue for more general sensory traces. We assess these possibilities by investigating linguistic STM in two distinct sensory-motor modalities, spoken and signed language. Hearing bilingual participants (native in English and American Sign Language) performed equivalent STM tasks in both languages during functional magnetic resonance imaging. Distinct, sensory-specific activations were seen during the maintenance phase of the task for spoken versus signed language. These regions have been previously shown to respond to nonlinguistic sensory stimulation, suggesting that linguistic STM tasks recruit sensory-specific networks. However, maintenance-phase activations common to the two languages were also observed, implying some form of common process. We conclude that linguistic STM involves sensory-dependent neural networks, but suggest that sensory-independent neural networks may also exist.

Automated syringe driver for acupoint injection in functional MRI studies: a case for quantified point injection in neuroimaging studies of acupuncture.

The investigation of proposed acupuncture models is experiencing increasing interest particularly since the inception of functional neuroimaging in the early 1990s, but difficulty in providing acceptable controls has been an ongoing limitation. The use of titrated stimulation to generate a dose response is implied in the nature of the stimulus and the timing of the response. To address the complexity of delivering an accurate stimulus during an imaging study while simultaneously maintaining synchrony and recording stimulus parameters, stimulus delivery needs to be an automated task. This report presents the design and general description of a system capable of delivering acupoint stimulation by injection of precisely timed and measured saline doses while simultaneously interfaced to biomonitoring or neuroimaging instruments. The results of instrument validation in a clinical environment are presented, along with a discussion of the usefulness and limitations of the device.

Identification of alternatively spliced dab1 isoforms in zebrafish.

We have investigated the genomic organization, the occurrence of alternative splicing and the differential expression of the zebrafish disabled1 (dab1) gene. Dab1 is a key effector of the Reelin pathway, which regulates neuronal migration during brain development in vertebrates. The coding region of the zebrafish dab1 gene spans over 600 kb of genomic DNA and is composed of 15 exons. Alternative splicing in a region enriched for tyrosine residues generates at least three different isoforms. These isoforms are developmentally regulated and show differential tissue expression. Comparison with mouse and human data shows an overall conservation of the genomic organization with different alternative splicing events generating species-specific isoforms. Because these alternative splicing events give rise to isoforms with different numbers of phosphorylateable tyrosines, we speculate that alternative splicing of the dab1 gene in zebrafish and in other vertebrates regulates the nature of the cellular response to the Reelin signal.

Metformin as treatment for overweight and obese adults: a systematic review.

PURPOSE: We wanted to determine whether metformin is an effective medication for treatment of overweight or obese adults who do not have diabetes mellitus or polycystic ovary syndrome (PCOS). METHODS: We searched MEDLINE (1966-2003), EMBASE (1986-2003), Allied and Complementary Medicine Database (1985-2003), International Pharmaceutical Abstracts (1970-2003), the Cochrane Library, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Controlled Trials Register, MEDLINE In-Process & Other Non-Indexed Citations, reference lists of retrieved articles, and articles by selected authors and pharmaceutical manufacturers. Inclusion criteria were being obese or overweight determined by a BMI of 25 kg/m2 or greater or waist-to-hip ratio (WHR) of more than 0.8, metformin use, and aged 18 years or older. Exclusion criteria were a diagnosis of diabetes mellitus, polycystic ovarian syndrome or descriptors of polycystic ovarian syndrome, human immunodeficiency virus infection, and concomitant antipsychotic medications. Trials were graded on an 11-point Jadad scale. Only randomized controlled and blinded trials were accepted. Two reviewers independently extracted data from each trial. Primary outcomes measured were changes in BMI, WHR, and weight. RESULTS: Fifty-seven potentially relevant studies were initially identified; 48 were excluded because of lack of randomization, lack of blinding, failure to meet inclusion or exclusion criteria, inaccessible outcomes, or improper study design. Nine clinical trials met criteria for validity assessment. Four studies used the parameter of waist-to-hip ratio, 3 studies included BMI, and 8 used weight. Two of the 9 studies showed a small reduction in WHR. CONCLUSION: Insufficient evidence exists for the use of metformin as treatment of overweight or obese adults who do not have diabetes mellitus or polycystic ovary syndrome. Further studies are needed to answer this clinical question.