bluuebunny/crossref_metadata_2025 huggingface dataset:
The long and the short of Huntington’s disease: how the sphingolipid profile is shifted in the caudate of advanced clinical cases
Authors: Phillips Gabrielle R. , Saville Jennifer T. , Hancock Sarah E. , Brown Simon H. J. , Jenner Andrew M. , McLean Catriona , Fuller Maria , Newell Kelly A. , Mitchell Todd W.
Published: December 2021

Huntington’s disease is a devastating neurodegenerative disorder that onsets in late adulthood as progressive and terminal cognitive, psychiatric and motor deficits. The disease is genetic, triggered by a CAG repeat (polyQ) expansion mutation in the Huntingtin gene and resultant huntingtin protein. Although the mutant huntingtin protein is ubiquitously expressed, the striatum degenerates early and consistently in the disease. The polyQ mutation at the N-terminus of the huntingtin protein alters its natural interactions with neural phospholipids in vitro, suggesting that the specific lipid composition of brain regions could influence their vulnerability to interference by mutant huntingtin; however, this has not yet been demonstrated in vivo. Sphingolipids are critical cell signalling molecules, second messengers and membrane components. Despite evidence of sphingolipid disturbance in Huntington’s mouse and cell models, there is limited knowledge of how these lipids are affected in human brain tissue. Using post-mortem brain tissue from five brain regions implicated in Huntington’s disease (control n = 13, Huntington’s n = 13), this study aimed to identify where and how sphingolipid species are affected in the brain of clinically advanced Huntington’s cases. Sphingolipids were extracted from the tissue and analysed using targeted mass spectrometry analysis; proteins were analysed by western blot. The caudate, putamen and cerebellum had distinct sphingolipid changes in Huntington’s brain whilst the white and grey frontal cortex were spared. The caudate of Huntington’s patients had a shifted sphingolipid profile, favouring long (C13–C21) over very-long-chain (C22–C26) ceramides, sphingomyelins and lactosylceramides. Ceramide synthase 1, which synthesizes the long-chain sphingolipids, had a reduced expression in Huntington’s caudate, correlating positively with a younger age at death and a longer CAG repeat length of the Huntington’s patients. The expression of ceramide synthase 2, which synthesizes very-long-chain sphingolipids, was not different in Huntington’s brain. However, there was evidence of possible post-translational modifications in the Huntington’s patients only. Post-translational modifications to ceramide synthase 2 may be driving the distinctive sphingolipid profile shifts of the caudate in advanced Huntington’s disease. This shift in the sphingolipid profile is also found in the most severely affected brain regions of several other neurodegenerative conditions and may be an important feature of region-specific cell dysfunction in neurodegenerative disease.
The neurovascular couplings between electrophysiological and hemodynamic activities in anticipatory selective attention
Authors: Zhao Chenguang , Li Dongwei , Guo Jialiang , Li Bingkun , Kong Yuanjun , Hu Yiqing , Du Boqi , Ding Yulong , Li Xiaoli , Liu Hanli , Song Yan
Published: December 2021

Selective attention is thought to involve target enhancement and distractor inhibition processes. Here, we recorded simultaneous electroencephalographic (EEG) and functional near-infrared spectroscopy (fNIRS) data from human adults when they were pre-cued by the visual field of coming target, distractor, or both of them. From the EEG data, we found alpha power relatively decreased contralaterally to the to-be-attended target, as reflected by the positive-going alpha modulation index. Late alpha power relatively increased contralaterally to the to-be-suppressed distractor, as reflected by the negative-going alpha modulation index. From the fNIRS data, we found enhancements of hemodynamic activity over the contralateral hemisphere in response to both the target and the distractor anticipation but within nonoverlapping posterior brain regions. More importantly, we described the specific neurovascular modulation between alpha power and oxygenated hemoglobin signal, which showed a positive coupling effect during target anticipation and a negative coupling effect during distractor anticipation. Such flexible neurovascular couplings between EEG oscillation and hemodynamic activity seem to play an essential role in the final behavioral outcomes. These results provide unique neurovascular evidence for the dissociation of the mechanisms of target enhancement and distractor inhibition. Individual behavioral differences can be related to individual differences in neurovascular coupling.
Household Contact Tracing With Intensified Tuberculosis and Human Immunodeficiency Virus Screening in South Africa: A Cluster-Randomized Trial
Authors: Martinson Neil A , Lebina Limakatso , Webb Emily L , Ratsela Andrew , Varavia Ebrahim , Kinghorn Anthony , Lala Sanjay G , Golub Jonathan E , Bosch Zama , Motsomi Kegaugetswe P , MacPherson Peter
Published: December 2021

Background

Household contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival.

Methods

Household contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV.

Results

From December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66–1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07–4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64–1.64).

Conclusions

Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits.

Clinical Trials Registration

ISRCTN16006202.
Pivotal Phase 3 Randomized Clinical Trial of the Safety, Tolerability, and Immunogenicity of 20-Valent Pneumococcal Conjugate Vaccine in Adults Aged ≥18 Years
Authors: Essink Brandon , Sabharwal Charu , Cannon Kevin , Frenck Robert , Lal Himal , Xu Xia , Sundaraiyer Vani , Peng Yahong , Moyer Lisa , Pride Michael W , Scully Ingrid L , Jansen Kathrin U , Gruber William C , Scott Daniel A , Watson Wendy
Published: December 2021

Background

Pneumococcal conjugate vaccines (PCVs) have significantly reduced pneumococcal disease, but disease from non-PCV serotypes remains. The safety, tolerability, and immunogenicity of a 20-valent PCV (PCV20) were evaluated.

Methods

This pivotal phase 3, randomized, double-blind study enrolled adults into 3 age groups (≥60, 50–59, and 18–49 years) at US and Swedish sites. Participants were randomized to receive 1 PCV20 or 13-valent PCV (PCV13) dose. After 1 month, participants aged ≥60 years also received 1 dose of saline or 23-valent polysaccharide vaccine (PPSV23). Safety assessments included local reactions, systemic events, adverse events, serious adverse events, and newly diagnosed chronic medical conditions. Opsonophagocytic activity geometric mean titers 1 month after PCV20 were compared with 13 matched serotypes after PCV13 and 7 additional serotypes after PPSV23 in participants aged ≥60 years; noninferiority was declared if the lower bound of the 2-sided 95% confidence interval for the opsonophagocytic activity geometric mean titer ratio (ratio of PCV20/saline to PCV13/PPSV23 group) was >0.5. PCV20-elicited immune responses in younger participants were also bridged to those in 60–64-year-olds.

Results

The severity and frequency of prompted local reactions and systemic events were similar after PCV20 or PCV13; no safety concerns were identified. Primary immunogenicity objectives were met, with immune responses after PCV20 noninferior to 13 matched serotypes after PCV13 and to 6 additional PPSV23 serotypes in participants aged ≥60 years; serotype 8 missed the statistical noninferiority criterion. PCV20 induced robust responses to all 20 vaccine serotypes across age groups.

Conclusions

PCV20 was safe and well tolerated, with immunogenicity comparable to that of PCV13 or PPSV23. PCV20 is anticipated to expand protection against pneumococcal disease in adults.

Clinical Trials Registration

NCT03760146.
Declarative Programming with Intensional Sets in Java Using JSetL
Authors: Cristiá Maximiliano , Fois Andrea , Rossi Gianfranco
Published: December 2021

Intensional sets are sets given by a property rather than by enumerating their elements. In a previous work, we have proposed a decision procedure for a first-order logic language which provides restricted intensional sets (RISs), i.e. a sub-class of intensional sets that are guaranteed to denote finite—though unbounded—sets. In this paper, we show how RIS can be exploited as a convenient programming tool also in a conventional setting, namely the imperative O-O language Java. We do this by considering a Java library, called JSetL, that integrates the notions of logical variable, (set) unification and constraints that are typical of constraint logic programming languages into the Java language. We show how JSetL is naturally extended to accommodate for RIS and RIS constraints and how this extension can be exploited; on the one hand, to support a more declarative style of programming and, on the other hand, to effectively enhance the expressive power of the constraint language provided by the library.
Fighting against sudden cardiac death: need for a paradigm shift—Adding near-term prevention and pre-emptive action to long-term prevention
Authors: Marijon Eloi , Garcia Rodrigue , Narayanan Kumar , Karam Nicole , Jouven Xavier
Published: December 2021

More than 40 years after the first implantable cardioverter-defibrillator (ICD) implantation, sudden cardiac death (SCD) still accounts for more than five million deaths worldwide every year. Huge efforts in the field notwithstanding, it is now increasingly evident that the current strategy of long-term prevention based on left ventricular ejection fraction as the key selection criterion is actually of very limited impact, also because the largest absolute numbers of SCD are encountered in the general population not known to be at risk. It has been recently reemphasized that SCD is often not so sudden, with almost half of the victims experiencing typical warning symptoms preceding the event. Importantly, heeded and prompt medical attention can dramatically improve survival. Essentially, such timely action increases the chances of the SCD event being witnessed by emergency medical services and provides the opportunity for early intervention. In addition, newer technologies incorporating digital data acquisition, transfer between interconnected devices, and artificial intelligence, should allow dynamic, real-time monitoring of diverse parameters and therefore better identification of subjects at short-term SCD risk. Along with warning symptoms, these developments allow a new approach of near-term prevention based on the hours and minutes preceding SCD. In the present review, we challenge the current paradigm of mid- and long-term prevention using ICD in patients at the highest risk of SCD, and introduce a complementary concept applicable to the entire population that would aim to pre-empt SCD by timely detection and intervention within the minutes or hours prior to the event.
Relationship between physical capacity and depression in heart failure patients undergoing hybrid comprehensive telerehabilitation vs. usual care: subanalysis from the TELEREH-HF Randomized Clinical Trial
Authors: Piotrowicz Ewa , Mierzyńska Anna , Jaworska Izabela , Opolski Grzegorz , Banach Maciej , Zaręba Wojciech , Kowalik Ilona , Pencina Michael , Orzechowski Piotr , Szalewska Dominika , Pluta Sławomir , Glowczynska Renata , Kalarus Zbigniew , Irzmanski Robert , Piotrowicz Ryszard
Published: December 2021

Aims

The hybrid comprehensive telerehabilitation (HCTR) consisting of telecare (with psychological telesupport), telerehabilitation, and remote monitoring of cardiovascular implantable electronic devices might be an option to improve both physical capacity and depressive symptoms. The aim of the study was to investigate the influence of HCTR on depressive symptoms and physical capacity in heart failure (HF) patients in comparison with usual care (UC).

Methods and results

The present analysis formed part of a multicentre, randomized trial that enrolled 850 HF patients (New York Heart Association I–III, left ventricular ejection fraction ≤ 40%). Patients were randomized 1:1 to HCTR or UC. Patients underwent an HCTR programme (1 week in hospital and 8 weeks at home; exercise training 5 times weekly) or UC with observation. The Beck Depression Inventory II (BDI-II) score (cut point for depression ≥ 14) was used to assess depression and the physical capacity was measured by peak oxygen consumption (peak VO2; mL/kg/min). Measurements were made before and after 9-week intervention/observation (HCTR/UC group). Both groups were comparable in terms of demographic and clinical characteristics. In HCTR group, at entry, 23% of the sample obtained BDI-II scores ≥14 vs. 27.5% in UC group. There were no significant differences between groups regarding ΔBDI-II score (P = 0.992) after 9-week HCTR/UC. There was a significant improvement in physical capacity only in the HCTR group in both patients with (P = 0.033) and without (P < 0.001) depression.

Conclusions

In HF patients, HCTR provided similar reduction of depressive symptoms as UC. HCTR resulted in a significant improvement in physical capacity in patients with and without depression.
Patient feedback and evaluation measures of a physical activity initiative: Exercise is Medicine program
Authors: De Guzman Kimberly R , Pratt Michael , Hwang Andrea , Linke Sarah E
Published: December 2021

Background

Nearly half of American adults fail to meet national guidelines for physical activity (PA). As a major contributor to the development of preventable chronic diseases, insufficient PA is an important target for health behaviour interventions. Exercise is Medicine (EIM) aims to increase PA levels among primary care patients through routine PA evaluation, prescription, brief counselling, and referral to community resources. PA is treated as a vital sign with the goal of increasing PA levels in prescribed manageable doses. EIM is currently being implemented in UC San Diego Health System’s primary care clinics.

Objective

(i) To collect and summarize patient perceptions of EIM and its components. (ii) To identify discrepancies between patient-reported feedback and primary care provider (PCP) documentation in corresponding visit notes in the electronic medical record (EMR).

Methods

Patient recall of EIM components was measured using a 10-item survey distributed via MyChart. PCP documentation of EIM was tracked in the EMR system.

Results

Patient feedback (n = 316) about EIM components was positive and reinforced patients’ confidence in their ability to increase PA. Approximately 70% of patients reported having a PA discussion with their PCP at their most recent visit, but only approximately 21% of these discussions were documented by PCPs using the preprogrammed smartphrase in the EMR.

Conclusion

Overall, patients reported positive perceptions of EIM. While patient perceptions of EIM suggested that PA discussions with PCPs are happening during the majority of visits, PCP documentation fell behind. Documentation via smartphrase may need to be modified for physicians to use.
Behaviour change for type 2 diabetes: perspectives of general practitioners, primary care academics, and behaviour change experts on the use of the 5As framework
Authors: Sturgiss Elizabeth , Advocat Jenny , Ball Lauren , Williams Lauren T , Prathivadi Pallavi , Clark Alexander M
Published: December 2021

Background

The 5As framework is a recognized underpinning of behaviour change guidelines, teaching, and research in primary care. Supporting patients to improve their lifestyle behaviours, including diet and physical activity, is a common aspect of type 2 diabetes mellitus (T2DM) management. The 5As framework often informs behaviour change for patients with T2DM.

Objective

To explore the experience and perspectives of general practitioners (GPs) and primary care academics and behaviour change experts regarding using the 5As framework when caring for patients with T2DM to better understand how and why the 5As are effective in practice.

Methods

We recruited 20 practising GPs, primary care academics, and behaviour change experts for an individual semistructured interview and analysed the data using a realist evaluation approach.

Results

There were diverse accounts of how GPs use the 5As in practice and few of the participants could name each “A.” The 5As were commonly regarded as a framework best suited to beginners and although GPs expressed they followed the broad direction of the 5As, they did not consciously follow the framework in an instructive manner. Elements that could enhance the 5As included more emphasis on motivational interviewing, changing how “Ask” is included in the consultation, and increased person-centredness.

Conclusion

Although it is a ubiquitous framework in primary care, the 5As are understood in diverse ways and applied variably in practice. There is room to enhance how the 5As support behaviour change consultations to optimize outcomes in primary care.
Assembly and potential transmission of the Lens culinaris seed microbiome
Authors: Morales Moreira Zayda P , Helgason Bobbi L , Germida James J
Published: December 2021

Soil is an important source of bacteria and fungi for the plant, but seeds can also provide microbial inocula through heritable or stochastic assembly. Seed-associated microbial communities can potentially interact with the host plant through multiple generations. Here, we assessed the impact of two different soil types on the seed microbiome assembly of seven lentil (Lens culinaris) genotypes under environmentally controlled conditions and examined the vertical transmission of bacterial communities from seed to seed across two generations. Bulk soil microbiomes and seed microbiomes were characterized using high-throughput amplicon sequencing of the bacterial 16S rRNA gene. Our results revealed that bacterial communities in the two soils differed significantly and that bacterial communities associated with seeds were significantly impacted by genotype (15%) in one of the soils. Co-occurrence of amplicon sequence variants between generations suggests that members of the genera Cutibacterium, Methylobacterium, Sphingomonas, Streptococcus and Tepidimonas are transmitted and preserved in lentil genotypes irrespective of the soil in which they were grown. Increasing our knowledge of how microbial communities carried by seeds are assembled, transmitted and preserved offers a promising way for future breeding programs to consider microbial communities when selecting for more resilient and productive cultivars.
Individual, household, and community-level predictors of modern contraceptive use among married women in Cameroon: a multilevel analysis
Authors: Zegeye Betregiorgis , Idriss-Wheeler Dina , Ahinkorah Bright Opoku , Ameyaw Edward Kwabena , Seidu Abdul-Aziz , Keetile Mpho , Yaya Sanni
Published: December 2021

Background

Unintended pregnancy remains a major public health and socio-economic problem in sub-Saharan African countries, including Cameroon. Modern contraceptive use can avert unintended pregnancy and its related problems. In Cameroon, the prevalence of modern contraceptive use is low. Therefore, this study investigated the individual/household and community-level predictors for modern contraceptive use among married women in Cameroon.

Methods

Data for this study were derived from the nationally representative 2018–2019 Cameroon Demographic and Health Survey. Analysis was done on 6080 married women in the reproductive age group (15–49 y) using Stata version 14 software. Pearson χ2 test and multilevel logistic regression analysis were conducted to examine the individual/household and community-level predictors of modern contraceptive use. Descriptive results were presented using frequencies and bar charts. Inferential results were presented using adjusted odds ratios (aORs) with 95% confidence intervals (CIs).

Results

The results show only 18.3% (95% CI 16.8 to 19.8) of married women in Cameroon use modern contraceptives. Women's age (45–49 y; aOR 0.22 [95% CI 0.12 to 0.39]), education level (secondary education; aOR 2.93 [95% CI 1.90 to 4.50]), occupation (skilled manual; aOR 1.46 [95% CI 1.01 to 2.11]), religion (Muslim; aOR 0.63 [95% CI 0.47 to 0.84]), wealth quintile (richest; aOR 2.22 [95% CI 1.35 to 3.64]) and parity (≥5; aOR 3.59 [95% CI 2.61 to 4.94]) were significant individual/household-level predictors. Region (East; aOR 3.63 [95% CI 1.97 to 6.68]) was identified as a community-level predictor.

Conclusions

Modern contraceptive use among married women in Cameroon is low. Women's education and employment opportunities should be prioritized, as well as interventions for married women, ensuring equity in the utilization of modern contraceptives across regions.
Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection
Authors: Gane Ed J. , Schwabe Christian , Berliba Elina , Tangkijvanich Pisit , Jucov Alina , Ghicavii Nelea , Verbinnen Thierry , Lenz Oliver , Talloen Willem , Kakuda Thomas N. , Westland Chris , Patel Megha , Yogaratnam Jeysen Z. , Dragone Leonard , Van Remoortere Pieter
Published: December 2021

Objectives

We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB) (Phase 1b, NCT03439488).

Methods

Twenty treatment-naive, HBeAg-positive or -negative CHB patients were randomized 4‍:‍1 to JNJ-64530440 750 mg once or twice daily, or placebo for 28 days.

Results

All patients (mean age 43.8 years; 85% male; 70% White; 20% HBeAg positive) completed dosing/28 day follow-up. Mild-to-moderate treatment-emergent adverse events occurred in 3/4 (placebo), 6/8 (once-daily) and 4/8 (twice-daily) patients; mostly fatigue, increased alanine aminotransferase, decreased neutrophil count, and headache. Hepatitis B virus (HBV) DNA was substantially reduced; mean (range) changes from baseline at day 29 were: −3.2 (−2.4 to −3.9) (once-daily) and −3.3 (−2.6 to −4.1) (twice-daily) log10 IU/mL; placebo 0.1 (0.7 to −0.6) log10 IU/mL. HBV DNA levels were below the lower limit of quantification (LLOQ) in 5/8 (once-daily) and 3/8 (twice-daily) patients. For patients with detectable baseline HBV RNA, mean (SE) changes versus baseline in HBV RNA at day 29 were: −2.65 (0.81) (once-daily) and −2.94 (0.33) (twice-daily) log10 copies/mL. HBV RNA levels were ‘target not detected’ in 4/6 (once-daily) and 3/7 (twice-daily) patients. JNJ-64530440 pharmacokinetics in CHB patients were comparable with those in healthy volunteers.

Conclusions

JNJ-64530440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved potent antiviral activity in CHB patients.
Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007–19
Authors: Golden Alyssa R. , Baxter Melanie R. , Karlowsky James A. , Mataseje Laura , Mulvey Michael R. , Walkty Andrew , Bay Denice , Schweizer Frank , Lagace-Wiens Philippe R. S. , Adam Heather J. , Zhanel George G.
Published: December 2021

Objectives

This study assessed in vitro activities of cefepime/taniborbactam and comparator antimicrobial agents against ertapenem-non-susceptible Enterobacterales (ENSE) clinical isolates collected from the CANWARD study 2007–19, and associations between MIC and various mechanisms of β-lactam resistance identified using WGS.

Methods

A total of 179 ENSE (MIC ≥ 1 mg/L) isolates underwent susceptibility testing using reference CLSI broth microdilution. WGS was performed using the Illumina NextSeq platform. Carbapenemases, ESBLs and other β-lactamases were identified using ResFinder 4.0. Alterations in ompC/F and ftsI (PBP3) were identified by comparing extracted sequences to the appropriate NCBI reference gene. Porin alterations were analysed with Provean v1.1.3. Specific alterations of interest in PBP3 included a YRIN or YRIK insertion after P333.

Results

Cefepime/taniborbactam was highly active (MIC50/MIC90, 0.5/2 mg/L; 177/179 isolates inhibited at ≤ 8 mg/L) against ENSE with various antimicrobial resistance phenotypes. Thirteen (7.3%) of the 179 ENSE isolates demonstrated cefepime/taniborbactam MIC values ≥ 4 mg/L and possessed combinations of β-lactam resistance mechanisms, including a carbapenemase and/or ESBL and/or other β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3. Of the two Escherichia coli isolates that demonstrated a cefepime/taniborbactam MIC of 32 mg/L, one possessed NDM-5, OXA-181 and TEM-1B, an OmpC alteration and P333_Y334insYRIN in PBP3, while the second contained CTX-M-71, a truncated OmpF and a large alteration in OmpC (F182_R195delinsMTTNGRDDVFE).

Conclusions

Cefepime/taniborbactam was highly active against ENSE with various antimicrobial resistance phenotypes/genotypes. ENSE isolates with cefepime/taniborbactam MIC values ≥ 4 mg/L possessed combinations of β-lactam resistance mechanisms, including β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3.
Expression Modalities: How Speaking Versus Writing Shapes Word of Mouth
Authors: Berger Jonah , Rocklage Matthew D , Packard Grant
Published: December 2021

Consumers often communicate their attitudes and opinions with others, and such word of mouth has an important impact on what others think, buy, and do. But might the way consumers communicate their attitudes (i.e., through speaking or writing) shape the attitudes they express? And, as a result, the impact of what they share? While a great deal of research has begun to examine drivers of word of mouth, there has been less attention to how communication modality might shape sharing. Six studies, conducted in the laboratory and field, demonstrate that compared to speaking, writing leads consumers to express less emotional attitudes. The effect is driven by deliberation. Writing offers more time to deliberate about what to say, which reduces emotionality. The studies also demonstrate a downstream consequence of this effect: by shaping the attitudes expressed, the modality consumers communicate through can influence the impact of their communication. This work sheds light on word of mouth, effects of communication modality, and the role of language in communication.
Felix Bamberg (1820–1893), a scholar and collector between Prussia, France, Italy and Romania
Authors: Gerard Powell Véronique
Published: December 2021

Born in Prussia to a Jewish family, Felix Bamberg (1820–1893) is known principally as the man who sold his collection of Old Masters to King Carol I of Romania (1839–1914), now mostly in the National Museum of Art of Romania in Bucharest. The first aim of this article is to provide a more accurate portrait of this cultured man, who moved to France in the early 1840s and whose main career as a German consul, disrupted by the Franco-Prussian War, was spent between Paris, Messina and Genoa. The second is to study how and why, from 1867 onwards, starting in the Parisian auction rooms and finishing with Italian private collections, he gathered an impressive collection of Old Masters, particularly from the Spanish and Northern schools. Finally, as far as possible, the reasons for the sale of his collection to Carol I between 1879 and 1890 and the terms they agreed are investigated.
flash-light on the ring: hydrodynamic simulations of expanding supernova shells near supermassive black holes
Authors: Barna B , Palouš J , Ehlerová S , Wünsch R , Morris M R , Vermot P
Published: December 2021

The way supermassive black holes (SMBHs) in Galactic Centres (GCs) accumulate their mass is not completely determined. At large scales, it is governed by galactic encounters, mass inflows connected to spirals arms and bars, or due to expanding shells from supernova (SN) explosions in the central parts of galaxies. The investigation of the latter process requires an extensive set of gas dynamical simulations to explore the multidimensional parameter space needed to frame the phenomenon. The aims of this paper are to extend our investigation of the importance of SNe for inducing accretion on to an SMBH and carry out a comparison between the fully hydrodynamic code flash and the much less computationally intensive code ring, which uses the thin shell approximation. We simulate 3D expanding shells in a gravitational potential similar to that of the GC with a variety of homogeneous and turbulent environments. In homogeneous media, we find convincing agreement between flash and ring in the shapes of shells and their equivalent radii throughout their whole evolution until they become subsonic. In highly inhomogeneous, turbulent media, there is also a good agreement of shapes and sizes of shells, and of the times of their first contact with the central 1-pc sphere, where we assume that they join the accretion flow. The comparison supports the proposition that an SN occurring at a galactocentric distance of 5 pc typically drives 1–3 M⊙ into the central 1 pc around the GC.
Dark-ages reionization and galaxy formation simulation XX. The Ly α IGM transmission properties and environment of bright galaxies during the epoch of reionization
Authors: Qin Yuxiang , Wyithe J Stuart B , Oesch Pascal A , Illingworth Garth D , Leonova Ecaterina , Mutch Simon J , Naidu Rohan P
Published: December 2021

The highly neutral intergalactic medium (IGM) during the epoch of reionization (EoR) is expected to suppress Ly α emission with damping-wing absorption, causing nearly no Ly α detection from star-forming galaxies at z ∼ 8. However, spectroscopic observations of the four brightest galaxies (H160 ∼ 25 mag) at these redshifts do reveal prominent Ly α line, suggesting locally ionized IGM. In this paper, we explore the Ly α IGM transmission and environment of bright galaxies during the EoR using the Meraxes semi-analytic model. We find brighter galaxies to be less affected by damping-wing absorption as they are effective at ionizing surrounding neutral hydrogen. Specifically, the brightest sources (H160 ≲ 25.5 mag) lie in the largest ionized regions in our simulation, and have low attenuation of their Ly α from the IGM (optical depth <1). Fainter galaxies (25.5 mag < H160 < 27.5 mag) have transmission that depends on UV luminosity, leading to a lower incidence of Ly α detection at fainter magnitudes. This luminosity-dependent attenuation explains why Ly α has only been observed in the brightest galaxies at z ∼ 8. Follow-up observations have revealed counterparts in the vicinity of these confirmed z ∼ 8 Ly α emitters. The environments of our modelled analogues agree with these observations in the number of nearby galaxies, which is a good indicator of whether Ly α can be detected among fainter galaxies. At the current observational limit, galaxies with ≥2–5 neighbours within 2 arcmin × 2 arcmin are ∼2–3 times more likely to show Ly α emission. JWST will discover an order of magnitude more neighbours, revealing ≳50 galaxies in the largest ionizing bubbles and facilitating direct study of reionization morphology.
Non-ideal magnetohydrodynamic simulations of subcritical pre-stellar cores with non-equilibrium chemistry
Authors: Tritsis A , Federrath C , Willacy K , Tassis K
Published: December 2021

Non-ideal magnetohydrodynamic (MHD) effects are thought to be gravity’s closest ally in overcoming the support of magnetic fields and in forming stars. Here, we modify the publicly available version of the adaptive mesh refinement code flash (Fryxell et al. 2000; Dubey et al. 2008) to include a detailed treatment of non-ideal MHD and study such effects in collapsing pre-stellar cores. We implement two very extended non-equilibrium chemical networks, the largest of which is comprised of ∼ 300 species and includes a detailed description of deuterium chemistry. The ambipolar diffusion, Ohmic and Hall resistivities are then self-consistently calculated from the abundances of charged species. We present a series of 2D axisymmetric simulations where we vary the chemical model, cosmic ray ionization rate, and grain distribution. We benchmark our implementation against ideal MHD simulations and previously published results. We show that, at high densities ($n_{\rm {H_2}}\gt ~10^6~\rm {cm^{-3}}$), the ion that carries most of the perpendicular and parallel conductivities is not $\rm {H_3^+}$ as was previously thought, but is instead $\rm {D_3^+}$.
Translesion DNA synthesis-driven mutagenesis in very early embryogenesis of fast cleaving embryos
Authors: Lo Furno Elena , Busseau Isabelle , Aze Antoine , Lorenzi Claudio , Saghira Cima , Danzi Matt C , Zuchner Stephan , Maiorano Domenico
Published: December 2021

In early embryogenesis of fast cleaving embryos, DNA synthesis is short and surveillance mechanisms preserving genome integrity are inefficient, implying the possible generation of mutations. We have analyzed mutagenesis in Xenopus laevis and Drosophila melanogaster early embryos. We report the occurrence of a high mutation rate in Xenopus and show that it is dependent upon the translesion DNA synthesis (TLS) master regulator Rad18. Unexpectedly, we observed a homology-directed repair contribution of Rad18 in reducing the mutation load. Genetic invalidation of TLS in the pre-blastoderm Drosophila embryo resulted in reduction of both the hatching rate and single-nucleotide variations on pericentromeric heterochromatin in adult flies. Altogether, these findings indicate that during very early Xenopus and Drosophila embryos TLS strongly contributes to the high mutation rate. This may constitute a previously unforeseen source of genetic diversity contributing to the polymorphisms of each individual with implications for genome evolution and species adaptation.
A modular RNA interference system for multiplexed gene regulation
Authors: Dwijayanti Ari , Storch Marko , Stan Guy-Bart , Baldwin Geoff S
Published: December 2021

The rational design and realisation of simple-to-use genetic control elements that are modular, orthogonal and robust is essential to the construction of predictable and reliable biological systems of increasing complexity. To this effect, we introduce modular Artificial RNA interference (mARi), a rational, modular and extensible design framework that enables robust, portable and multiplexed post-transcriptional regulation of gene expression in Escherichia coli. The regulatory function of mARi was characterised in a range of relevant genetic contexts, demonstrating its independence from other genetic control elements and the gene of interest, and providing new insight into the design rules of RNA based regulation in E. coli, while a range of cellular contexts also demonstrated it to be independent of growth-phase and strain type. Importantly, the extensibility and orthogonality of mARi enables the simultaneous post-transcriptional regulation of multi-gene systems as both single-gene cassettes and poly-cistronic operons. To facilitate adoption, mARi was designed to be directly integrated into the modular BASIC DNA assembly framework. We anticipate that mARi-based genetic control within an extensible DNA assembly framework will facilitate metabolic engineering, layered genetic control, and advanced genetic circuit applications.
Modulating gene expression in breast cancer via DNA secondary structure and the CRISPR toolbox
Authors: Kretzmann Jessica A , Irving Kelly L , Smith Nicole M , Evans Cameron W
Published: December 2021

Breast cancer is the most commonly diagnosed malignancy in women, and while the survival prognosis of patients with early-stage, non-metastatic disease is ∼75%, recurrence poses a significant risk and advanced and/or metastatic breast cancer is incurable. A distinctive feature of advanced breast cancer is an unstable genome and altered gene expression patterns that result in disease heterogeneity. Transcription factors represent a unique therapeutic opportunity in breast cancer, since they are known regulators of gene expression, including gene expression involved in differentiation and cell death, which are themselves often mutated or dysregulated in cancer. While transcription factors have traditionally been viewed as ‘undruggable’, progress has been made in the development of small-molecule therapeutics to target relevant protein–protein, protein–DNA and enzymatic active sites, with varying levels of success. However, non-traditional approaches such as epigenetic editing, transcriptional control via CRISPR/dCas9 systems, and gene regulation through non-canonical nucleic acid secondary structures represent new directions yet to be fully explored. Here, we discuss these new approaches and current limitations in light of new therapeutic opportunities for breast cancers.
Differential analysis of binarized single-cell RNA sequencing data captures biological variation
Authors: Bouland Gerard A , Mahfouz Ahmed , Reinders Marcel J T
Published: December 2021

Single-cell RNA sequencing data is characterized by a large number of zero counts, yet there is growing evidence that these zeros reflect biological variation rather than technical artifacts. We propose to use binarized expression profiles to identify the effects of biological variation in single-cell RNA sequencing data. Using 16 publicly available and simulated datasets, we show that a binarized representation of single-cell expression data accurately represents biological variation and reveals the relative abundance of transcripts more robustly than counts.
Predicting Non-Adherence With Very Low Nicotine Content Cigarettes Among Adults With Serious Mental Illness Who Smoke
Authors: Reed Grace L , Colby Suzanne M , Sokolovsky Alexander W , Snell L Morgan , DeAtley Teresa , Tidey Jennifer W
Published: December 2021

Introduction

Reducing the nicotine content of cigarettes is a promising policy intervention to decrease cigarette dependence among people who smoke. Randomized trials support the potential efficacy of a reduced nicotine product standard for cigarettes. However, interpretation of such trials is challenged by incomplete adherence to the randomized treatment assignment, as some participants may continue to use commercial cigarettes not provided by the trial. The current study examined prevalence and predictors of non-adherence among trial participants with serious mental illness (SMI).

Aims and Methods

Adults with SMI who smoke daily and were not trying to quit (N = 58) were randomized to receive very low nicotine content (VLNC) or normal nicotine content cigarettes over 6 weeks. We investigated predictors of biologically assessed non-adherence in participants assigned to VLNC cigarettes (n = 30). Predictors included subjective responses to VLNC cigarettes, baseline nicotine dependence and dependence motives, and psychiatric symptom severity. We fit a series of linear models regressing non-adherence metrics onto covariates (gender; menthol preference) and focal predictors.

Results

Nearly all participants (96%) were estimated to be less than completely adherent to VLNC cigarettes. Lower enjoyment ratings of respiratory tract sensations of VLNC cigarettes predicted a greater degree of non-adherence (b = −.40, SE = .14, 95% CI: −0.71, −0.10).

Conclusions

Less positive subjective response to smoking VLNC cigarettes was the only significant predictor of incomplete adherence among individuals with SMI, consistent with prior research in a general population sample. This suggests the potential for shared strategies to help different smoking populations adjust to a reduced nicotine product standard.

Implications

Results offer preliminary insight into potential barriers to adherence in SMI populations. Adherence might be enhanced by supplementing VLNC cigarettes with alternative sources of non-combusted nicotine, paired with educational campaigns to encourage quitting or switching to less harmful products. Future studies should replicate these analyses in a larger sample of individuals with SMI who smoke.
Functional Analyses of the Two Distinctive Types of Two-Pore Channels and the Slow Vacuolar Channel in Marchantia polymorpha
Authors: Hashimoto Kenji , Koselski Mateusz , Tsuboyama Shoko , Dziubinska Halina , Trębacz Kazimierz , Kuchitsu Kazuyuki
Published: December 2021

The two-pore channel (TPC) family is widely conserved in eukaryotes. Many vascular plants, including Arabidopsis and rice, possess a single TPC gene which functions as a slow vacuolar (SV) channel—voltage-dependent cation-permeable channel located in the vacuolar membrane (tonoplast). On the other hand, a liverwort Marchantia polymorpha genome encodes three TPC homologs: MpTPC1 is similar to TPCs in vascular plants (type 1 TPC), while MpTPC2 and MpTPC3 are classified into a distinctive group (type 2 TPC). Phylogenetic analysis suggested that the type 2 TPC emerged before the land colonization in plant evolution and was lost in vascular plants and hornworts. All of the three MpTPCs were shown to be localized at the tonoplast. We generated knockout mutants of tpc1, tpc2, tpc3 and tpc2 tpc3 double mutant by clustered regularly interspaced short palindromic repeats/Cas9 genome editing and performed patch-clamp analyses of isolated vacuoles. The SV channel activity was abolished in the Mptpc1 loss-of-function mutant (Mptpc1-1KO), while Mptpc2-1KO, Mptpc3-1KO and Mptpc2-2/tpc3-2KO double mutant exhibited similar activity to the wild type, indicating that MpTPC1 (type 1) is solely responsible for the SV channel activity. Activators of mammalian TPCs, phosphatidylinositol-3,5-bisphosphate and nicotinic acid adenine dinucleotide phosphate, did not affect the ion channel activity of any MpTPCs. These results indicate that the type 1 TPCs, which are well conserved in all land plant species, encode the SV channel, while the type 2 TPCs likely encode other tonoplast cation channel(s) distinct from the SV channel and animal TPCs.
Receptor-like cytoplasmic kinases PBL34/35/36 are required for CLE peptide-mediated signaling to maintain shoot apical meristem and root apical meristem homeostasis in Arabidopsis
Authors: Wang Wenping , Hu Chong , Li Xiaonan , Zhu Yafen , Tao Liang , Cui Yanwei , Deng Dingqian , Fan Xiaoxuan , Zhang Hong , Li Jia , Gou Xiaoping , Yi Jing
Published: December 2021

Shoot apical meristem (SAM) and root apical meristem (RAM) homeostasis is tightly regulated by CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION-related (CLE) peptide signaling. However, the intracellular signaling components after CLV3 is perceived by the CLV1–CLV3-INSENSITIVE KINASE (CIK) receptor complex and CLE25/26/45 are sensed by the BARELY ANY MERISTEM (BAM)–CIK receptor complex are unknown. Here, we report that PBS1-LIKE34/35/36 (PBL34/35/36), a clade of receptor-like cytoplasmic kinases, are required for both CLV3-mediated signaling in the SAM and CLE25/26/45-mediated signaling in the RAM. Physiological assays showed that the SAM and RAM of pbl34 pbl35 pbl36 were resistant to CLV3 and CLE25/26/45 treatment, respectively. Genetic analyses indicated that pbl34 pbl35 pbl36 greatly enhanced the SAM defects of clv2 and rpk2 but not clv1, and did not show additive effects with bam3 and cik2 in the RAM. Further biochemical assays revealed that PBL34/35/36 interacted with CLV1, BAM1/3, and CIKs, and were phosphorylated by CLV1 and BAM1. All these results suggest that PBL34/35/36 act downstream of CLV1 and BAM1/3 to mediate the CLV3 and CLE25/26/45 signals in maintaining SAM and RAM homeostasis, respectively. Our findings shed light on how CLE signals are transmitted intracellularly after being perceived by cell surface receptor complexes.
A Novel circUBR4/miR-491-5p/NRP2 ceRNA Network Regulates Oxidized Low-density Lipoprotein-induced Proliferation and Migration in Vascular Smooth Muscle Cells
Authors: Peng Huaiyu , Liu Shunfan , Li Yi , Wang Chengyang , Zhong Yongjin
Published: December 2021

Vascular smooth muscle cells (VSMCs) play critical roles in the progression of atherosclerosis. Circular RNA (circRNA) ubiquitin protein ligase E3 component n-recognin 4 (circUBR4) has been shown to regulate VSMC migration and proliferation. In this study, we sought to identify the mechanism in the regulation of circUBR4. CircUBR4, microRNA (miR)-491-5p, and Neuropilin-2 (NRP2) were quantified by quantitative real-time polymerase chain reaction (PCR) and western blot. Cell proliferation was evaluated by Cell Counting Kit-8 and 5-Ethynyl-2′-Deoxyuridine assays. Cell migration was examined by wound-healing and transwell invasion assays. The direct relationship between miR-491-5p and circUBR4 or NRP2 was validated by dual-luciferase reporter and RNA immunoprecipitation assays. Our data indicated that in VSMCs, ox-LDL induced circUBR4 expression. Silencing endogenous circUBR4 attenuated VSMC proliferation and migration induced by ox-LDL. Mechanistically, circUBR4 targeted miR-491-5p by pairing to miR-491-5p. Moreover, miR-491-5p was identified as a downstream mediator of circUBR4 function in ox-LDL–treated VSMCs. NRP2 was a direct target of miR-491-5p, and circUBR4 acted as a competing endogenous RNA for miR-491-5p to regulate NRP2 expression. In addition, NRP2 was a functionally downstream effector of miR-491-5p in regulating ox-LDL–evoked VSMC proliferation and migration. Our findings identify a new competing endogenous RNA network, the circUBR4/miR-491-5p/NRP2 axis, for the regulation of circUBR4 in VSMC migration and proliferation.
Should all patients undergoing genetic testing for hereditary breast cancer syndromes be offered a multigene panel?
Authors: Silver Erica L. , Niell-Swiller Mariana
Published: December 2021

Purpose of review

We aim to demonstrate why multigene panel testing (MGPT) is the superior testing option for individuals undergoing hereditary cancer genetic testing. We will outline the clinical benefits and possible limitations of MGPT for individuals at risk for a hereditary cancer syndrome.

Recent findings

The use of MGPT increases the identification of individuals with hereditary cancer syndromes. Recent studies continue to prove that MGPT is a superior option to single gene/or syndrome testing. MGPT is a cost-effective testing approach for those meeting criteria for genetic testing. Individuals interested in MGPT should understand the benefits and limitations of this approach, including an increase in variant identification and possible incidental findings. MGPT also increases the number of individuals who would benefit from cascade testing.

MGPT should be considered as the standard approach to hereditary cancer genetic testing as opposed to single gene or single syndrome testing. MGPT identifies a larger proportion of individuals with a hereditary cancer syndrome and leads to better management and improved uptake of cascade testing.