bluuebunny/crossref_metadata_2025 huggingface dataset:
Blowout Fracture Assessment Based on Computed Tomography and Endoscopy: The Effectiveness of Endoscopy for Fracture Repair
Authors: Hong Suji , Kim Joohyun , Baek Sehyun
Published: October 2021

The purpose of this study was to compare the configuration of blowout fracture observed through orbital computed tomography (CT) and endoscopy, then present the effectiveness of using an endoscope in reconstruction surgery of blowout fracture. We retrospectively reviewed the clinical records of 337 patients who underwent reconstruction surgery of blowout fracture between January 2017 and December 2020 in the Department of Ophthalmology at Korea University Guro Hospital. The patients were categorized into 3 groups based on preoperative CT findings as follows: combined orbital medial and floor wall fractures, trapdoor fractures, and large blowout fractures. The images obtained through CT and endoscopy were compared among the 3 groups. Endoscopy helped identify herniated soft tissue and posterior fracture margins, and it also provides better magnification and a brighter view of the posterior aspects of the fracture site. Furthermore, endoscopy can also provide educational opportunities to visualize the fracture site and help trainees understand the surgical procedure approach or orbital anatomy. Based on our results, we suggest using an endoscope during blowout fracture surgery as an effective approach to reduce postoperative complications due to endoscopy's advantages in clear visualization of the fracture site during operation.
Combined Treatment of High-Flow Scalp Arteriovenous Malformations
Authors: Janssen Pierce L. , Taub Peter J. , Marayati Naoum Fares , Shigematsu Tomoyoshi , Berenstein Alejandro
Published: October 2021

Introduction:

Appropriate treatment of scalp arteriovenous malformations (SAVMs) remains largely unclear given the rarity of reported cases. This single-institution case series presents consecutive patients with extracranial SAVMs and long-term follow up.

The primary aim of this study was to review treatment decisions, evaluate clinical outcomes, and compare our experience to available literature in order to better understand SAVMs and improve future outcomes.

Materials and Methods:

A retrospective review of consecutive patients with extracranial SAVMs between January 2015 and December 2019 was performed. Treatment factors of interest included embolization method, embolic agents, and decision to proceed with surgical resection. Relevant clinical outcomes included recurrence rates, cure rates, and complications.

Results:

Seven patients were included in the present series. Satisfactory outcomes were ultimately achieved for all 7 patients using embolization with or without combined surgical resection. Embolizations performed in combination with resection were curative in 4 of 4 cases (100%). Embolizations performed without resection were curative in 0 of 4 cases (0%), satisfactory in 2 of 4 cases (50%), and unsatisfactory in 2 of 4 cases (50%).

Discussion:

All SAVM patients in this series were treated satisfactorily using embolization with or without operative resection. This study strongly suggests that embolization combined with surgical resection during the same admission yields the best treatment outcomes for SAVMs, specifically demonstrating lower rates of recurrence and embolization-related complications. Decisions on whether or not to proceed with resection should be made by the interventional radiologist, the plastic surgeon, and the patient together.
The Impact of Magnetic Sphincter Augmentation (MSA) on Esophagogastric Junction (EGJ) and Esophageal Body Physiology and Manometric Characteristics
Authors: Ayazi Shahin , Schwameis Katrin , Zheng Ping , Newhams Kirsten , Myers Brittney M. , Grubic Andrew D. , Hoppo Toshitaka , Jobe Blair A.
Published: October 2021

Objective:

To evaluate the impact of MSA on lower esophageal sphincter (LES) and esophageal body using high resolution impedance manometry.

Background:

MSA is an effective treatment in patients with gastroesophageal reflux disease, but there is limited data on its impact on esophageal functional physiology.

Methods:

Patients who underwent MSA were approached 1-year after surgery for objective foregut testing consists of upper endoscopy, esophagram, high resolution impedance manometry, and esophageal pH-monitoring. Postoperative data were then compared to the preoperative measurements.

Results:

A total of 100 patients were included in this study. At a mean follow up of 14.9(10.1) months, 72% had normalization of esophageal acid exposure. MSA resulted in an increase in mean LES resting pressure [29.3(12.9) vs 25(12.3), P < 0.001]. This was also true for LES overall length [2.9(0.6) vs 2.6(0.6), P = 0.02] and intra-abdominal length [1.2(0.7) vs 0.8(0.8), P < 0.001]. Outflow resistance at the EGJ increased after MSA as demonstrated by elevation in intrabolus pressure (19.6 vs 13.5 mmHg, P < 0.001) and integrated relaxation pressure (13.5 vs 7.2, P < 0.001). MSA was also associated with an increase in distal esophageal body contraction amplitude [103.8(45.4) vs 94.1(39.1), P = 0.015] and distal contractile integral [2647.1(2064.4) vs 2099.7(1656.1), P < 0.001]. The percent peristalsis and incomplete bolus clearance remained unchanged (P = 0.47 and 0.08, respectively).

Conclusions:

MSA results in improvement in the LES manometric characteristics. Although the device results in an increased outflow resistance at the EGJ, the compensatory increase in the force of esophageal contraction will result in unaltered esophageal peristaltic progression and bolus clearance.
Antiseptic Skin Agents to Prevent Surgical Site Infection After Incisional Surgery
Authors: Smith Stephen Ridley , Gani Jon , Carroll Rosemary , Lott Natalie , Hampton Jacob , Oldmeadow Christopher , Clapham Mathew , Attia John
Published: October 2021

Objective:

To compare SSI rates between the skin preparation agents: PI-Aq, povidone-iodine with alcohol (PI-Alc), and chlorhexidine with alcohol (C-Alc).

Background:

Guidelines suggest that alcohol-containing chlorhexidine solutions are the gold standard for skin preparation before surgery. It remains difficult to determine whether it is the chlorhexidine component or the addition of alcohol that confers the most benefit.

Methods:

We conducted a multicenter, prospective, combined non-inferiority (PI-Alc vs C-Alc) and superiority (PI-Alc vs PI-Aq) randomized clinical trial. Participants were randomized 1:1:1 to receive either C-Alc, PI-Alc, or PI-Aq. The primary outcome was SSI rate as defined by the Centers for Disease Control. Secondary outcomes were complication rates, length of hospital stay, readmissions, and skin reactions.

Results:

Between January 2015 and December 2018, 3213 patients were randomized (C-Alc: 1076, PI-Alc: 1075, and PI-Aq: 1062). Mean age of participants was 57% and 55% were female. SSI rates were: C-Alc 11.09%, PI-Alc 10.88%, and PI-Aq 12.56%. PI-Alc was found to be non-inferior to C-Alc (mean difference, −0.21%; 95% confidence interval, −2.85 to 2.44; P = 0.0009 non-inferiority), whereas PI-Alc was not superior to PI-Aq (mean difference, −1.68%; 95% confidence interval, −4.40 to 1.05; P = 0.2302). There were no differences seen in secondary outcomes between groups and no treatment related adverse events or deaths occurred.

Conclusions:

PI-Alc is non-inferior to C-Alc and not superior to PI-Aq. This is at odds with current guidelines that suggest alcohol-based chlorhexidine solutions should routinely be used for surgical skin preparation.

Trial Registration:

Australia and New Zealand Clinical Trials Registry: ANZCTRN12615000021571. www.anzctr.org.au
Liver Transplantation as Definitive Treatment of Post-cholecystectomy Bile Duct Injury
Authors: Vilatobá Mario , Chávez-Villa Mariana , Figueroa-Méndez Rodrigo , Domínguez-Rosado Ismael , Cruz-Martínez Rodrigo , Leal-Villalpando Rafael P. , García-Juárez Ignacio , Mercado Miguel A.
Published: October 2021

Objective:

To analyze the perioperative and long-term outcomes of patients undergoing LT due to BDI in a tertiary care center.

Background:

BDI is associated with significant morbidity and long-term impact on quality of life. LT represents the only possibility of a cure in patients with BDI who develop SBC.

Methods:

Retrospective cohort study from a prospective LT database. Between 2008 and 2019, patients with SBC due to BDI after cholecystectomy and requiring LT were identified. Perioperative and long-term outcomes were analyzed.

Results:

Among 354 LT, 12 patients underwent LT to treat post-cholecystectomy BDI and accounted for 3.4% of all LT. The median time from BDI to SBC diagnosis was 9.3 years (2.4–14). The mean time from SBC to inclusion on the waitlist was 2.4years (± 2.2). Postoperative complications occurred in 11 patients (91.6%); mainly infectious (9/12 patients, 75%), followed by renal complications (4/12 patients, 33.3%). Only 2 patients developed major complications, which were the patients who died, resulting in a 90-day mortality of 16.7%. After a mean follow-up of 40.3 months (± 42.2) survival at 1, 3, and 5 years was 83%.

Conclusions:

Although BDI is an unusual indication for LT worldwide, it accounted for 3.4% of all LT in our center. Although postoperative mortality remains high, LT is the only possibility of a cure, with acceptable long-term outcomes. Early referral to a tertiary care center is essential to avoid long-term complications of BDI, such as SBC.
Objective Activity Parameters Track Patient-specific Physical Recovery Trajectories After Surgery and Link With Individual Preoperative Immune States
Authors: Fallahzadeh Ramin , Verdonk Franck , Ganio Ed , Culos Anthony , Stanley Natalie , Maric Ivana , Chang Alan L. , Becker Martin , Phongpreecha Thanaphong , Xenochristou Maria , De Francesco Davide , Espinosa Camilo , Gao Xiaoxiao , Tsai Amy , Sultan Pervez , Tingle Martha , Amanatullah Derek F. , Huddleston James I. , Goodman Stuart B. , Gaudilliere Brice , Angst Martin S. , Aghaeepour Nima
Published: October 2021

Objective:

The longitudinal assessment of physical function with high temporal resolution at a scalable and objective level in patients recovering from surgery is highly desirable to understand the biological and clinical factors that drive the clinical outcome. However, physical recovery from surgery itself remains poorly defined and the utility of wearable technologies to study recovery after surgery has not been established.

Background:

Prolonged postoperative recovery is often associated with long-lasting impairment of physical, mental, and social functions. Although phenotypical and clinical patient characteristics account for some variation of individual recovery trajectories, biological differences likely play a major role. Specifically, patient-specific immune states have been linked to prolonged physical impairment after surgery. However, current methods of quantifying physical recovery lack patient specificity and objectivity.

Methods:

Here, a combined high-fidelity accelerometry and state-of-the-art deep immune profiling approach was studied in patients undergoing major joint replacement surgery. The aim was to determine whether objective physical parameters derived from accelerometry data can accurately track patient-specific physical recovery profiles (suggestive of a ‘clock of postoperative recovery’), compare the performance of derived parameters with benchmark metrics including step count, and link individual recovery profiles with patients’ preoperative immune state.

Results:

The results of our models indicate that patient-specific temporal patterns of physical function can be derived with a precision superior to benchmark metrics. Notably, 6 distinct domains of physical function and sleep are identified to represent the objective temporal patterns: ‘‘activity capacity’’ and ‘‘moderate and overall activity (declined immediately after surgery); ‘‘sleep disruption and sedentary activity (increased after surgery); ‘‘overall sleep’’, ‘‘sleep onset’’, and ‘‘light activity’’ (no clear changes were observed after surgery). These patterns can be linked to individual patients preopera-tive immune state using cross-validated canonical-correlation analysis. Importantly, the pSTAT3 signal activity in monocytic myeloid-derived suppressor cells predicted a slower recovery.

Conclusions:

Accelerometry-based recovery trajectories are scalable and objective outcomes to study patient-specific factors that drive physical recovery.
What the COVID-19 pandemic reveals about science, policy and society
Authors: Ball Philip
Published: October 2021

The global COVID-19 pandemic of 2020–2021 required politicians to work alongside and depend on scientists more closely than any other event in recent times. It also saw science unfold in real time under intense public scrutiny. As a result, it highlighted as never before the ways in which science interacts with policy-making and with society, showing with sometimes painful clarity that science does not operate in a social or political vacuum. With the advent of vaccines against the coronavirus that has caused the pandemic, science has come to be seen as something of a saviour. But at other times and in other contexts it has also been cast as a villain and an inconvenience, and has run into stark conflict with political leadership. In this article, I consider these issues with particular reference to the situation in the UK—which, as with any nation, illustrated some considerations of more general applicability but also had aspects unique to this country. I argue that there are many lessons to be learnt, and that, as this is surely not the last infectious-disease crisis of such magnitude that the world will face, we must hope they will be heeded.
How COVID-19 has changed medical research funding
Authors: Chinnery Patrick F. , Pearce Jonathan J. , Kinsey Anna M. , Jenkinson Joanna M. , Wells Glenn , Watt Fiona M.
Published: October 2021

Here, we consider how the lessons we learned in 2020 from funding COVID-19 research could have a long-term impact on the way that we fund medical research. We look back at how UK government funding for COVID-19 medical research evolved, beginning with the early calls for proposals in February that pump-primed funding for vaccines and therapeutics, and culminating in the launch of the government's National Core Studies programme in October. We discuss how the research community mobilized to submit and review grants more rapidly than ever before, against a background of laboratory and office closures. We also highlight the challenges of running clinical trials as the number of hospitalized patients fluctuated with different waves of the disease.
A year of living distantly: global trends in the use of stay-at-home orders over the first 12 months of the COVID-19 pandemic
Authors: Phillips Toby , Zhang Yuxi , Petherick Anna
Published: October 2021

During the first year of the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) were the main pillar of defence to protect human society against the virus. While a variety of modelling studies try to quantify the effects of NPIs, this paper investigates when and how national and subnational governments have taken actions. We observe longitudinal changes in the global pattern of policymaking to combat the COVID-19 pandemic, with a particular focus on stay-at-home orders. Drawing on data from the Oxford COVID-19 Government Response Tracker, we show several important trends. First, while national governments exhibited a strong alignment in policy settings initially in March and April 2020, their cross-country policy heterogeneity has grown since May 2020, although countries within global regions continue to display similarities in their approaches. Second, most governments that have implemented multiple stay-at-home orders over the course of the pandemic have become less sensitive to case levels (insofar as they implement subsequent restrictions at progressively higher case levels), apart from a small number of contrast cases which have mostly eliminated domestic community transmission. Third, pandemic policies are increasingly specific to subnational levels, and there is often significant heterogeneity with regard to policy approaches even within the same country.
Relating evolutionary selection and mutant clonal dynamics in normal epithelia
Authors: Hall Michael W. J. , Jones Philip H. , Hall Benjamin A.
Published: October 2021

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In the normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behaviour. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental dataset showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.
Impacts of vacancy-induced polarization and distortion on diffusion in solid electrolyte Li
3
OCl
Authors: Mehmedović Zerina , Wei Vanessa , Grieder Andrew , Shea Patrick , Wood Brandon C. , Adelstein Nicole
Published: October 2021

Lithium-rich oxychloride antiperovskites are promising solid electrolytes for enabling next-generation batteries. Here, we report a comprehensive study varying Li
+
concentrations in

Li

3

OCl

using
ab initio
molecular dynamics simulations. The simulations accurately capture the complex interactions between Li
+
vacancies (

V

Li

′

), the dominant mobile species in

Li

3

OCl

. The

V

Li

′

polarize and distort the host lattice, inducing additional non-vacancy-mediated diffusion mechanisms and correlated diffusion events that reduce the activation energy barrier at concentrations as low as 1.5%

V

Li

′

. Our analyses of discretized diffusion events in both space and time illustrate the critical interplay between correlated dynamics, polarization and local distortion in promoting ionic conductivity in

Li

3

OCl

.

This article is part of the Theo Murphy meeting issue ‘Understanding fast-ion conduction in solid electrolytes’.
Paradigms of frustration in superionic solid electrolytes
Authors: Wood Brandon C. , Varley Joel B. , Kweon Kyoung E. , Shea Patrick , Hall Alex T. , Grieder Andrew , Ward Michael , Aguirre Vincent P. , Rigling Dylan , Lopez Ventura Eduardo , Stancill Chimara , Adelstein Nicole
Published: October 2021

Superionic solid electrolytes have widespread use in energy devices, but the fundamental motivations for fast ion conduction are often elusive. In this Perspective, we draw upon atomistic simulations of a wide range of superionic conductors to illustrate some ways frustration can lower diffusion cation barriers in solids. Based on our studies of halides, oxides, sulfides and hydroborates and a survey of published reports, we classify three types of frustration that create competition between different local atomic preferences, thereby flattening the diffusive energy landscape. These include chemical frustration, which derives from competing factors in the anion–cation interaction; structural frustration, which arises from lattice arrangements that induce site distortion or prevent cation ordering; and dynamical frustration, which is associated with temporary fluctuations in the energy landscape due to anion reorientation or cation reconfiguration. For each class of frustration, we provide detailed simulation analyses of various materials to show how ion mobility is facilitated, resulting in stabilizing factors that are both entropic and enthalpic in origin. We propose the use of these categories as a general construct for classifying frustration in superionic conductors and discuss implications for future development of suitable descriptors and improvement strategies.

This article is part of the Theo Murphy meeting issue ‘Understanding fast-ion conduction in solid electrolytes’.
Cellular and Antibody Immunity after COVID-19 Vaccination at >4-Month Follow Up in Immunocompetent and Immunocompromised Subjects
Authors: Sindhi Rakesh , Ashokkumar Chethan , Singh Vineeta , Spishock Brianna , Saunders Maggie , Mabasa Angelo , Sindhi Elizabeth , Sethi Pradeep , Reddy Ashok , Subramaniam Shankar , Nibhanupudy Bobby
Published: October 2021

We evaluated post-vaccination immunity after COVID-19 vaccination with serial changes in cellular and antibody responses to the spike protein S, its S2 component which is conserved between SARS-CoV-2 and human coronaviruses, and the S1 component, which is specific to SARS-CoV-2 and also contains its receptor binding domain (RBD). In 21 healthy immunocompetent subjects all of whom demonstrated circulating IgG antibodies 4 months after mRNA1273 or BNT162b vaccination, a) the strength of S-IgG was stable while RBD-IgG declined, b) S2-reactive B-cell frequencies increased progressively (p=0.002) c) S1-reactive CD8+T-cells and CD19+B-cells were undetectable after a transient increase, and d) monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSC, PMN-MDSC) increased after the first vaccine dose. Compared with 4-month measurements from immunocompetent subjects, single samples from 20 vaccinated immunocompromised (IC) subjects revealed a) circulating S-IgG and RBD-IgG in 13 (65%) and 9 (45%) subjects, respectively, b) no differences in S2-reactive T- and B-cells, c) undetectable S1-reactive T- and B-cells, and d) fewer S-reactive CD8+T-cells and CD19+B-cells (p<0.05). Among 11 IC recipients who failed to make RBD-IgG, frequencies of PMN-MDSC were significantly higher (p<0.0004) compared with IC or immunocompetent subjects with RBD-IgG. COVID-19 vaccination induces stable antibodies to the spike protein and expands circulating B-cells reactive to the conserved spike protein sequence in immunocompetent subjects. MDSC which are known to suppress T- and B-cells, and which increase after vaccination, may limit post-vaccination responses especially among immunocompromised subjects. Antibody and cellular responses to SARS-CoV-2-specific spike antigenic sequences appear to be less durable.
Impact of the COVID-19 pandemic on mental healthcare consultations among children and adolescents in Norway: a nationwide registry study
Authors: Evensen Miriam , Hart Rannveig , Godøy Anna Aasen , Hauge Lars Johan , Lund Ingunn Olea , Knudsen Ann Kristin Skrindo , Grøtting Maja Weemes , Surén Pål , Reneflot Anne
Published: October 2021

The COVID-19 pandemic and its associated restrictions may have affected children and adolescent’s mental health adversely. We cast light on this question using primary and specialist consultations data for the entire population of children 6-19 years in Norway (N=908 272). Our outcomes are the monthly likelihood of having a consultation or hospitalization related to mental health problems and common mental health diagnoses. We compared a pandemic (2019-2021) to a pre-pandemic (2017-2019) cohort using event study and difference-in-difference designs that separate the shock of the pandemic from linear period trends and seasonal variation. We found temporary reductions in all mental health consultations during lockdown in spring 2020. In fall 2020 and winter 2021, consultation volumes in primary care increased, stabilizing at a higher level in 2021. Consultations in specialist care increased from spring 2021. Our findings could suggest a worsening of mental health among adolescents.
Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders
Authors: Pintacuda Greta , Hsu Yu-Han H. , Tsafou Kalliopi , Li Ka Wan , Martín Jacqueline M. , Riseman Jackson , Biagini Julia C. , Ching Joshua K.T. , Gonzalez-Lozano Miguel A. , Egri Shawn B. , Jaffe Jake , Smit August B. , Fornelos Nadine , Eggan Kevin C. , Lage Kasper
Published: October 2021

Sequencing studies of autism spectrum disorders (ASDs) have identified numerous risk genes with enriched expression in the human brain, but it is still unclear how these genes converge into cell type-specific networks and how their encoded proteins mechanistically contribute to ASDs. To address this question, we performed brain cell type-specific interaction proteomics to build a protein-protein interaction network for 13 ASD risk genes in human excitatory neurons derived from iPS cells. The network contains many (>90%) interactions not reported in the literature and is enriched for transcriptionally perturbed genes observed in layer 2/3 cortical neurons of ASD patients, indicating that it can be explored for ASD-relevant biological discovery. We leveraged the network dataset to show that the brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and characterized a PTEN-AKAP8L interaction that influences neuronal growth through the mTOR pathway. The IGF2BP1-3 complex emerges as a point of convergence in the network, and we showed that this complex is involved in a transcriptional circuit concentrating both common and rare variant risk of ASDs. Finally, we found the network itself enriched for ASD rare variant risk, indicating that it can complement genetic datasets for prioritizing additional risk genes. Our findings establish brain cell type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in ASDs and illustrate how both individual and convergent interactions lead to biological insights into the disease.
Virulence constrains transmission even in the absence of a genetic trade-off
Authors: Godinho Diogo P. , Rodrigues Leonor R. , Lefevre Sophie , Delteil Laurane , Mira André F. , Fragata Inês R. , Magalhães Sara , Duncan Alison B.
Published: October 2021

The virulence-transmission trade-off predicts that parasite fitness peaks at intermediate virulence. However, whether this relationship is driven by the environment or genetically determined and if it depends on transmission opportunities remains unclear. We tackled these issues using inbred lines of the macro-parasitic spider-miteTetranychus urticae. When transmission was not possible during the infection period, we observed a hump-shaped relationship between virulence and parasite fitness, as predicted by theory. This was environmentally driven, as no genetic correlation between traits was detected. However, when transmission to uninfected hosts occurred during the infection period, virulence was positively, environmentally and genetically correlated with parasite fitness. Therefore, the virulence-transmission trade-off depends on within-host dynamics and on the timing of transmission, rather than on a genetic correlation. This fundamental correlation may thus be easier to manipulate than previously thought.
Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis
Authors: Ollinger Tomye L. , Vu Bao , Murante Daniel , Parker Josie E. , Simonicova Lucia , Doorley Laura , Stamnes Mark A. , Kelly Steven L. , Rogers P. David , Moye-Rowley W. Scott , Krysan Damian J.
Published: October 2021

Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress induced transcription factors such as Upc2 and Upc2A as well as homologs of Sterol Response Element Binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other Candida spp., we used a serial passaging strategy to isolate suppressors of the fluconazole hypersusceptibility of a upc2AΔ deletion mutant. This led to the identification of loss of function mutants in two genes: ROX1, the homolog of a hypoxia gene transcriptional suppressor in Saccharomyces cerevisiae, and CST6, a transcription factor that is involved in the regulation of carbon dioxide response in C. glabrata. Here, we describe a detailed analysis of the genetic interaction of ROX1 and UPC2A. In the presence of fluconazole, loss of Rox1 function restores ERG11 expression to the upc2AΔ mutant and inhibits the expression of ERG3 and ERG6, leading to increased levels or ergosterol and decreased levels of the toxic sterol, 14α methyl-ergosta-8,24(28)-dien-3β, 6α-diol, relative to upc2AΔ. Our observations establish that Rox1 is a negative regulator of ERG gene biosynthesis and indicate that a least one additional positive transcriptional regulator of ERG gene biosynthesis must be present in C. glabrata.

Importance

Candida glabrata is one of the most important human fungal pathogens and has reduced susceptibility to azole class inhibitors of ergosterol biosynthesis. Although ergosterol is the target of two of the three classes of antifungal drugs, relatively little is known about the regulation of this critical cellular pathway. Sterols are both essential components of the eukaryotic plasma membrane and potential toxins; therefore, sterol homeostasis is critical for cell function. Here, we identified two new negative regulators of C. glabrata of ergosterol (ERG) biosynthesis gene expression. Our results also indicate that in addition to Upc2A, the only known activator of ERG genes, additional positive regulators of this pathway must exist.s
Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes
Authors: Zhou Xueya , Feliciano Pamela , Wang Tianyun , Astrovskaya Irina , Shu Chang , Hall Jacob B. , Obiajulu Joseph U. , Wright Jessica , Murali Shwetha , Xu Simon Xuming , Brueggeman Leo , Thomas Taylor R. , Marchenko Olena , Fleisch Christopher , Barns Sarah D. , Snyder LeeAnne Green , Han Bing , Chang Timothy S. , Turner Tychele N. , Harvey William , Nishida Andrew , O’Roak Brian J. , Geschwind Daniel H. ,   The SPARK Consortium, Michaelson Jacob J. , Volfovsky Natalia , Eichler Evan E. , Shen Yufeng , Chung Wendy K.
Published: October 2021

Despite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.
Neandertal introgression dissects the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes
Authors: Dannemann Michael , Milaneschi Yuri , Yermakovich Danat , Stiglbauer Victoria , Friese Manuel A. , Otte Christian , Penninx Brenda W.J.H. , Kelso Janet , Gold Stefan M.
Published: October 2021

Background

Advances have recently been made in identifying the genetic basis of psychiatric and neurological disorders, however, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm.

Methods

We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions as a proxy for disease, and related non-disease phenotypes in the UK biobank (UKBB), the NESDA cohort and the Biobank Japan.

Results

While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumptions. Several of these associations were also observed in NESDA and the Biobank Japan, suggesting their evolutionary relevance across different ancestry backgrounds. Intriguingly, in some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide.

Conclusions

Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute pathology in modern humans, possibly due to changes in lifestyle and maladaptation.
Prospective predictors of risk and resilience trajectories during the early stages of the COVID-19 pandemic: a longitudinal study
Authors: Shilton Tal , Mancini Anthony D , Perlstein Samantha , Didomenico Grace E , Visoki Elina , Greenberg David M , Brown Lily A , Gur Raquel E , Waller Rebecca , Barzilay Ran
Published: October 2021

Background

The COVID-19 pandemic is a rapidly evolving stressor with significant mental health consequences. We aimed to delineate distinct anxiety-response trajectories during the early stages of the pandemic and to identify baseline risk and resilience factors as predictors of anxiety responses.

Methods

Using a crowdsourcing website, we enrolled 1,362 participants, primarily from the United States (n = 1064) and Israel (n = 222) over three time-points from April-September 2020. We used latent growth mixture modeling to identify anxiety trajectories over time. Group comparison and multivariate regression models were used to examine demographic and risk and resilience factors associated with class membership.

Results

A four-class model provided the best fit. The resilient trajectory (stable low anxiety) was the most common (n = 961, 75.08%), followed by chronic anxiety (n = 149, 11.64%), recovery (n = 96, 7.50%) and delayed anxiety (n = 74, 5.78%). While COVID-19 stressors did not differ between trajectories, resilient participants were more likely to be older, living with another person and to report higher income, more education, fewer COVID-19 worries, better sleep quality, and more dispositional resilience factors at baseline. Multivariate analyses suggested that baseline emotion regulation capabilities and low conflictual relationships uniquely distinguished participants in distinct trajectories.

Conclusions

Consistent with prior resilience research following major adversities, a majority of individuals showed stable low levels of low anxiety in response to the COVID-19 pandemic. Knowledge about dispositional resilience factors may prospectively inform mental health trajectories early in the course of ongoing adversity.
Level and determinants of willingness to pay for rapid COVID-19 testing delivered through private retail pharmacies in Kenya
Authors: Kazungu Jacob , Mumbi Audrey , Kilimo Precious , Vernon Jessica , Barasa Edwine , Mugo Peter
Published: October 2021

Introduction

To support the government response to the coronavirus disease 2019 (COVID-19) pandemic, accessible and sustainable testing approaches are needed. Private retail pharmacies are a key channel through which communities can access COVID-19 testing. We examined the level and determinants of the willingness to pay (WTP) for rapid COVID-19 testing delivered through private retail pharmacies in Kenya.

Methods

Data was collected following a cross-sectional double-bounded dichotomous choice contingent valuation survey across 341 clients visiting five private retail pharmacies in Nairobi, Kisumu and Siaya counties.

Results

Our findings indicate mean and median WTP levels of KES 611 (US$ 5.59) and KES 506 (US$ 4.63), respectively. Estimated WTP varied across counties and increased with household income and self-reported interest in pharmacy-based COVID-19 rapid testing.

Conclusion

These findings can inform price setting, price differentiation, price subsidization and other program design features geared towards enhancing affordability, equity, and uptake.

Key Questions

What is already known?

The Coronavirus disease 2019 (COVID-19) global pandemic continues to cause great morbidity, mortality, social and economic burden.

Pharmacies in Kenya have been involved in the delivery of several health interventions, such as malaria rapid testing, HIV self-testing, and other disease screening services.

While COVID-19 testing remains an important response strategy to the ongoing COVID-19 pandemic, it is not clear how much pharmacy clients in Kenya and similar settings would be willing to pay (WTP) to obtain rapid COVID-19 testing at pharmacies

What are the new findings?

The mean and median willingness to pay (WTP) for a rapid test delivered at a private retail pharmacy was KES 611 (US$ 5.59) and KES 506 (US$ 4.63), respectively.

WTP varied by county, hence, the need for county-specific price-setting for pharmacy-based COVID-19 testing.

WTP increased with household income and interest in getting the COVID-19 test at a private retail pharmacy.

What do the new findings imply?

A better understanding of the user’s willingness to pay price that can guide price setting, price differentiation, price subsidization and other program design features geared towards enhancing affordability, equity, and uptake.
The sperm-associated microbiota of crickets and their local variation and rapid turnover
Authors: Eckel Barbara A. , Illner Anastasia V. , Otti Oliver , Reinhardt Klaus
Published: October 2021

While studying aspects of the sperm biology and immunity of two species of crickets, we encountered bacteria that were released from the male sperm container, the spermatophore, alongside sperm. We describe a presumably rich microbe flora in the sperm population (‘sperm-associated microbiota’). These sperm-associated microbiota differed between the two species of cricket and between different populations and showed functional diversity. Further, sperm-associated microbiota killed sperm, highlighting their potential role in fitness, especially since they are most likely transferred to females during mating.
Defunctionalizing Intracellular Organelles with Genetically-Encoded Molecular Tools Based on Engineered Phospholipase A/Acyltransferases (PLAATs)
Authors: Watanabe Satoshi , Nihongaki Yuta , Itoh Kie , Watanabe Shigeki , Inoue Takanari
Published: October 2021

Organelles vitally achieve multifaceted functions to maintain cellular homeostasis. Genetic and pharmacological approaches to manipulate individual organelles are powerful in probing their physiological roles. However, many of them are either slow in action, limited to certain organelles, or rely on toxic agents. Here, we designed a generalizable molecular tool utilizing phospholipase A/acyltransferases (PLAATs) for rapid induction of organelle defunctionalization via remodeling of the membrane phospholipid composition. In particular, we identified a minimal, fully catalytic PLAAT with no unfavorable side effects. Chemically-induced translocation of the engineered PLAAT to the mitochondria surface resulted in their rapid deformation in a phospholipase activity dependent manner, followed by loss of luminal proteins as well as dissipated membrane potential, thus invalidating the functionality. To demonstrate wide applicability, we then adapted the molecular tool in peroxisomes, and observed leakage of matrix-resident functional proteins. The technique was compatible with optogenetic control, viral delivery and operation in primary neuronal cultures. Due to such versatility, the PLAAT strategy should present a novel utility in organelle biology of diverse contexts.
The Activity of the Stress Modulated Arabidopsis Ubiquitin Ligases PUB46 and PUB48 is Partially Redundant
Authors: Zizelski-Valenci Gal , Raveh Dina , Bar-Zvi Dudy
Published: October 2021

The Arabidopsis ubiquitin ligases PUB46, PUB47 and PUB48 are encoded by paralogus genes; pub46 and pub48 mutants display increased drought sensitivity compared to wild type (WT). Although the phenotype displayed in the single gene mutants, suggest that each has specific biological activity, PUB46 and PUB48 activity may be also redundant. To test functional redundancy between two gene products requires a double mutant. Unfortunately, the close proximity of the PUB46 and PUB48 gene loci precludes obtaining a double mutant by crossing the available single mutants. We thus applied microRNA technology to reduce the activity of all three gene products of the PUB46-48 subfamily by constructing an artificial microRNA (aMIR) targeted to this subfamily. Expressing aMIR46-48 in WT plants resulted in increased drought-sensitivity, a phenotype resembling that of the single pub46 and pub48 mutants, and enhanced sensitivity to methyl viologen, similar to that observed for the pub46 mutant. Furthermore, the WT plants expressing aMIR46-48 also revealed reduced inhibition by ABA at seed germination, a phenotype not evident in the single mutants. Expressing aMIR46-48 in pub46 and pub48 mutants further enhanced the drought sensitivity of each parental single mutant and of WT expressing aMIR46-48. Thus, whereas the gene-specific activity of the PUB46 and PUB48 E3s is partially redundant in that absence of either E3 leads to drought sensitivity, our ability to eliminate the activity of both PUB46 and PUB48 in the same plant reveals additional gene specific facets of their activity in the reaction to abiotic stress.
Dispersal and polyandry evolve as competing inbreeding avoidance strategies
Authors: Bocedi Greta
Published: October 2021

Understanding evolution of complex life-histories requires explicitly considering their multiple interactions, feedbacks, and shared drivers. Inbreeding depression is hypothesized to drive evolution of two life-histories which have far-reaching ecological and evolutionary consequence: dispersal and polyandry. Yet, the role of inbreeding depression in the separate evolution of these key life-histories is still debated, while the possibility for their joint evolution and consequent covariation has not been considered. I propose that dispersal and polyandry might be competing means of inbreeding avoidance which negatively feedback on each other’s evolution. Using a genetically explicit individual-based model, I first demonstrate that inbreeding depression can drive the separate evolution of dispersal and polyandry. Although this is largely known for dispersal, it is not as well established for polyandry evolution, which generally remains an evolutionary puzzle. Here, I show that polyandry can indeed evolve as means of indirect inbreeding avoidance in spatially structured populations. Second, when dispersal and polyandry can evolve jointly, a negative feedback emerges, such that they evolve as alternative inbreeding avoidance strategies across replicate systems, especially if there are fitness costs associated. Finally, although both dispersal and polyandry might be expected to shape the level of inbreeding depression, this is mainly affected by dispersal, while polyandry has a much more limited effect. These results emphasize the need to consider the potential joint evolution of dispersal and mating system in general, together with their genetic effects, to further our understanding of life-history evolution in spatially structured systems, and provide theoretical expectations for new empirical testing.
An ancestral interaction module promotes oligomerization in divergent mitochondrial ATP synthases
Authors: Gahura Ondřej , Mühleip Alexander , Hierro-Yap Carolina , Panicucci Brian , Jain Minal , Hollaus David , Slapničková Martina , Zíková Alena , Amunts Alexey
Published: October 2021

Mitochondrial ATP synthase forms stable dimers arranged into oligomeric assemblies that generate the inner-membrane curvature essential for efficient energy conversion. Here, we report cryo-EM structures of the intact ATP synthase dimer from Trypanosoma brucei in ten different rotational states. The model consists of 25 subunits, including nine lineage-specific, as well as 36 lipids. The rotary mechanism is influenced by the divergent peripheral stalk, conferring a greater conformational flexibility. Proton transfer in the lumenal half-channel occurs via a chain of five ordered water molecules. The dimerization interface is formed by subunit-g that is critical for interactions but not for the catalytic activity. Although overall dimer architecture varies among eukaryotes, we find that subunit-g together with subunit-e form an ancestral oligomerization motif, which is shared between the trypanosomal and mammalian lineages. Therefore, our data defines the subunit-g/e module as a structural component determining ATP synthase oligomeric assemblies.