bluuebunny/crossref_metadata_2025 huggingface dataset:
“I felt I needed help, but I did not get any”: A multiple stakeholder qualitative study of risk and protective factors, and barriers to addressing common mental health problems among perinatal adolescents in Malawi
Authors: Mhango Wezi , Michelson Daniel , Gaysina Darya
Published: October 2023

Common mental health problems (particularly depression and anxiety) are common among adolescents during the perinatal period. Previous research has identified the distinctive needs of this group and called for contextually appropriate psychosocial interventions. The current study conducted in Malawi aimed to explore risk and protective factors for common mental health problems, and barriers to accessing mental health care, among perinatal adolescents, to develop a contextually relevant intervention for preventing and treating perinatal depression and anxiety. An exploratory qualitative study was conducted in antenatal and postnatal clinics in Zomba district, Malawi in January–March 2022. In-depth individual interviews were completed with perinatal adolescents aged ≤19 (n = 14); their family members (n = 4); and healthcare workers (n = 8). Interview data were subjected to thematic framework analysis. Data were organised around two themes: “psychosocial risk and protective factors” (potential causes of common mental health problems among adolescents); and “health care services” (maternal and mental health services available, and adolescents’ experiences of using these services). Interventions need to go beyond targeting symptoms of depression and anxiety to addressing the wider contextual risk factors and barriers to care at the different socioecological levels.
Measuring seismic attenuation in polar firn: method and application to Korff Ice Rise, West Antarctica
Authors: Agnew Ronan S. , Clark Roger A. , Booth Adam D. , Brisbourne Alex M. , Smith Andrew M.
Published: October 2023

We present seismic measurements of the firn column at Korff Ice Rise, West Antarctica, including measurements of compressional-wave velocity and attenuation. We describe a modified spectral-ratio method of measuring the seismic quality factor (Q) based on analysis of diving waves, which, combined with a stochastic method of error propagation, enables us to characterise the attenuative structure of firn in greater detail than has previously been possible. Q increases from 56 ± 23 in the uppermost 12 m to 570 ± 450 between 55 and 77 m depth. We corroborate our method with consistent measurements obtained via primary reflection, multiple, source ghost, and critically refracted waves. Using the primary reflection and its ghost, we find Q = 53 ± 20 in the uppermost 20 m of firn. From the critical refraction, we find Q = 640 ± 400 at 90 m depth. Our method aids the understanding of the seismic structure of firn and benefits characterisation of deeper glaciological targets, providing an alternative means of correcting seismic reflection amplitudes in cases where conventional methods of Q correction may be impossible.
NOTES ON SACKS’ SPLITTING THEOREM
Authors: AMBOS-SPIES KLAUS , DOWNEY ROD G. , MONATH MARTIN , NG KENG MENG
Published: October 2023

We explore the complexity of Sacks’ Splitting Theorem in terms of the mind change functions associated with the members of the splits. We prove that, for any c.e. set A, there are low computably enumerable sets

$A_0\sqcup A_1=A$

splitting A with

$A_0$

and

$A_1$

both totally

$\omega ^2$

-c.a. in terms of the Downey–Greenberg hierarchy, and this result cannot be improved to totally

$\omega $

-c.a. as shown in [9]. We also show that if cone avoidance is added then there is no level below

$\varepsilon _0$

which can be used to characterize the complexity of

$A_1$

and

$A_2$

.
MWA rapid follow-up of gravitational wave transients: Prospects for detecting prompt radio counterparts
Authors: Tian J. , Anderson G. E. , Cooper A. J. , Gourdji K. , Sokolowski M. , Rowlinson A. , Williams A. , Sleap G. , Dobie D. , Kaplan D. L. , Murphy Tara , Tingay S. J. , Panther F. H. , Lasky P. D. , Bahramian A. , Miller-Jones J. C. A. , James C. W. , Meyers B. W. , McSweeney S. J. , Hancock P. J.
Published: October 2023

We present and evaluate the prospects for detecting coherent radio counterparts to gravitational wave (GW) events using Murchison Widefield Array (MWA) triggered observations. The MWA rapid-response system, combined with its buffering mode ($\sim$4 min negative latency), enables us to catch any radio signals produced from seconds prior to hours after a binary neutron star (BNS) merger. The large field of view of the MWA ($\sim$$1\,000\,\textrm{deg}^2$at 120 MHz) and its location under the high sensitivity sky region of the LIGO-Virgo-KAGRA (LVK) detector network, forecast a high chance of being on-target for a GW event. We consider three observing configurations for the MWA to follow up GW BNS merger events, including a single dipole per tile, the full array, and four sub-arrays. We then perform a population synthesis of BNS systems to predict the radio detectable fraction of GW events using these configurations. We find that the configuration with four sub-arrays is the best compromise between sky coverage and sensitivity as it is capable of placing meaningful constraints on the radio emission from 12.6% of GW BNS detections. Based on the timescales of four BNS merger coherent radio emission models, we propose an observing strategy that involves triggering the buffering mode to target coherent signals emitted prior to, during or shortly following the merger, which is then followed by continued recording for up to three hours to target later time post-merger emission. We expect MWA to trigger on$\sim$$5-22$BNS merger events during the LVK O4 observing run, which could potentially result in two detections of predicted coherent emission.
Widowhood status, morbidity, and mortality in India: evidence from a follow-up survey
Authors: Hossain Babul , James K. S.
Published: October 2023

A known health effect of widowhood is an increased mortality risk among surviving spouses, with gender- and age-specific observations. While morbidity conditions with socio-economic factors may exacerbate the effect of widowhood on mortality, no research has attempted to predict mortality among the widowed over the married population with the presence of morbidity in India. Thus, the present study concurrently examines marital status and health in the Indian setting, bringing substantial empirical evidence to explore the link between marital status, morbidity, and mortality. The study used prospective data from India Human Development Survey (IHDS) wave 1 (2004–2005) and wave 2 (2011–2012). In total, 82,607 individuals aged 25 years and above were considered for the analysis. To present the preliminary findings, descriptive statistics and bivariate analysis were used. Using multivariable logistic regression, the interaction effect of marital status and morbidity status was estimated to predict the likelihood of mortality. Across all socio-economic groups, widowed individuals reporting any morbidity had a higher mortality proportion than married people. Young widowers with any morbidity are more susceptible to increased mortality. Asthma among young widowers and cardiovascular diseases among elderly widowers significantly elevate the probability of mortality. However, older widowed women with diabetes had a lower probability of mortality than older married women with diabetes. The widowers’ disadvantage in mortality and morbidity may be attributable to less care-receiving and the greater incidence of unhealthy lifestyle practices during the post-widowhood period, indicating the need for more research.
Living with obesity in Ireland: determinants, policy and future perspectives
Authors: Donovan C. M. , McNulty B.
Published: October 2023

Globally, the prevalence of those living with obesity (≥30 kg/m2) is rising, with this trend expected to continue if firm and decisive policy interventions are not introduced. Across Europe, despite many consecutive policies aiming to reverse rising trends in weight status over recent decades, no country is currently on track to halt and reverse current trends in the coming years. This is evident in Ireland too, whereby the reporting of nationally representative weight status data show that targets have not been achieved since reporting began. The aim of this review is to critically appraise recent evidence relating to the key determinants of obesity including weight status, diet quality and physical activity with an emphasis on socioeconomic inequalities. And to consider these in the context of respective policy measures and propose future-focused recommendations. Furthermore, as with the complex nature of obesity, multifaceted approaches that shift the focus from the individual and place responsibility at a societal level will be reviewed.
Trauma-focused therapy in early psychosis: results of a feasibility randomized controlled trial of EMDR for psychosis (EMDRp) in early intervention settings
Authors: Varese Filippo , Sellwood William , Pulford Daniel , Awenat Yvonne , Bird Leanne , Bhutani Gita , Carter Lesley-Anne , Davies Linda , Aseem Saadia , Davis Claire , Hefferman-Clarke Rebecca , Hilton Claire , Horne Georgia , Keane David , Logie Robin , Malkin Debra , Potter Fiona , van den Berg David , Zia Shameem , Bentall Richard P.
Published: October 2023

Background

Trauma is prevalent amongst early psychosis patients and associated with adverse outcomes. Past trials of trauma-focused therapy have focused on chronic patients with psychosis/schizophrenia and comorbid Post-Traumatic Stress Disorder (PTSD). We aimed to determine the feasibility of a large-scale randomized controlled trial (RCT) of an Eye Movement Desensitization and Reprocessing for psychosis (EMDRp) intervention for early psychosis service users.

Methods

A single-blind RCT comparing 16 sessions of EMDRp + TAU v. TAU only was conducted. Participants completed baseline, 6-month and 12-month post-randomization assessments. EMDRp and trial assessments were delivered both in-person and remotely due to COVID-19 restrictions. Feasibility outcomes were recruitment and retention, therapy attendance/engagement, adherence to EMDRp treatment protocol, and the ‘promise of efficacy’ of EMDRp on relevant clinical outcomes.

Results

Sixty participants (100% of the recruitment target) received TAU or EMDR + TAU. 83% completed at least one follow-up assessment, with 74% at 6-month and 70% at 12-month. 74% of EMDRp + TAU participants received at least eight therapy sessions and 97% rated therapy sessions demonstrated good treatment fidelity. At 6-month, there were signals of promise of efficacy of EMDRp + TAU v. TAU for total psychotic symptoms (PANSS), subjective recovery from psychosis, PTSD symptoms, depression, anxiety, and general health status. Signals of efficacy at 12-month were less pronounced but remained robust for PTSD symptoms and general health status.

Conclusions

The trial feasibility criteria were fully met, and EMDRp was associated with promising signals of efficacy on a range of valuable clinical outcomes. A larger-scale, multi-center trial of EMDRp is feasible and warranted.
The impact of botanical fermented foods on metabolic syndrome and type 2 diabetes: a systematic review of randomised controlled trials
Authors: Chan Miin , Larsen Nadja , Baxter Helen , Jespersen Lene , Ekinci Elif I. , Howell Kate
Published: October 2023

Our systematic review assessed the impact of botanical fermented food (BFF) consumption on glucose, lipid, anthropometric, inflammatory and gut microbiota parameters, in adults with metabolic syndrome (MetS), MetS components or type 2 diabetes mellitus (T2DM). Embase, MEDLINE, Cochrane CENTRAL and Google Scholar were searched with no language limits, from inception to 31 August 2022, for eligible randomised controlled trials (RCTs). Two independent reviewers screened 6873 abstracts and extracted relevant data. Risk of bias (ROB) was assessed using the Cochrane Collaboration’s ROB2 tool. The final review included twenty-six RCTs, with thirty-one reports published between 2001 and 2022. Significant (p < 0·05) within-group and between-group changes in cardiometabolic outcome means were reported in twenty-three and nineteen studies, respectively. Gut microbiota composition was assessed in four studies, with two finding significant between-group differences. No significant difference between groups of any measured outcomes was observed in five studies. There were fourteen studies at low ROB; ten were of some concern; and two were at high ROB. In 73% of included studies, BFF consumption by participants with obesity, MetS or T2DM led to significant between-group improvements in discrete cardiometabolic outcomes, including fasting blood glucose, lipid profile, blood pressure, waist circumference, body fat percentage and C-reactive protein. BFF consumption increased the abundance of beneficial gut bacteria, such as Bifidobacterium and LAB, whilst reducing potential pathogens such as Bacteroides. To determine the clinical significance of BFFs as therapeutic dietary adjuncts, their safety, tolerability and affordability must be balanced with the limited power and magnitude of these preliminary findings.
Some Applications of Gas Turbine to Helicopter Propulsion
Authors: Brown John
Published: October 2023

The CHAIRMAN, in introducing the lecturer, said that they were fortunate in having an extremely topical lecture The subject of gas turbines and their application to helicopters was currently taking a great deal of attention from designers and industry, and the Association were happy to have it in the programme so early in the session

Mr BROWN had been educated at the City Boys Secondary Grammar School, Leicester, and was a State Scholar and a College Exhibitioner at Jesus College, Cambridge He had taken an Honours degree in the Mechamcal Sciences Tripos, and in 1944 joined Power Jets (Research and Development) Ltd, remaining when it became the National Gas Turbine Estabhshment He had been engaged as a research and development engineer on combustion processes and was now employed as a Senior Scientific Officer at the N G T E, being engaged on the examination of gas turbine projects and their thermodynamic performance
Helicopter Production
Authors: Boulger F J
Published: October 2023

Introducing the lecturer, the Chairman said that like other learned societies they naturally had many papers on learned subjects, on the theory of this or that and the future of this or that It was a good thing from time to time for them all to realise that they were all engaged in building or using an actual vehicle which brought many problems with it It was only right and proper therefore, that from time to time they should come down to earth and face those problems

Mr BOULGER, of the Westland Aircraft Company, would speak on the problems associated with helicopter production He had been apprenticed at the R A E, had gone to the drawing office at Westlands, and had thence graduated to the design office For a time he had been with Messrs Normalair, an associated company, and then had returned to the Westland side of the family, where he had become Chief Planning Engineer It was from his work as Chief Planning Engineer that his intimate knowledge of the production problems arose He was now Contracts Manager of the Company
Part II Piloting Aspects
Authors: Reid J W
Published: October 2023

In a short time from now the civil licenced helicopter will be required to include among its capabilities the ability to operate in Instrument Flight conditions to lower limits than those currently laid down for fixed-wing aircraft operations

At the moment I estimate that the problem is roughly half solved and, if there is a helicopter suitable for city centre operations by 1961, the aids and equipment under development should be able to give safe flight conditions in 150 feet ceilings and 150 yard visibilities
The Digital Computer as a Helicopter Flight Simulator
Authors: Harrison J M
Published: October 2023

A method suitable for dealing with extended longitudinal manoeuvres is outlined, based on a step-by-step integration process It is shown how the necessary calculation is carried out on a digital computer, using a programme consisting of two parts A general part is applicable to any manoeuvre, and a special part idealises the pilot's action in performing the particular manoeuvre under consideration Using two illustrative examples, it is demonstrated how the method can be used to deal with problems which usually come under the heading of performance, but nevertheless involve handling qualities Some numerical results aid in the illustration
Some ways of obtaining an Integrated Aircraft
Authors: Kuchemann D
Published: October 2023

The CHAIRMAN, in introducing the Author, said that Dr Kuchemann had been a member of the scientific staff at the R A E, Farnborough, since 1946, and was now head of the Supersonics Division of the Aerodynamics Department From 1930 to 1936 he studied at the Universities of Munich and Gottingen, where he obtained the degree of Dr rer nat, and from 1936 to 1946 he had worked in the Aerodynamics Research Establishment at Gottingen under Professor Betz He was, perhaps, best known on both sides of the Atlantic for his classic textbook with J Weber “Aerodynamics of Propulsion”

The integration of the aerodynamics of a propulsive system with the aerodynamics of a lifting system as achieved in the helicopter was of fundamental significance in aeronautics and promised to become much more so in the future The Author had undertaken to discuss the generalised subject of an integrated aircraft, and it would be difficult to find anyone better qualified to present a paper of this nature
Is Man-Powered Rotating-Wing Flight a Future Possibility
Authors: Kendall E R
Published: October 2023

The Association is pleased to announce that the prize of £50 for the 1958 Cierva Essay Competition has been awarded to Mr E R Kendall

Mr Kendall, who is 25 years of age, is a Project Aerodynamicist with the Helicopter Division of Saunders-Roe Ltd He served his apprenticeship with that Company and in 1955 was nominated by the S B A C for a two year course at the College of Aeronautics, where he specialised in helicopter aerodynamics For his exceptional ability in technical study whilst at the College, he received the 1957 Alan Marsh Memorial Award which enabled him to take a short course of helicopter piloting instruction at Air Service Training He is an Associate Member of the Association
The place of the Helicopter in a Modern Army
Authors: Mead P W
Published: October 2023

The CHAIRMAN, in opening the meeting, said that it was a privilege to introduce Lt -Col MEAD, who tonight would give us a soldier's viewpoint on helicopters It would be agreed that this was rather a red-letter occasion It had been very difficult to get the Army, except in little private corners, to say very much No doubt Colonel Mead would say that the views he expressed were purely personal opinions, as he had to do, but from his antecedents it was obvious that he knew what he was talking about
“The Application of the Jet Flap to Helicopter Rotor Control”
Authors: Dorand R
Published: October 2023

The Chairman, in opening the meeting, said that it was a pleasure to welcome at that meeting of the Association a distinguished engineer from France, Monsieur Rene Dorand, who was well known internationally as a pioneer of the helicopter M Dorand’s name became associated with that of Louis Breguet in 1931 when they built in collaboration a helicopter with co-axial rotors That machine had achieved considerable success both in hovering and in forward flight It established international records for a flight duration of more than one hour and a forward speed of more than 100 k p h, and it also demonstrated an autorotative descent from 100 meters

M Dorand became a graduate engineer in 1921, and in the same year took a diploma in electrical engineering He then joined the Louis Breguet Aircraft Company as a graduate engineer and became Technical Director of the Breguet-Dorand Helicopter development group
Developments in Rotating Wing Aircraft
Authors: Hafner Raoul
Published: October 2023

Raoul Hafner came to this country in 1932 and continued his earlier helicopter experiments with the successful design and construction in 1937 of the Hafner AR. Ill Gyroplane. He is now Chief Designer of the Helicopter Department of the Bristol Aeroplane Company.

This paper was read in the first instance on 6th March, 1945 before The Bristol Branch of The Royal Aeronautical Society, and subsequently to a joint meeting of The Society of Licenced Aircraft Engineers and The Helicopter Association on the 27th April, 1946.
Helicopter Research and Development
Authors: Pullin C G
Published: October 2023

Ladies and Gentlemen, I feel that an introduction to our lecturer this afternoon is hardly necessary, as I am sure he is well known to most of you, but perhaps one or two may not be so well acquainted either with his background, or his work in rotating wing aircraft

Mr Pullin is the Managing Director and Chief Designer of the Cierva Autogiro Co Ltd, a Founder Memb2r of our Association, a Fellow of the Royal Aeronautical Society, and a Member of the Institute of Mechanical Engineers He has been actively engaged in the research and development of rotary wing aircraft since 1932, but his interest in aviation goes back to pre-1914 when he learnt to fly at Brooklands in the good old days He has been engaged in engineering for about 30 years, covering in this time, several of its different branches
Airscrew Characteristics and Aeroplane Performance Prediction
Authors: Blyth J D
Published: October 2023

IN approaching any problem in Aerodynamics the student, and the severely practical engineer, whose academic knowledge may be limited, are too frequently confronted with two difficulties The first of these is that though the literature on the subject is extensive, yet the information sought usually has to be collected from a number of sources and the second is that when found the information is frequently presented in such a manner as to be of little immediate practical value without a certain amount of simplification

The object of this paper is to collate and present in an immediately useful form the information contained in parts of the following publications
Antarctic Ice Sheet Freshwater Discharge Drives Substantial Southern Ocean Changes Over the 21st Century
Authors: Gorte Tessa , Lovenduski Nicole S. , Nissen Cara , Lenaerts Jan T. M.
Published: October 2023

Multidecadal satellite observations indicate that the Antarctic Ice Sheet (AIS) is losing mass at an accelerating rate, which has the potential to impact many aspects of the climate system. While previous studies demonstrated the importance of AIS freshwater (FW) discharge for regional and global climate processes using climate model experiments, many have applied unrealistic FW forcings. Here, we explore potential Southern Ocean (SO) impacts of realistic AIS mass loss over the 21st century in the Community Earth System Model version 2 by applying observation‐based historical and ice sheet model‐based future AIS FW forcing. The added FW reduces wintertime deep convective area by 72% while retaining 83% more sea ice. Congruent with other studies, we find the increased FW discharge extensively impacts local and remote SO surface and subsurface temperature and stratification. These results demonstrate the necessity of accounting for AIS mass loss in global climate models for projecting future climate.
Constraining Historical Earthquake Sequences With Coulomb Stress Models: An Example From Western Türkiye
Authors: Diercks M.‐L. , Mildon Z. K. , Boulton S. J. , Hussain E. , Alçiçek M. C. , Yıldırım C. , Aykut T.
Published: October 2023

Knowledge of earthquake source faults is crucial for the calculation of robust Coulomb stress models. However, source faults are often poorly constrained, especially for pre‐instrumental events, and these historical earthquakes are commonly studied with little or no consideration of other nearby events. We introduce an approach using Coulomb Stress Transfer (CST) modeling to investigate historical earthquake sequences and constrain possible source faults. Using historical and instrumental records from the Büyük Menderes Graben, western Türkiye, we create an ensemble of earthquake sequences featuring multiple rupture scenarios for individual earthquakes, and model both coseismic and interseismic CST. We filter and evaluate the models based on criteria to gain knowledge on historical earthquakes and their source faults and assess the current stress state and related seismic hazard of the investigated fault network. For our study area, the results provide further constraints on the source faults of several historical earthquakes, including the destructive MW 7.0 earthquake in 1899. The approach presented herein is applicable to other tectonically active areas where the causative faults of historical earthquakes are poorly constrained from existing data sets (e.g., paleoseismology, damage records), providing a new tool to help decipher historical earthquake sequences and improve modeling studies.
Analysis and Application of the Electromagnetic Wave Propagation, Fields, and Dispersion Relation in an Elliptical Chiro Plasma Waveguide Immersed in Magnetized Plasma
Authors: Gholamshahi N. , Abdoli‐Arani A.
Published: October 2023

This research proposes and investigates an elliptical waveguide filled with chiro plasma as its core and magnetized plasma as its clad region. The clad region is in the constant infinite magnetic field, and its direction is the same as the wave propagation in the chiro plasma elliptical waveguide. The electromagnetic wave propagation in the considered waveguide is studied. The expressions for electromagnetic field components in the chiro plasma core and magnetized plasma cladding are derived. The dispersion relations for the hybrid modes are calculated considering appropriate boundary conditions at the chiro plasma and magnetized plasma interface. The behavior of the energy flux and the dispersion curves are numerically and graphically studied. It is seen that the magnitude of the power density decreases with the increase of the cyclotron frequency and it increases with the increase of the plasma frequency and supports power flow in the backward direction for the considered mode. Furthermore, it is shown higher values of the chirality parameter cause the magnitude of the power flux to increase in the backward direction.
A human-machine collaborative approach measures economic development using satellite imagery
Authors: Ahn Donghyun , Yang Jeasurk , Cha Meeyoung , Yang Hyunjoo , Kim Jihee , Park Sangyoon , Han Sungwon , Lee Eunji , Lee Susang , Park Sungwon
Published: October 2023

Machine learning approaches using satellite imagery are providing accessible ways to infer socioeconomic measures without visiting a region. However, many algorithms require integration of ground-truth data, while regional data are scarce or even absent in many countries. Here we present our human-machine collaborative model which predicts grid-level economic development using publicly available satellite imagery and lightweight subjective ranking annotation without any ground data. We applied the model to North Korea and produced fine-grained predictions of economic development for the nation where data is not readily available. Our model suggests substantial development in the country’s capital and areas with state-led development projects in recent years. We showed the broad applicability of our model by examining five of the least developed countries in Asia, covering 400,000 grids. Our method can both yield highly granular economic information on hard-to-visit and low-resource regions and can potentially guide sustainable development programs.
Knowledge-driven design of solid-electrolyte interphases on lithium metal via multiscale modelling
Authors: Wagner-Henke Janika , Kuai Dacheng , Gerasimov Michail , Röder Fridolin , Balbuena Perla B. , Krewer Ulrike
Published: October 2023

Due to its high energy density, lithium metal is a promising electrode for future energy storage. However, its practical capacity, cyclability and safety heavily depend on controlling its reactivity in contact with liquid electrolytes, which leads to the formation of a solid electrolyte interphase (SEI). In particular, there is a lack of fundamental mechanistic understanding of how the electrolyte composition impacts the SEI formation and its governing processes. Here, we present an in-depth model-based analysis of the initial SEI formation on lithium metal in a carbonate-based electrolyte. Thereby we reach for significantly larger length and time scales than comparable molecular dynamic studies. Our multiscale kinetic Monte Carlo/continuum model shows a layered, mostly inorganic SEI consisting of LiF on top of Li2CO3 and Li after 1 µs. Its formation is traced back to a complex interplay of various electrolyte and salt decomposition processes. We further reveal that low local Li+ concentrations result in a more mosaic-like, partly organic SEI and that a faster passivation of the lithium metal surface can be achieved by increasing the salt concentration. Based on this we suggest design strategies for SEI on lithium metal and make an important step towards knowledge-driven SEI engineering.
RNA-based translation activators for targeted gene upregulation
Authors: Cao Yang , Liu Huachun , Lu Shannon S. , Jones Krysten A. , Govind Anitha P. , Jeyifous Okunola , Simmons Christine Q. , Tabatabaei Negar , Green William N. , Holder Jimmy. L. , Tahmasebi Soroush , George Alfred L. , Dickinson Bryan C.
Published: October 2023

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present “translation-activating RNAs” (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.
FHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design
Authors: Ng Wern Hann , Liu Xiang , Ling Zheng L. , Santos Camilla N. O. , Magalhães Lucas S. , Kueh Andrew J. , Herold Marco J. , Taylor Adam , Freitas Joseph R. , Koit Sandra , Wang Sainan , Lloyd Andrew R. , Teixeira Mauro M. , Merits Andres , Almeida Roque P. , King Nicholas J. C. , Mahalingam Suresh
Published: October 2023

Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1−/− mice, which when infected with CHIKV or o’nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1−/− and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.
Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
Authors: Kolb Julia , Tsata Vasiliki , John Nora , Kim Kyoohyun , Möckel Conrad , Rosso Gonzalo , Kurbel Veronika , Parmar Asha , Sharma Gargi , Karandasheva Kristina , Abuhattum Shada , Lyraki Olga , Beck Timon , Müller Paul , Schlüßler Raimund , Frischknecht Renato , Wehner Anja , Krombholz Nicole , Steigenberger Barbara , Beis Dimitris , Takeoka Aya , Blümcke Ingmar , Möllmert Stephanie , Singh Kanwarpal , Guck Jochen , Kobow Katja , Wehner Daniel
Published: October 2023

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.
Enzymatic synthesis and nanopore sequencing of 12-letter supernumerary DNA
Authors: Kawabe Hinako , Thomas Christopher A. , Hoshika Shuichi , Kim Myong-Jung , Kim Myong-Sang , Miessner Logan , Kaplan Nicholas , Craig Jonathan M. , Gundlach Jens H. , Laszlo Andrew H. , Benner Steven A. , Marchand Jorge A.
Published: October 2023

The 4-letter DNA alphabet (A, T, G, C) as found in Nature is an elegant, yet non-exhaustive solution to the problem of storage, transfer, and evolution of biological information. Here, we report on strategies for both writing and reading DNA with expanded alphabets composed of up to 12 letters (A, T, G, C, B, S, P, Z, X, K, J, V). For writing, we devise an enzymatic strategy for inserting a singular, orthogonal xenonucleic acid (XNA) base pair into standard DNA sequences using 2′-deoxy-xenonucleoside triphosphates as substrates. Integrating this strategy with combinatorial oligos generated on a chip, we construct libraries containing single XNA bases for parameterizing kmer basecalling models for commercially available nanopore sequencing. These elementary steps are combined to synthesize and sequence DNA containing 12 letters – the upper limit of what is accessible within the electroneutral, canonical base pairing framework. By introducing low-barrier synthesis and sequencing strategies, this work overcomes previous obstacles paving the way for making expanded alphabets widely accessible.
Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination
Authors: Mitsi Elena , Diniz Mariana O. , Reiné Jesús , Collins Andrea M. , Robinson Ryan E. , Hyder-Wright Angela , Farrar Madlen , Liatsikos Konstantinos , Hamilton Josh , Onyema Onyia , Urban Britta C. , Solórzano Carla , Belij-Rammerstorfer Sandra , Sheehan Emma , Lambe Teresa , Draper Simon J. , Weiskopf Daniela , Sette Alessandro , Maini Mala K. , Ferreira Daniela M.
Published: October 2023

Respiratory mucosal immunity induced by vaccination is vital for protection from coronavirus infection in animal models. In humans, the capacity of peripheral vaccination to generate sustained immunity in the lung mucosa, and how this is influenced by prior SARS-CoV-2 infection, is unknown. Here we show using bronchoalveolar lavage samples that donors with history of both infection and vaccination have more airway mucosal SARS-CoV-2 antibodies and memory B cells than those only vaccinated. Infection also induces populations of airway spike-specific memory CD4+ and CD8+ T cells that are not expanded by vaccination alone. Airway mucosal T cells induced by infection have a distinct hierarchy of antigen specificity compared to the periphery. Spike-specific T cells persist in the lung mucosa for 7 months after the last immunising event. Thus, peripheral vaccination alone does not appear to induce durable lung mucosal immunity against SARS-CoV-2, supporting an argument for the need for vaccines targeting the airways.
Stapling strategy for slowing helicity interconversion of α-helical peptides and isolating chiral auxiliary-free one-handed forms
Authors: Ousaka Naoki , MacLachlan Mark J. , Akine Shigehisa
Published: October 2023

In nature, α-helical peptides adopt right-handed conformations that are dictated by L-amino acids. Isolating one-handed α-helical peptides composed of only achiral components remains a significant challenge. Here, this goal is achieved by optical resolution of the corresponding racemic (quasi-)static α-helical peptide with double stapling, which effectively freezes the interconversion between the right-handed (P)- and left-handed (M)-α-helices. An as-obtained doubly stapled analogue having an unprotected L-valine residue at the C-terminus transforms from a kinetically trapped (M)-α-helix to a thermodynamically stable (P)-α-helix upon heating. In contrast, the corresponding singly stapled α-helical peptide undergoes an acid/base-triggered and solvent-induced reversible inversion of its preferred helicity within minutes. The interconversion rates of the singly and doubly stapled α-helical peptide foldamers are approximately 106 and 1012 times slower, respectively, than that of a non-stapled dynamic helical peptide. Therefore, the enantiopure doubly-stapled (quasi-)static α-helical peptide would retain its optical activity for several years at 25 °C.
Learning diffractive optical communication around arbitrary opaque occlusions
Authors: Rahman Md Sadman Sakib , Gan Tianyi , Deger Emir Arda , Işıl Çağatay , Jarrahi Mona , Ozcan Aydogan
Published: October 2023

Free-space optical communication becomes challenging when an occlusion blocks the light path. Here, we demonstrate a direct communication scheme, passing optical information around a fully opaque, arbitrarily shaped occlusion that partially or entirely occludes the transmitter’s field-of-view. In this scheme, an electronic neural network encoder and a passive, all-optical diffractive network-based decoder are jointly trained using deep learning to transfer the optical information of interest around the opaque occlusion of an arbitrary shape. Following its training, the encoder-decoder pair can communicate any arbitrary optical information around opaque occlusions, where the information decoding occurs at the speed of light propagation through passive light-matter interactions, with resilience against various unknown changes in the occlusion shape and size. We also validate this framework experimentally in the terahertz spectrum using a 3D-printed diffractive decoder. Scalable for operation in any wavelength regime, this scheme could be particularly useful in emerging high data-rate free-space communication systems.
Redox signaling-driven modulation of microbial biosynthesis and biocatalysis
Authors: Chen Na , Du Na , Shen Ruichen , He Tianpei , Xi Jing , Tan Jie , Bian Guangkai , Yang Yanbing , Liu Tiangang , Tan Weihong , Yu Lilei , Yuan Quan
Published: October 2023

Microbial communication can drive coordinated functions through sensing, analyzing and processing signal information, playing critical roles in biomanufacturing and life evolution. However, it is still a great challenge to develop effective methods to construct a microbial communication system with coordinated behaviors. Here, we report an electron transfer triggered redox communication network consisting of three building blocks including signal router, optical verifier and bio-actuator for microbial metabolism regulation and coordination. In the redox communication network, the Fe3+/Fe2+ redox signal can be dynamically and reversibly transduced, channeling electrons directly and specifically into bio-actuator cells through iron oxidation pathway. The redox communication network drives gene expression of electron transfer proteins and simultaneously facilitates the critical reducing power regeneration in the bio-actuator, thus enabling regulation of microbial metabolism. In this way, the redox communication system efficiently promotes the biomanufacturing yield and CO2 fixation rate of bio-actuator. Furthermore, the results demonstrate that this redox communication strategy is applicable both in co-culture and microbial consortia. The proposed electron transfer triggered redox communication strategy in this work could provide an approach for reducing power regeneration and metabolic optimization and could offer insights into improving biomanufacturing efficiency.
Electrochemical halogen-atom transfer alkylation via α-aminoalkyl radical activation of alkyl iodides
Authors: Sun Xiang , Zheng Ke
Published: October 2023

Alkyl halides, widely recognized as important building blocks and reagents in organic synthesis, can serve as versatile alkyl radical precursors in radical-based transformations. However, generating alkyl radicals directly from unactivated alkyl halides under mild conditions remains a challenge due to their extremely low reduction potentials. To address this issue, α-aminoalkyl radicals were employed as efficient halogen-atom transfer (XAT) reagents in the photoredox activation of unactivated alkyl halides. Here, we report an effective electrooxidation strategy for generating alkyl radicals from unactivated alkyl iodides via an electrochemical halogen-atom transfer (e-XAT) process under mild conditions. The α-aminoalkyl radicals generated by anodic oxidation are demonstrated to be efficient XAT reagents in these transformations. This facile electricity-driven strategy obviates the need for sacrificial anodes and external chemical oxidants. The method successfully applies to a wide variety of alkyl iodides, including primary, secondary, and tertiary, as well as structurally diverse olefins, exhibiting excellent functional group tolerance. Moreover, we further demonstrate the utility of this strategy by rapidly functionalizing complex molecules and biomolecules.
Transient polymorphisms in parental care strategies drive divergence of sex roles
Authors: Long Xiaoyan , Weissing Franz J.
Published: October 2023

The parental roles of males and females differ considerably between and within species. By means of individual-based evolutionary simulations, we strive to explain this diversity. We show that the conflict between the sexes creates a sex bias (towards maternal or paternal care), even if the two sexes are initially identical. When including sexual selection, there are two outcomes: either female mate choice and maternal care or no mate choice and paternal care. Interestingly, the care pattern drives sexual selection and not vice versa. Longer-term simulations exhibit rapid switches between alternative parental care patterns, even in constant environments. Hence, the evolutionary lability of sex roles observed in phylogenetic studies is not necessarily caused by external changes. Overall, our findings are in striking contrast to the predictions of mathematical models. We show that the discrepancies are caused by transient within-sex polymorphisms in parental strategies, a factor largely neglected in current sex-role theory.
Tandem-biocatalysis reactors constructed by topological evolution of CaCO3 particles into hollow metal hydroxide spheres
Authors: Han Sang Yeong , Kim Nayoung , Yun Gyeongwon , Lee Hojae , Choi Insung S.
Published: October 2023

Despite remarkable advances in the design and synthesis of hollow inorganic spheres (HISs), the harsh synthetic conditions have precluded the applications of HISs to biochemical and biological fields. Herein we report a biocompatible strategy for synthesizing metal hydroxide HISs (MH-HISs) by simply mixing CaCO3 particles with metal ions in water. The ion-exchange reaction between Ca2+ and metal ions leads to the structural and chemical evolution from solid CaCO3 particles to hollow MH-HISs via core-shell and yolk-shell structures, while enabling the encapsulation of enzymes to the shells without loss of catalytic activities. The biocompatible protocol makes multienzymatic cascade reactions achievable, with great recyclability due to mechanical durability of MH-HISs.
A single amino acid substitution in the capsid protein of Zika virus contributes to a neurovirulent phenotype
Authors: Song Guang-Yuan , Huang Xing-Yao , He Meng-Jiao , Zhou Hang-Yu , Li Rui-Ting , Tian Ying , Wang Yan , Cheng Meng-Li , Chen Xiang , Zhang Rong-Rong , Zhou Chao , Zhou Jia , Fang Xian-Yang , Li Xiao-Feng , Qin Cheng-Feng
Published: October 2023

Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins.