bluuebunny/crossref_metadata_2025 huggingface dataset:
The ringworm campaign in Serbia (former Yugoslavia) in the 1950s
Authors: Shvarts Shifra , Sevo Goran , Tasic Marija , Shani Mordechai , Sadetzki-Jackobson Siegal
Published: February 2022

In 1950, a full-scale eradication campaign for ringworm (tinea capitis, mycosis) employing ionizing radiation was launched in former Yugoslavia (Serbia today), with UNICEF’s assistance. The number of individuals treated (49,389) was among the highest ever reported in a public health campaign in Europe and North America. Treatment was compulsory, and children were treated in the absence of their parents, with full compliance to the medical authorities, as was common practice under President Tito’s Communist regime. Despite the large numbers of children who were irradiated for ringworm in Yugoslavia, the mass treatment was entirely forgotten. Discovery of documentation of ringworm irradiation in Serbia in 2006 made it possible to publicize the fact, to identify and to locate children who had been treated for ringworm in Serbia who today are aged 65 to 75, and to inform the medical community caring for this population.
Psychotic disorders
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

The term psychosis is often misunderstood. It can be considered an ‘umbrella-term’ for symptoms that suggest the individual is unable to distinguish between what is real and what isn’t, e.g. believing things that cannot be true (delusions) or seeing or hearing things that are not there (visual or auditory hallucinations). It is, however, the context and pattern of these symptoms that define the underlying diagnosis. This chapter presents the key features of psychotic disorders. It opens by discussing the misunderstanding, particularly in medical circles, of the term ‘psychosis’, providing a simplified explanation of the concepts, essential for all clinicians working with patients. It then describes key diagnostic features of schizophrenia, factors that influence outcome, and general principles on management. The text ends with a discussion of other, less common psychotic disorders, including schizo-affective disorder and specific delusional disorders.
This chapter provides knowledge about:
• Clinical features of schizophrenia.
• How to manage schizophrenia.
• Key facts about aetiology.
• Factors that influence prognosis.
Practical tips include:
• How to identify ‘negative’ symptoms of schizophrenia.
• Simplified representation of management strategies for schizophrenia.
Psycho-active substance use
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

The patterns of substance abuse are changing. Alcohol and alcohol-related problems continue to present in large numbers and are reviewed in this chapter. However, other patterns of presentation, including benzodiazepine withdrawal and novel patterns of substance-abuse, are also discussed. These newer issues presenting to clinicians include the impact of increases in purity and potency of existing classes of drugs; newer psychoactive substances developed to mimic the effects of controlled drugs and avoid legal controls, and the effects of poly-drug abuse. This chapter provides key information about psycho-active substance use including:
• Key features of alcohol dependency—how to recognize it and how to prevent (or manage) alcohol withdrawal.
• Physical and psychological consequences of alcohol abuse.
• Interventions to promote abstinence (physical and psychological).
• Key features of heroin abuse, consequences, and how to manage withdrawal.
• Information about novel patterns and substances of abuse presenting to the ED.
Practical tips include:
• ‘Clues’ of alcohol dependency.
• ‘Rules’ for recognizing and managing benzodiazepine withdrawal.
Emergencies: urgent, serious, and high-risk scenarios in psychiatry
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

The term ‘emergency’ causes many people to freeze, gripped by panic, rendering them unable to have a clear plan of action. This is particularly likely for inexperienced, newly qualified doctors. Examples of urgent, serious, high risk scenarios in psychiatry (particularly those likely to present in medical settings) include acute behavioural disturbance, risk of harm to self or others, neuroleptic malignant syndrome, serotonin syndrome, and lithium toxicity. This is not an exhaustive list. Discussion on some ‘emergencies’ is already embedded in the chapters on the illnesses with which they present. In every interaction with our patients we need to consider risk and safety This chapter provides an outline for the recognition and management of a variety of high-risk scenarios.
This chapter provides knowledge about:
• Acute behavioural disturbance—initial response, safety and management.
• Risk of harm to self.
• Risk of harm to others.
• Medication-related emergencies, including neuroleptic malignant syndrome, serotonin syndrome, and lithium toxicity.
Practical tips include:
• Key factors to promote safety.
• A protocol (guide) for rapid tranquillization.
Professionalism, boundaries, and well-being
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

The concept of ‘professionalism’ is now at the centre of much discussion in medicine. While the term itself only came to prominence in recent decades, it has long been recognized that becoming a doctor brings responsibilities beyond the work itself, and also commitments to a code of behaviour and service to others.
This chapter outlines some of the (almost impossible) roles of being a doctor, the gains and costs of professionalism, and suggests measures that can help doctors (and patients) in these challenging situations. It focuses on the challenges and rewards of working in medicine. It discusses what is expected of practitioners, suggests ways they can protect and strengthen themselves, enabling them to best look after their patients. It reminds practitioners that in preparing for a role of a life-time of caring for others, they would do well to first ensure they have put in place strategies to look after themselves.
The chapter provides knowledge about:
• The roles of a doctor.
• The gains and costs of professionalism.
• Confidentiality.
• Boundaries and how to maintain them.
• Setting limits.
• Self-care and resilience.
Practical tips include:
• How to promote appropriate boundaries.
• How to set limits.
• How to promote self-care and resilience.
Graph-based discovery and analysis of atomic-scale one-dimensional materials
Authors: Li Shunning , Chen Zhefeng , Wang Zhi , Weng Mouyi , Li Jianyuan , Zhang Mingzheng , Lu Jing , Xu Kang , Pan Feng
Published: February 2022

Recent decades have witnessed an exponential growth in the discovery of low-dimensional materials (LDMs), benefiting from our unprecedented capabilities in characterizing their structure and chemistry with the aid of advanced computational techniques. Recently, the success of two-dimensional compounds has encouraged extensive research into one-dimensional (1D) atomic chains. Here, we present a methodology for topological classification of structural blocks in bulk crystals based on graph theory, leading to the identification of exfoliable 1D atomic chains and their categorization into a variety of chemical families. A subtle interplay is revealed between the prototypical 1D structural motifs and their chemical space. Leveraging the structure graphs, we elucidate the self-passivation mechanism of 1D compounds imparted by lone electron pairs, and reveal the dependence of the electronic band gap on the cationic percolation network formed by connections between structure units. This graph-theory-based formalism could serve as a source of stimuli for the future design of LDMs.
An Efficient Coalescent Epoch Model for Bayesian Phylogenetic Inference
Authors: Bouckaert Remco R
Published: February 2022

We present a two-headed approach called Bayesian Integrated Coalescent Epoch PlotS (BICEPS) for efficient inference of coalescent epoch models. Firstly, we integrate out population size parameters, and secondly, we introduce a set of more powerful Markov chain Monte Carlo (MCMC) proposals for flexing and stretching trees. Even though population sizes are integrated out and not explicitly sampled through MCMC, we are still able to generate samples from the population size posteriors. This allows demographic reconstruction through time and estimating the timing and magnitude of population bottlenecks and full population histories. Altogether, BICEPS can be considered a more muscular version of the popular Bayesian skyline model. We demonstrate its power and correctness by a well-calibrated simulation study. Furthermore, we demonstrate with an application to SARS-CoV-2 genomic data that some analyses that have trouble converging with the traditional Bayesian skyline prior and standard MCMC proposals can do well with the BICEPS approach. BICEPS is available as open-source package for BEAST 2 under GPL license and has a user-friendly graphical user interface.[Bayesian phylogenetics; BEAST 2; BICEPS; coalescent model.]
Intramedullary Nailing for Lower Limb Polyostotic Fibrous Dysplasia in Children: A Long-term Follow-up Study
Authors: Ippolito Ernesto , Farsetti Pasquale , Caterini Roberto , Micciulli Enrico , Gorgolini Giulio , Ruzzini Laura
Published: February 2022

Background:

In children, intramedullary nailing (IN) has been proposed as the best treatment when the femur and tibia are totally affected by fibrous dysplasia (FD). However, in younger children IN must be repeated to maintain stabilization of the affected skeletal segment during growth. We report the long-term results in a cohort of patients in whom more than two-thirds of cases had IN repeated during growth.

Methods:

Twenty-nine femurs and 14 tibias totally affected by FD were treated by IN in 21 patients with polyostotic FD and McCune-Albright syndrome. Thirteen patients with 35 femoral and tibial deformities had a painful limp whereas 8 presented fractures. The patients had their first IN at a mean age of 9.26±2.68 years (range: 4 to 14 y). IN was repeated during growth in the younger patients, and all the patients underwent a mean of 2.13 femoral and 1.50 tibial IN per limb. The last IN was performed at a mean age of 16.42±1.95 years (range: 11 to 19 y). Titanium elastic nails and adult humeral nails were used in younger children, whereas adult femoral cervicodiaphyseal and interlocking tibial nails were used in older children and adolescents. At the latest follow-up, the patients were evaluated with a clinicoradiographic scale. All the data were statistically analyzed.

Results:

The mean length of follow-up from the last IN was 6.47±3.10 years (range: 3 to 14 y), and the mean age of the patients at follow-up was 22.85±3.53 years (range: 14 to 29 y) when lower limbs were fully grown in all but 1 patient. Satisfactory long-term results were obtained in about 81% of our patients, while complications occurred in 32.5% of the 43 cases.

Conclusion:

Lower limb IN—that was repeated in younger children during growth—provided satisfactory long-term results in most of our patients, with fracture and deformity prevention and pain control, regardless of the high rate of complications that mainly affected the femoral cases. Missing scheduled follow-ups was the main predictor of a poor result.

Level of Evidence:

Level IV—case series.
Prolonged Brace Treatment Does Not Result in Improved Acetabular Indices in Infantile Dislocated Hips
Authors: Upasani Vidyadhar V. , Bomar James D. , Fitzgerald Ryan E. , Schupper Alexander J. , Kelley Simon P. ,   International Hip Dysplasia Registry
Published: February 2022

Background:

The Pavlik harness (PH) is commonly used to treat infantile dislocated hips. However, significant variability exists in the duration of brace treatment after successful reduction of the dislocated hip. The purpose of this study was to evaluate the effect of prescribed time in brace on acetabular index (AI) at two years of age using a prospective, international, multicenter database.

Methods:

We retrospectively studied prospectively enrolled infants with at least 1 dislocated hip that were initially treated with a PH and had a recorded AI at 2-year follow-up. Subjects were treated at 1 of 2 institutions. Institution 1 used the PH until they observed normal radiographic acetabular development. Institution 2 followed a structured shorter brace treatment protocol. Hip dislocation was defined as <30% femoral head coverage at rest on the pretreatment ultrasound or International Hip Dysplasia Institute (IHDI) grade III or IV on the pretreatment radiograph.

Results:

Fifty-three hips met our inclusion criteria. Hips from Institution 1 were treated with a brace ×3 longer than hips from institution 2 (adjusted mean 8.9±1.3 vs. 2.6±0.2 mo) (P<0.001). Institution 1 had an 88% success rate and institution 2 had an 85% success rate at achieving hip reduction (P=0.735). At 2-year follow-up, we observed no significant difference in AI between Institution 1 (adjusted mean 25.6±0.9 degrees) compared with Institution 2 (adjusted mean 23.5±0.8 degrees) (P=0.1). However, 19% of patients from Institution 1 and 44% of patients from Institution 2 were at or below the 50th percentile of previously published age-matched and sex-matched AI normal data (P=0.049). Also, 27% (7/26) of hips from Institution 1 had significant acetabular dysplasia (more than 2 SD from the mean), compared with a 22% (6/27) from Institution 2 (P=0.691). We found no correlation between age at initiation of bracing and AI at 2-year follow-up (P=0.071).

Conclusions:

The PH brace can successfully treat dislocated infant hips, however, prolonged brace treatment was not found to result in improved acetabular development at 2-year follow-up.

Level of Evidence:

Level III.
Stem cell-derived retinal pigment epithelium transplantation in age-related macular degeneration: recent advances and challenges
Authors: Kashani Amir H.
Published: February 2022

Purpose of review

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss in the world with more than 80% of the prevalence accounted for by the nonneovascular (NNAMD) or ‘dry’ form of the disease. NNAMD does not have any definitive treatment once vision loss has ensued and presents a major unmet medical need. This review will highlight stem cell-based therapies that are a promising form of treatment for advanced NNAMD.

Recent findings

In the past decade, clinical trials utilizing both induced pluripotent stem cell-derived RPE and human embryonic stem cell-derived RPE have been aggressively pursued as potential treatments of RPE loss and prevention of overlying neurosensory atrophy. While promising preliminary results demonstrating safety and potential efficacy have been published, new challenges have also been identified. These include selecting the most appropriate cell-based therapy, identifying and managing potential immune response as well as characterizing anatomic and functional efficacy. In this review, we will discuss some of these challenges in light of the available data from several early phase clinical trials and discuss the strategies that are being considered to further advance the field.

Cell-based therapies demonstrate promising potential to treat advanced stages of NNAMD. Several early phase clinical trials using both induced pluripotent stem cells (iPSC) and human embryonic stem cell derived (hESC) have demonstrated safety and preliminary signs of efficacy and highlighted remaining challenges which appear surmountable. These challenges include development of selection criteria for use of cell suspensions versus RPE sheets, especially in light of immunological properties of RPE that are intrinsic to the status of RPE differentiation in each of these cell formulations.
Soft Palate Mucosal Adhesion with Muscle Release: An Option in “Wide” Cleft Palates in a Cohort in Southern Africa
Authors: Adams Saleigh , Lentin Roslyn , Hendricks Rushdi , Hudson Donald , Breugem Corstiaan C.
Published: February 2022

Objective:

Comparison of speech outcomes in 2 similar groups of “wide” cleft palate. One received a Furlow double-opposing Z- plasty (FZP) versus a group (non-FZP) that received only a muscle release at the second stage after both received a soft palate mucosal adhesion (SPA) at the first stage.

Methods:

Retrospective review. Thirty-three patients (non-FZP) versus 29 patients (FZP) between 2010 and 2016. Both groups had SPA at approximately 6 months of age. After 12 months, an FZP with hard palate closure was performed in the FZP group. in the non-FZP group, only the muscle was released from the posterior palatal shelves with hard palate closure. Speech and velopharyngeal insufficiency (VPi) were determined clinically and by videofluoroscopy.

Results:

The FZP group (15 M: 14 F) with Veau (III = 14; IV = 5; II = 10) had a mean palate length (MPL) of 20.5 mm and mean palate width (MPW) of 11.2 mm at 8.3 months. MPW decreased to 7 mm after 20.7 months. 21% (n = 6) had fistulae. 14% (n = 4) (all males) had VPI. Their MPL was 16.3 mm. The mean follow-up was 5.5 years. In the non-FZP group, (18 M: 15 F) with Veau (III = 22; IV = 7; II = 4), the MPL was 20.5 mm and MPW was 11 mm at 8.4 months. MPW decreased to 6.5 mm after 12.5 months (P = 0.006). The fistula rate was 18% (n = 6). 24% (n = 8) predominantly male (87%) had VPI (P = 0.432). Their MPL was 17 mm; the mean follow-up was 4.7 years.

Conclusions:

SPA as a first stage performed in “wide” cleft palate narrows the subsequent hard palate repair and with a muscle release, may be adequate in some patients.
The impact of digital interventions on help-seeking behaviour for mental health problems: a systematic literature review
Authors: Evans-Lacko Sara , Hahn Jane Sungmin , Peter Lina-Jolien , Schomerus Georg
Published: February 2022

Purpose of review

Interventions that facilitate help-seeking could help individuals to get care earlier on which could also help avert some mental health crises. Delivering interventions via a digital format could mitigate some key barriers to mental healthcare. We reviewed the literature for digital interventions which facilitate formal or informal help-seeking for mental health problems. We examined the impact of identified interventions on actual and intended help-seeking and attitudes towards help-seeking.

Recent findings

We identified 35 interventions. About half (51%) of studies showed an improvement in at least one help-seeking outcome with the greatest number showing an improvement in help-seeking intentions and the fewest studies showing an improvement in actual behaviour (29%). Findings suggest that interventions that promote active participation and personal involvement through sharing one's own narrative seem to be promising practices to facilitate help-seeking.

Our findings suggest digital interventions can improve help-seeking for mental health problems among a range of populations. Given speciality mental health resources are scarce, further research needs to consider how these interventions could best target the most vulnerable groups to link them with mental healthcare and how these interventions might facilitate earlier intervention in a way that might reduce need for crisis care and support.
Phylogenetic analysis of SARS-CoV-2 data is difficult
Authors: Morel Benoit , Barbera Pierre , Czech Lucas , Bettisworth Ben , Hübner Lukas , Lutteropp Sarah , Serdari Dora , Kostaki Evangelia-Georgia , Mamais Ioannis , Kozlov Alexey M , Pavlidis Pavlos , Paraskevis Dimitrios , Stamatakis Alexandros
Published: February 2022

Numerous studies covering some aspects of SARS-CoV-2 data analyses are being published on a daily basis, including a regularly updated phylogeny onnextstrain.org. Here, we review the difficulties of inferring reliable phylogenies by example of a data snapshot comprising all virus sequences available on May 5, 2020 fromgisaid.org. We find that it is difficult to infer a reliable phylogeny on these data due to the large number of sequences in conjunction with the low number of mutations. We further find that rooting the inferred phylogeny with some degree of confidence either via the bat and pangolin outgroups or by applying novel computational methods on the ingroup phylogeny does not appear to be possible. Finally, an automatic classification of the current sequences into sub-classes based on statistical criteria is also not possible, as the sequences are too closely related. We conclude that, although the application of phylogenetic methods to disentangle the evolution and spread of COVID-19 provides some insight, results of phylogenetic analyses, in particular those conducted under the default settings of current phylogenetic inference tools, as well as downstream analyses on the inferred phylogenies, should be considered and interpreted with extreme caution.
The association between work situation and life satisfaction during the COVID-19 pandemic: prospective cohort study in Norway
Authors: Øen Carlsen Ellen , Caspersen Ida Henriette , Ask Helga , Brandlistuen Ragnhild Eek , Trogstad Lill , Magnus Per
Published: February 2022

Objectives

To analyse the population effects on life quality of being laid off from work, having to work from home, or having been diagnosed with COVID-19.

Design

Nationwide population-based cohort study.

Setting

Norway.

Participants

We followed more than 80,000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. We analysed current life satisfaction in April and again in September/October 2020 for subjects whose work situation and infection status had changed.

Main outcome measures

Self-reported satisfaction with life, using a scale from 0 (worst) to 10 (best).

Results

Temporary and permanent layoffs, working from a home-based office, and getting a COVID-19 diagnosis were associated with modestly, but significantly lower concurrent life satisfaction, both on a population level and for subjects who changed status. The associations with change in work situation were stronger for men. For men with permanent job loss, the adjusted odds ratio for low life satisfaction (<6) was 3.2 (95% CI 2.4 to 4.2) in April and 4.9 (95% CI 3.5 to 6.9) in autumn. A suspected or confirmed COVID-19 diagnosis was associated with an adjusted odds ratio for low life satisfaction of 1.9 (95% CI 1.6 to 2.3) in spring. The strength of associations between work situation and life satisfaction did not vary much across socio-economic strata, but layoffs were more common among those with low education.

Conclusion

Layoffs, home office and infection status had clear impact on the quality of life as measured with a global life satisfaction scale. These findings suggest that social differentials in quality of life, are increasing during the pandemic.

Funding

This work was funded by the Norwegian Research Council’s Centres of Excellence Funding Scheme (no. 262700) and by the Norwegian Institute of Public Health (NIPH).

SUMMARY BOXES

What is already known on this topic

−

Being laid off from work or having to work from a home-based office is usually associated with reduced life quality.

−

The population effect has not been estimated during the present surge in cases of COVID-19 in Europe.

What this study adds

−

This population-based study shows that life satisfaction in Norway has been stable from the first to the second wave of the pandemic, but that both layoffs and working from home is associated with reduced life satisfaction, especially among men.

−

The reduced life satisfaction in people working from a home-based office implies that large proportions of the population are affected.
Protective immune trajectories in early viral containment of non-pneumonic
SARS-CoV-2 infection
Authors: Pekayvaz Kami , Leunig Alexander , Kaiser Rainer , Brambs Sophia , Joppich Markus , Janjic Aleksandar , Popp Oliver , Polewka Vivien , Wange Lucas E. , Gold Christoph , Kirchner Marieluise , Muenchhoff Maximilian , Hellmuth Johannes C , Scherer Clemens , Eser Tabea , Deák Flora , Kuhl Niklas , Linder Andreas , Saar Kathrin , Tomas Lukas , Schulz Christian , Enard Wolfgang , Kroidl Inge , Geldmacher Christof , von Bergwelt-Baildon Michael , Keppler Oliver T. , Zimmer Ralf , Mertins Philipp , Hubner Norbert , Hölscher Michael , Massberg Steffen , Stark Konstantin , Nicolai Leo
Published: February 2022

The immune system of most SARS-CoV-2 infected individuals limits viral
spread to the upper airways without pulmonary involvement. This prevents the
development of pneumonic COVID-19. However, the protective immunological
responses causative of successful viral containment in the upper airways remain
unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic
profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte
subsets and multiplex plasma interferon profiling to uncover temporally resolved
protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected
patients.

We compare host responses in a high-risk patient population infected with
SARS-CoV-2 but without pulmonary involvement to patients with COVID-19
pneumonia. Our data reveal a distinct immunological signature of successful
viral containment, characterized by an early prominent interferon stimulated
gene (ISG) upregulation across immune cell subsets. In addition, reduced
cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte
phenotype with immune-modulatory potential are hallmarks of protective immunity.
Temporal resolution across disease trajectories highlights ISG upregulation as
particularly prominent early in the disease and confirms increased expression
also in comparison to healthy controls.

We validate this distinct temporal ISG signature by in-depth RNA-seq of
FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2
infected cohort confirming early and robust ISG upregulation particularly in
monocytes and T cells. In conclusion, our data demonstrate a protective ISG
phenotype in patients with successful containment of SARS-CoV-2 infection
without progression to COVID-19. This early protective interferon response might
be exploited as a therapeutic approach and for disease course
prediction.
Reduced neutralisation of SARS-COV-2 Omicron-B.1.1.529 variant by post-immunisation serum
Authors: Dejnirattisai Wanwisa , Shaw Robert H , Supasa Piyada , Liu Chang , Stuart Arabella SV , Pollard Andrew J , Liu Xinxue , Lambe Teresa , Crook Derrick , Stuart Dave I , Mongkolsapaya Juthathip , Nguyen-Van-Tam Jonathan S , Snape Matthew D , Screaton Gavin R ,   the Com-COV2 study group
Published: February 2022

In this report, we present live neutralisation titres against SARS-CoV-2 Omicron variant, compared with neutralisation against Victoria, Beta and Delta variants. Sera from day-28 post second-dose were obtained from participants in the Com-COV2 study who had received a two-dose COVID-19 vaccination schedule with either AstraZeneca (AZD1222) or Pfizer (BNT162b2) vaccines. There was a substantial fall in neutralisation titres in recipients of both AZD1222 and BNT16b2 primary courses, with evidence of some recipients failing to neutralise at all. This will likely lead to increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection, although there is currently no evidence of increased potential to cause severe disease, hospitalization or death.
mRNA Treatment Rescues Niemann-Pick Disease Type C1 in Patient Fibroblasts
Authors: Furtado Denzil , Cortez-Jugo Christina , Hung Ya Hui , Bush Ashley I. , Caruso Frank
Published: February 2022

Messenger RNA (mRNA) holds great potential as a disease-modifying treatment for a wide array of monogenic disorders. Niemann-Pick disease type C1 (NP-C1) is an ultra-rare monogenic disease that arises due to loss-of-function mutations in theNPC1gene, resulting in the entrapment of unesterified cholesterol in the lysosomes of affected cells and a subsequent reduction in their capacity for cholesterol esterification. This causes severe damage to various organs including the brain, liver, and spleen. In this work, we describe the use of NPC1-encoded mRNA to rescue the protein insufficiency and pathogenic phenotype caused by biallelicNPC1mutations in cultured fibroblasts derived from an NP-C1 patient. We first evaluated engineering strategies for the generation of potent mRNAs capable of eliciting high protein expression across multiple cell types. We observed that “GC3” codon optimization, coupled with N1-methylpseudouridine base modification, yielded an mRNA that was approximately a thousand-fold more potent than wildtype, unmodified mRNA in a luciferase reporter assay, and consistently superior to other mRNA variants. Our data suggest that the improved expression associated with this design strategy was due in large part to the increased secondary structure of the designed mRNAs. Both codon optimization and base modification appear to contribute to increased secondary structure. Applying these principles to the engineering of NPC1-encoded mRNA, we observed a normalization in NPC1 protein levels after mRNA treatment, as well as a rescue of the mutant phenotype. Specifically, mRNA treatment restored the cholesterol esterification capacity of patient cells to wildtype levels, and induced a significant reduction in both unesterified cholesterol levels (>57% reduction compared to Lipofectamine-treated control in a cholesterol esterification assay) and lysosome size (157 μm2reduction compared to lipofectamine-treated control). These findings show that engineered mRNA can correct the deficit caused byNPC1mutations. More broadly, they also serve to further validate the potential of this technology to correct diseases associated with loss-of-function mutations in genes coding for large, complex, intracellular proteins.
The immune profile of Major Dysmood Disorder: proof of concept and mechanism using the precision nomothetic psychiatry approach
Authors: Maes Michael , Rachayon Muanpetch , Jirakran Ketsupar , Sodsai Pimpayao , Klinchanhom Siriwan , Gałecki Piotr , Sughondhabirom Atapol
Published: February 2022

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class namely Major Dysmood Disorder, a new pathway phenotype namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, M1, T helper (Th)1, Th2, Th17, Tregulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into one a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS / CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.
Spinning Disk Multifocal Microscopy for Dynamic Arbitrarily Shaped Surface Imaging at Centimetre Scale and Micrometre Resolution
Authors: Xie Hao , Han Xiaofei , Xiao Guihua , Xu Hanyun , Zhang Yuanlong , Zhang Guoxun , Li Qingwei , He Jin , Zhu Dan , Yu Xinguang , Dai Qionghai
Published: February 2022

The large-scale fluorescence microscopy has enabled the observation of dynamic physiological activities at the single cellular level across the mouse cortex, such as distributed neuronal population representations. However, video-rate high-resolution microscopy at sophisticated biological surfaces in nature keeps a challenging task for the tradeoff between the speed, resolution, and field of view. Here we propose Spinning Disk Multifocal Microscopy (SDiM) for arbitrarily shaped surfaces, which enables imaging at centimeter field-of-view, micrometer resolution and up to 30 frames per second across the depth range of 450 µm. We apply this technique in various microscopic systems, including customized macroscopic systems and the Real-time Ultra-large-Scale imaging at High resolution macroscopy (RUSH), in both the reflective mode and the fluorescence mode, and in the study of cortex-wide single-neuron imaging and immune cell tracking. SDiM provides an opportunity for studying the cortex-wide multi-scale cellular interactions in biological tissues.
Odorant receptor orthologues in conifer-feeding beetles display conserved responses to ecologically relevant odors
Authors: Roberts Rebecca E. , Biswas Twinkle , Yuvaraj Jothi Kumar , Grosse-Wilde Ewald , Powell Daniel , Hansson Bill S. , Löfstedt Christer , Andersson Martin N.
Published: February 2022

Insects are able to detect a plethora of olfactory cues using a divergent family of odorant receptors (ORs). Despite the divergent nature of this family, related species frequently express several evolutionarily conserved OR orthologues. In the largest order of insects, Coleoptera, it remains unknown whether OR orthologues have conserved or divergent functions in different species. Using HEK293 cells, we addressed this question through functional characterization of two groups of OR orthologues in three species of the Curculionidae (weevil) family, the conifer-feeding bark beetlesIps typographusL. (‘Ityp’) andDendroctonus ponderosaeHopkins (‘Dpon’) (Scolytinae), and the pine weevilHylobius abietisL. (‘Habi’; Molytinae). The ORs ofH. abietiswere annotated from antennal transcriptomes. Results show highly conserved response specificities, with one group of orthologues (HabiOR3/DponOR8/ItypOR6) responding exclusively to 2-phenylethanol (2-PE), and the other group (HabiOR4/DponOR9/ItypOR5) responding to angiosperm green leaf volatiles (GLVs). Both groups of orthologues belong to the coleopteran OR subfamily 2B, and share a common ancestor with OR5 in the cerambycidMegacyllene caryae, also tuned to 2-PE, suggesting a shared evolutionary history of 2-PE receptors across two beetle superfamilies. The detected compounds are ecologically relevant for conifer-feeding curculionids, and are probably linked to fitness, with GLVs being used to avoid angiosperm non-host plants, and 2-PE being important for intraspecific communication and/or playing a putative role in beetle-microbe symbioses. To our knowledge, this study is the first to reveal evolutionary conservation of OR functions across several beetle species and hence sheds new light on the functional evolution of insect ORs.
Confirming Multiplex Q-PCR Use in COVID-19 with Next Generation Sequencing: Strategies for Epidemiological Advantage
Authors: Carpenter Rob E. , Tamrakar Vaibhav , Chahar Harendra , Vine Tyler , Sharma Rahul
Published: February 2022

Rapid classification and tracking of emerging SARS-CoV-2 variants are critical for understanding the transmission dynamics and developing strategies for interrupting the transmission chain. Next-Generation Sequencing (NGS) is an exceptional tool for whole-genome analysis and deciphering new mutations. The technique has been instrumental in identifying the Variants of Concern and tracking this pandemic. However, NGS remains expensive and time-consuming for large-scale monitoring of COVID-19. This study analyzed a total of 78 de-identified samples that screened positive for SARS-CoV-2 from two timeframes, August 2020 and July 2021. All 78 samples were classified into WHO lineages by whole genome sequencing then compared with two commercially available Q-PCR assays for spike protein mutation(s). The data showed good concordance with Q-PCR and NGS analysis for specific SARS-COV-2 lineages and characteristic mutations.

Deployment of Q-PCR testing to detect known SARS-COV-2 variants may be extremely beneficial. These assays are quick and cost-effective, thus can be implemented as an alternative to sequencing for screening known mutations of SARS-COV-2 for clinical and epidemiological interest. The findings support the great potential for Q-PCR to be an effective strategy offering several COVID-19 epidemiological advantages.
Sensory-motor computations in a cortico-pontine pathway
Authors: Darlington Timothy R. , Lisberger Stephen G.
Published: February 2022

Subcortical circuits decode the output from multiple cortical areas to create commands for movement. By recording during monkeys’ smooth pursuit eye movements, we reveal how the dorsolateral pontine nucleus (DLPN) and nucleus reticularis tegmenti pontis (NRTP) decode cortical output. Preparatory activity is inherited from the smooth eye movement region of the frontal eye fields (FEFSEM). Consistent with its effects on eye movement responses to visual motion, preparatory activity modulates the gain of pontine responses to visual motion input from visual area MT. Furthermore, the “place” code for target speed in area MT becomes the motor command’s “rate” code in the pons, through linear weighting of MT’s output. The division into decoding that happens in the pons and residual computations that occur downstream reveals that the pons is neither a relay nor the source of a final motor command. It is part of a complex, distributed cortical decoder for motor control.
Trends in Arabidopsis Research post genome sequencing- A Scientometric study
Authors: Kumar Sandeep , Kushwaha Amar Kant , Thribhuvan R , Balakrishnan M , Krishnan P
Published: February 2022

1.

Arabidopsis thaliana, a model plant, is intensively researched because of the intrinsic advantages associated with its life cycle, genetics, and other characteristics. In the present study, we analysed the publication data of research work done on A. thaliana during 2001-2020, a period when the whole genome sequence of the plant was available to the researchers. The current meta-analysis showed that 31965 research papers were published globally on Arabidopsis during the study period. The USA topped the countries with the maximum share of publications (28.97%), followed by China, Japan, and West European countries. The analysis showed a temporal shift in the number of publications from different countries and their research focus. After 2013, the research output from China was higher than that from the USA, and there was a shift in focus from developmental biology to stress-related topics. Plant Physiology journal carried the most research work (2490 publications) on Arabidopsis, which was followed by Plant Cell (2376), the Plant Journal (2260) and the Journal of Experimental Botany (1121). However, there was a progressive decline in the publication in these journals, and a shift was evident in favour of open access journals like Frontiers in Plant Science. The publication and citation numbers also show ongoing Arabidopsis research’s relevance to plant sciences, particularly curiosity-driven and discovery-based science. This article delves into the patterns in the prominence of research areas, ideas and foci for the future Arabidopsis research roadmap.
Frequency dependent growth of bacteria in living materials
Authors: Lewis Daniel D. , Gong Ting , Xu Yuanwei , Tan Cheemeng
Published: February 2022

The fusion of living bacteria and man-made materials represents a new frontier in medical and biosynthetic technology. However, the principles of bacterial signal processing inside three dimensional and fluctuating environments of synthetic materials remain elusive. Here, we study bacterial growth in a three-dimensional hydrogel. We find that bacteria expressing an antibiotic resistance module can take advantage of ambient kinetic disturbances to improve growth while encapsulated. We show that these changes in bacterial growth are specific to disturbance frequency and hydrogel density. This remarkable specificity is consistent with stochastic resonance theory, which we leverage to explain how bacteria can integrate spatial and temporal information to control growth. This research provides a quantitative foundation for the control of living materials and a systematic framework towards understanding bacterial information processing in three-dimensional environments.
Condensin II is required for efficient Spindle Assembly Checkpoint activation in Drosophila male meiosis
Authors: Horta Cintia , Tavares Alexandra , Oliveira Raquel A.
Published: February 2022

Reductional nuclear division in meiosis is essential for diploid life. A fundamental event in meiosis is chromatin condensation, through mechanisms not yet fully understood. Current data suggest that Condensins are key players in building and sustaining mitotic and meiotic chromosome structure. In Drosophila, Condensin II appears to be dispensable for faithful mitosis in somatic tissues yet essential in the germline. Previous work has demonstrated that in Drosophila male meiosis, Condensin II is required for the segregation of homologous chromosomes into distinct territories during prophase I, possibly through the resolution of chromosomal intertwines. Here we show that in addition to this well-established function in meiotic chromatin assembly, Condensin II is required for robust Spindle Assembly Checkpoint (SAC) signaling in male meiosis. In the absence of Condensin II, spermatocytes undergo faster meiotic divisions and display reduced ability to prolong meiosis in the presence of spindle poisons. This is attributed to the inability to recruit a key SAC component (Mad1) to the kinetochore. Importantly, we demonstrate that the absence of a robust SAC response in Condensin II mutants, and consequent accelerated meiosis, is a strong contributor to the meiotic defects associated with these mutants. We show that artificial prolongation of meiotic divisions, using conditions that delay anaphase onset in a SAC-independent manner, is sufficient to rescue segregation defects and aneuploidy associated with Condensin II mutations. We therefore conclude that Condensin II can be dispensable for the resolution of topological problems and chromosome condensation if cells are able to prolong meiosis. Yet, the newly found role of this complex in the robustness of the SAC reduces meiotic timing leading to severe chromosome segregation defects.
Topologically frustrated dynamics in an uncharged Tetra-PEG gel
Authors: Jia Di , Tsuji Yui , Shibayama Mitsuhiro , Muthukumar Murugappan
Published: February 2022

Based on our previous discovery of non-diffusive topologically frustrated dynamics in a charged system where electrostatic interactions between the charged guest and the charged host gel play a role (Nature Communications, 2018, 9, 2248; Physical Review Letters, 2021, 126, 057802), we have investigated the onset of this effect in an uncharged gel matrix. Using sodium (polystyrene sulfonate) as the guest macromolecule and the ideal tetra-PEG gel, we find the emergence of the non-diffusive topologically frustrated dynamical state with a hierarchy of segmental dynamics represented by a stretched exponential of exponent β around 1/3. Our results demonstrate the universal behavior of the topologically frustrated dynamical state.
Human septins in cells organize as octamer-based filaments mediating actin-membrane anchoring
Authors: Martins Carla Silva , Taveneau Cyntia , Castro-Linares Gerard , Baibakov Mikhail , Buzhinsky Nicolas , Eroles Mar , Milanović Violeta , Iv Francois , Bouillard Léa , Llewellyn Alex , Gomes Maxime , Belhabib Mayssa , Kuzmić Mira , Verdier-Pinard Pascal , Lee Stacey , Badache Ali , Kumar Sanjay , Chandre Cristel , Brasselet Sophie , Rico Felix , Rossier Olivier , Koenderink Gijsje H. , Wenger Jerome , Cabantous Stéphanie , Mavrakis Manos
Published: February 2022

Septins are cytoskeletal proteins conserved from algae and protists to mammals. Septin knock-out animals have established that septins are essential for animal physiology, but their molecular function remains elusive. A unique feature of septins is their presence as heteromeric complexes that polymerize into filaments in solution and on lipid membranes. Although animal septins associate extensively with actin-based structures in cells, whether actin-decorating septins organize as filaments and if septin organization impacts septin function is not known. Customizing a tripartite split-GFP complementation assay for probing the presence and composition of septin filamentsin situin cells, we show that all septins decorating actin stress fibers are present as filaments whose integrity depends on octameric septin protomers. Atomic force microscopy nanoindentation measurements on cells confirmed that cell stiffness depends on the presence of octamer-containing septin filaments. Super-resolution structured illumination microscopy revealed septin fibers with widths compatible with their organization as paired septin filaments. Nanometer-resolved distance measurements and single-protein tracking further showed that actin-associated septin filaments are membrane-bound and largely immobilized. Finally, reconstitution assays on supported lipid bilayers showed that septin filaments mediate actin-membrane anchoring. We propose that septin organization as octamer-based filaments is essential for septin function in anchoring and stabilizing actin fibers at the plasma membrane.
Epidermal basal domains organization highlights skin robustness to environmental exposure
Authors: Ghuwalewala Sangeeta , Lee Seon A , Jiang Kevin , Baidya Joydeep , Chovatiya Gopal , Kaur Pritinder , Shalloway David , Tumbar Tudorita
Published: February 2022

Adult interfollicular epidermis (IFE) renewal is likely orchestrated by physiological demands of its complex tissue architecture comprising spatial and cellular heterogeneity. Mouse tail and back skin display two kinds of basal IFE spatial domains that regenerate at different rates. Here we elucidate the molecular and cellular states of basal IFE domains by marker expression and single cell transcriptomics in mouse and human skin. We uncover two paths of basal cell differentiation that reflect in part the IFE spatial domain organization. We unravel previously unrecognized similarities between mouse tail IFE basal domains defined as scales and interscales versus human rete ridges and inter-ridges, respectively. Second, our basal IFE transcriptomics and gene targeting in mice provide evidence supporting a physiological role of IFE domains: adaptation to differential UV exposure. We identify Sox6 as a novel UV-induced and interscale/inter-ridge basal IFE-domain transcription factor, important for IFE proliferation and survival. The spatial, cellular, and molecular organization of IFE basal domains underscores skin adaptation to environmental exposure and its unusual robustness in adult homeostasis.

Synopsis