bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflections on Indirect (Co-)Perpetration through an Organization
Authors: Orozco López Hernán Darío , Silva Santaularia Natalia
Published: August 2022

This article deals with the question of the attribution of criminal responsibility to leaders of large criminal organizations for crimes which were committed by their subordinates in compliance with their orders. It presents a critical assessment of Roxin’s theory of indirect perpetration through an organized apparatus of power, as well as of the International Criminal Court’s theory of indirect co-perpetration through an organized structure of power. Both theories have serious shortcomings and, in addition, fail to conceptually capture the greater responsibility of the leaders of the organization vis-à-vis the executors. Thus, this article presents an outline of a typological system of the influence over the crime, which constitutes an alternative system of criminal participation and offers a better solution to the problem of criminal responsibility of the members of an organized apparatus of power.
Genetic modification of PIN genes induces causal mechanisms of stay-green drought adaptation phenotype
Authors: Borrell Andrew K , Wong Albert C S , George-Jaeggli Barbara , van Oosterom Erik J , Mace Emma S , Godwin Ian D , Liu Guoquan , Mullet John E , Klein Patricia E , Hammer Graeme L , McLean Greg , Hunt Colleen , Jordan David R
Published: August 2022

The stay-green trait is recognized as a key drought adaptation mechanism in cereals worldwide. Stay-green sorghum plants exhibit delayed senescence of leaves and stems, leading to prolonged growth, a reduced risk of lodging, and higher grain yield under end-of-season drought stress. More than 45 quantitative trait loci (QTL) associated with stay-green have been identified, including two major QTL (Stg1 and Stg2). However, the contributing genes that regulate functional stay-green are not known. Here we show that the PIN FORMED family of auxin efflux carrier genes induce some of the causal mechanisms driving the stay-green phenotype in sorghum, with SbPIN4 and SbPIN2 located in Stg1 and Stg2, respectively. We found that nine of 11 sorghum PIN genes aligned with known stay-green QTL. In transgenic studies, we demonstrated that PIN genes located within the Stg1 (SbPIN4), Stg2 (SbPIN2), and Stg3b (SbPIN1) QTL regions acted pleiotropically to modulate canopy development, root architecture, and panicle growth in sorghum, with SbPIN1, SbPIN2, and SbPIN4 differentially expressed in various organs relative to the non-stay-green control. The emergent consequence of such modifications in canopy and root architecture is a stay-green phenotype. Crop simulation modelling shows that the SbPIN2 phenotype can increase grain yield under drought.
Add-on effectiveness of methotrexate or iguratimod in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors: The ANSWER cohort study
Authors: Ebina Kosuke , Hirano Toru , Maeda Yuichi , Okita Yasutaka , Etani Yuki , Hirao Makoto , Yamamoto Wataru , Hashimoto Motomu , Murata Koichi , Onishi Akira , Jinno Sadao , Hara Ryota , Son Yonsu , Amuro Hideki , Kotani Takuya , Shiba Hideyuki , Katayama Masaki , Yamamoto Keiichi , Kumanogoh Atsushi , Okada Seiji , Nakata Ken
Published: August 2022

Objectives

This multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis).

Methods

Forty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients’ background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months.

Results

Thirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p < 0.05; IGU, 3.3 to 2.1, p < 0.001) and clinical disease activity index (MTX, 16.7 to 8.8, p < 0.05; IGU, 14.6 to 6.5, p < 0.01) improved significantly from baseline. Using the 2019 European League Against Rheumatism criteria, 45.4% (MTX) and 39.1% (IGU) achieved moderate or good response and 40.9% (MTX) and 39.1% (IGU) achieved American College of Rheumatology 20% improvement criteria.

Conclusions

Adding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.
The serum immunoglobulin G titres against Porphyromonas gingivalis as a predictor of clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: A retrospective cohort study
Authors: Kobayashi Tetsuo , Ito Satoshi , Murasawa Akira , Ishikawa Hajime , Tabeta Koichi
Published: August 2022

Objectives

The aim is to evaluate the relevance of serum immunoglobulin G (IgG) titres against periodontopathic bacteria to predict the clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients.

Methods

Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after 1-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titres against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements.

Results

Twenty-five patients with low anti-P. gingivalis IgG titres showed significantly greater decreases in changes in the Clinical Disease Activity Index and swollen joint count than 25 patients with high anti-P. gingivalis IgG titres (p = .04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titres with Clinical Disease Activity Index changes (p = .02 and p = .002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titre groups.

Conclusions

Baseline serum anti-P. gingivalis IgG titres are predictive of the clinical response to 1-year treatment with bDMARDs in RA patients.
Saving Brown Women from Brown Men? “Refugee Women”, Gender and the Racialised Politics of Protection
Authors: Crawley Heaven
Published: August 2022

White feminist scholarship in the Global North has drawn attention to the challenges facing women seeking protection under international refugee law (IRL). Whilst these efforts have improved outcomes for some women, they have largely failed to reconfigure the ways in which gendered experiences of persecution are conceptualised and represented. Drawing on postcolonial feminist scholarship, this article suggests that white feminist scholars have been largely complicit in a script that essentialises the experiences of women originating from the Global South. Where gender is taken into account, women from the Global South are typically understood and represented through a neo-imperial frame as disempowered, helpless “victims”, or as “Exotic Others” who need to be rescued from their “backward” cultures. The framing of “Refugee Women” as a homogenous and undifferentiated category ignores the complex intersections of race and gender shaping both women’s experiences and the racialised politics of protection. Moreover, because white feminist approaches have a colonial “blind spot”, they ignore the ways in which the international refugee regime is deeply entangled with the history of colonialism. In so doing, they replicate and reinforce racialised representations of Black and Muslim men as perpetrators of violence against women.
Effects of DNA template preparation on variability in cell-free protein production
Authors: Romantseva Eugenia , Alperovich Nina , Ross David , Lund Steven P , Strychalski Elizabeth A
Published: August 2022

DNA templates for protein production remain an unexplored source of variability in the performance of cell-free expression (CFE) systems. To characterize this variability, we investigated the effects of two common DNA extraction methodologies, a postprocessing step and manual versus automated preparation on protein production using CFE. We assess the concentration of the DNA template, the quality of the DNA template in terms of physical damage and the quality of the DNA solution in terms of purity resulting from eight DNA preparation workflows. We measure the variance in protein titer and rate of protein production in CFE reactions associated with the biological replicate of the DNA template, the technical replicate DNA solution prepared with the same workflow and the measurement replicate of nominally identical CFE reactions. We offer practical guidance for preparing and characterizing DNA templates to achieve acceptable variability in CFE performance.
La sécurité sur les marchés financiers de l’espace OHADA
Authors: Mouhouain Salifou
Published: August 2022

The growth of the Member States of OHADA would be difficult if security was not a guiding principle in their financial markets. And so, the CEMAC and UEMOA authorities have taken measures to prevent and address the risks of financial market transactions, namely abuse and default. Thus, on the preventive side, controls are instituted to prevent abuses as well as a guarantee of the default. On the curative side, proceedings and indemnities are provided in case of abuse and, outcome of position and compensation for the victims to provide a guarantee against default.
OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CHOROIDAL MELANOMA-ASSOCIATED SUBRETINAL FLUID
Authors: Guner Melis Kabaalioglu , Ferenchak Kevin , Olsen Timothy W. , Dalvin Lauren A.
Published: August 2022

Purpose:

To report optical coherence tomography findings of choroidal melanoma with subretinal fluid (SRF).

Methods:

Single-center, retrospective review of spectral-domain optical coherence tomography in treatment-naive choroidal melanoma with associated SRF presenting between July 2009 and August 2021.

Results:

Of 236 included patients, choroidal melanoma was small (n = 98, 41.5%), medium (n = 99, 41.9%), or large (n = 39, 16.5%). The most common optical coherence tomography feature was ellipsoid zone loss/disruption (n = 174, 73.7%), with unique features of bacillary layer detachment (n = 67, 28.4%), and heterogenous (n = 72, 30.5%) or homogenous (n = 48, 20.3%) subretinal hyperreflective material. Comparison (small vs. medium vs. large) revealed greater SRF extent with increasing tumor size (SRF ≥2 quadrants: 6.1% vs. 27.2% vs. 67.7%, P < 0.001). Ellipsoid zone disruption was less common in small tumors (52.0% vs. 86.9% vs. 94.9%, P < 0.001). Bacillary layer detachment was more common in medium tumors (16.3% vs. 40.4% vs. 28.2%, P < 0.001) and, compared with eyes without bacillary layer detachment, was associated with more SRF (minimal SRF vs. SRF ≥1 quadrant: likelihood ratio 18.8, P < 0.001) and more frequent heterogenous subretinal hyperreflective material (58.2% vs. 19.5%, P < 0.001).

Conclusion:

Optical coherence tomography features of choroidal melanoma–associated SRF vary by tumor size, with greater SRF extent in larger tumors, less ellipsoid zone disruption in small tumors, and more bacillary layer detachment in medium tumors.
REPRODUCTIVE OPHTHALMOLOGY
Authors: Park Jong G. , Xu Christine L. , Boyd Allison , Aghajanova Lusine , Mahajan Vinit B. , Wood Edward H.
Published: August 2022

Purpose:

To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing.

Methods:

Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children.

Results:

Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children.

Conclusion:

A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.
EFFECT OF PHYSICIAN FACE MASK USE ON POSTINJECTION ENDOPHTHALMITIS
Authors: Fortes Blake H. , Astafurov Konstantin V. , Hodge David O. , Smith Wendy M. , Barkmeier Andrew J. , Olsen Timothy W. , Iezzi Raymond , Bakri Sophie J.
Published: August 2022

Purpose:

To examine the impact of physician face mask use on the rates and outcomes of postinjection endophthalmitis.

Methods:

A multicenter retrospective, comparative cohort study comparing endophthalmitis rate and visual acuity of eyes that developed endophthalmitis after antivascular endothelial growth factor injections at Mayo Clinic Rochester (MCR) and at Mayo Clinic Health System sites depending on physician masking.

Results:

A total of 164,824 injections were performed at MCR and Mayo Clinic Health System sites. Of these, 66,098 injections were in the no mask group and 98,726 injections were in the mask group. Overall, there were no differences in the rates of infectious endophthalmitis in the no mask versus mask cohorts (overall: no mask: 20 cases [0.0303%] vs. mask: 41 cases (0.0415%); P = 0.24; infectious: no mask: 12 cases [0.018%] versus mask: 13 cases [0.0132%]; P = 0.42). At MCR alone, there was a significant reduction in infectious endophthalmitis between the no mask versus mask groups (no mask: 9 cases [0.0297%] versus mask: 2 cases [0.003%]; P < 0.001). Only 2 cases of infectious endophthalmitis occurred at MCR after the face mask policy was implemented (1 in 30,000 injections). At presentation and at 6 months, the average visual acuity was similar for patients who developed endophthalmitis between the no mask versus mask groups.

Conclusion:

Physician face mask use did not affect the rate or outcome of postinjection endophthalmitis. However, there was a significant reduction at MCR after masking along with other quality improvement measures, including performance of injections in a dedicated procedure room and preparation of patients by nurses, that led to a low rate of endophthalmitis.
RHEGMATOGENOUS RETINAL DETACHMENT AFTER INITIATION OF PILOCARPINE HYDROCHLORIDE OPHTHALMIC SOLUTION 1.25% FOR TREATMENT OF PRESBYOPIA
Authors: Eton Emily A. , Zhao Peter Y. , Johnson Mark W. , Rao Rajesh C. , Huvard Michael J.
Published: August 2022

Background/Purpose:

Retinal detachment has previously been reported in association with topical miotic use for the treatment of glaucoma. Pilocarpine hydrochloride 1.25% was recently approved by the Food and Drug Administration for the treatment of presbyopia, with no reports of associated retinal detachments in the clinical trial data.

Methods:

Case report.

Results:

Two novel cases of unilateral retinal detachment occurring within 10 days of the initiation of pilocarpine 1.25% for the treatment of presbyopia were described. The patients were pseudophakic men in their 60s or 70s with preexisting retinal detachment risk factors, such as high myopia, lattice degeneration, and prior retinal detachment. Both affected eyes were treated with pars plana vitrectomy and gas endotamponade with an uncomplicated postoperative course.

Conclusion:

Retinal detachment may be associated with the use of pilocarpine 1.25%. Caution should be used when considering prescribing this medication in patients with preexisting retinal abnormality.
Impact of a Pandemic as a Forced Disruption in Nursing Education
Authors: Foote Jane M. , Grimsley Amy T. , Forsyth Diane McNally
Published: August 2022

The purpose of this study was to determine the impact of a pandemic as a forced disruption in nursing education to recover from and prepare for current and future disruptions. Four qualitative themes from Midwestern nursing professional development providers (n = 60) noted impacts. Recommendations for nursing professional development leaders to support staff during turbulent times include preparation for online teaching and learning, and improved communication regarding essential education.
The Concept of Strength Through Synergy Applied to the Search of Powerful Prognostic Biomarkers in Gastroesophageal Cancer
Authors: Delgado Bolton Roberto C. , Calapaquí Terán Adriana K. , Fanti Stefano , Giammarile Francesco
Published: August 2022

Integrating clinical and pathological data together with imaging-derived information, such as radiomics and sarcopenia status, creating new combined biomarkers that increase the prognostic value compared with each of them used independently. The concept of strength through synergy, applicable in so many areas of life, is also demonstrated in this area of science and opens up innumerable pathways for improving patient care in cancer. This is as an example on how we can explore and make the most of all the information we already have (clinical, pathological, imaging), without the need for new invasive tests.
18F-FDG PET/CT in Urethral Metastases From Bladder Cancer
Authors: Beyhan Ediz , Baykal Koca Sevim , Yücetaş Uğur , Çermik Tevfik Fikret , Ergül Nurhan
Published: August 2022

Urethral metastasis of bladder cancer after surgery is rare. We present a 63-year-old man who had surgery for invasive bladder carcinoma and prostate adenocarcinoma 4 years ago and referred for urethral hemorrhage. 18F-FDG PET/CT was performed for restaging and showed intense linear 18F-FDG activity in the proximal urethra. The patient underwent urethrectomy, and histopathology determined urethral metastasis.
Osteomyelitis and Gentamicin-PMMA Chains
Authors: Février Agathe , Boursot Charles , Tannugi Kévin Cohen
Published: August 2022

In chronic osteomyelitis, effective local antibiotic therapy after surgical debridement can be achieved by implantation of gentamicin-PMMA chains. The gentamicin concentrations at the site of infection are higher than that after systemic application of the same antibiotic. The appearance of this treatment is a particular aspect from a radiological point of view. Even if this is rare, these images deserve to be known when looking for osteomyelitis. We report a case of a 21-year-old man from Russia who had a bone scan in the context of chronic osteomyelitis persisting since a shin splints operation in a context of bilateral trauma in his country with antibiotic beads application.
Motivation as a Predictor of Aphasia Treatment Outcomes
Authors: Weatherill Maryanne , Tibus Elizabeth O. , Rodriguez Amy D.
Published: August 2022

Purpose:

Motivation is a complex phenomenon that can influence a person's ability to make progress in treatment. We sought to understand how motivation is currently measured and utilized in aphasia rehabilitation by identifying treatment studies that (1) include measurement of motivation and (2) use motivation to predict treatment response.

Method:

A scoping review was conducted by systematically searching PubMed, CINAHL, EBSCO, Ovid MEDLINE, and APA PsycInfo using the following search terms: (measurement OR treatment OR rehabilitation OR predict*) AND (motiv* OR engagement OR adherence OR compliance) AND (aphasia OR dysphasia).

Results:

Two studies met our inclusion criteria. Motivation was measured differently across studies. No studies used motivation to predict treatment outcomes.

Discussion/Conclusions:

Despite the importance of motivation in aphasia rehabilitation success, studies that include its measurement are sparse. Additional research is needed and should include development of measurement tools and evaluation of the predictive value of motivation on treatment outcomes.
Is There a Relationship Between Cortisol and Treatment Response in Chronic Aphasia?
Authors: Gravier Michelle L. , Hula William D. , Johnson Jeffrey P. , Autenreith Alyssa , Dickey Michael Walsh
Published: August 2022

Purpose:

To evaluate whether levels of cortisol, a stress-related hormone, predicted response to intensive speech–language intervention for individuals with chronic aphasia (IWA). Secondary analyses explored baseline cortisol levels, change following intervention, association between cortisol levels and aphasia severity, self-reported communicative distress, and chronic stress.

Method:

Afternoon salivary cortisol levels were measured in 14 IWA during the first and last weeks of a 4-week intensive speech–language intervention epoch. Behavioral outcome measures were collected pre- and postintervention.

Results:

Cortisol levels did not significantly predict treatment response in this sample of IWA, although a positive trend was present. Baseline cortisol levels were not abnormally elevated, did not change from pre- to postintervention, and were not significantly correlated with any of the behavioral outcome measures.

Discussion:

Although afternoon salivary cortisol levels did not robustly predict treatment response in this participant sample, future studies may be warranted that include IWA with elevated levels of cortisol at pretreatment.
Neutral genetic diversity in mixed mating systems
Authors: Uyenoyama Marcy K.
Published: August 2022

Systems of reproduction differ with respect to the magnitude of neutral genetic diversity maintained in a population. In particular, the partitioning of reproductives into mating types and regular inbreeding have long been recognized as key factors that influence effective population number. Here, a range of reproductive systems (full gonochorism, full hermaphroditism, androdioecy, and gynodioecy) are compared with respect to the maintenance of neutral genetic diversity. The analysis assumes anisogamy, with reproduction limited by the availability of large gametes (ova or seeds) but not small gametes (sperm or pollen). Levels of neutral genetic diversity respond to the relative proportions of gonochores and hermaphrodites in different ways under androdioecy versus gynodioecy. The manner in which effective number, sex-specific viability differences, and the evolving quantitative trait of the population influence the level of neutral genetic diversity is described across the systems of reproduction studied.
Stricter protocols combined with a clinical serum biomarker can increase replicability and causality for dietary intervention studies. Plus empirical data on BPA regrettable substitutions
Authors: Perdue W. Lewis , Reus Victor I. , van Breemen Richard B. , Muchiri Ruth N. , Yeamans-Irwin Rebecca L.
Published: August 2022

Effective regulation of harmful environmental chemicals found in wide variety of consumer products and consumables has been thwarted by the lack of agreement between government scientists and university/academic laboratories regarding the quantification of significant human harms. This is particularly relevant regarding plastic-derived chemicals (PDCs), such as Bisphenol A, now that the federal CLARITY-BPA program has failed to achieve any credible, human-significant scientific consensus. Because of this disagreement, direct, clinical human experimental data is vital to resolving this situation. In an effort to develop direct human-relevant data, some academic investigators have employed dietary intervention studies in an attempt to shed light on the controversy. Unfortunately, dietary intervention efforts thus far have not demonstrated causality or replicability.

Investigators of this study propose a novel human dietary intervention protocol that can be both replicable and causal. This first-of-a-kind dietary intervention study explores a potential causal relationship between human serum levels of BPA and High-Sensitivity C-Reactive Protein (hsCRP), a proven clinical indicator of inflammation. Investigators used the equivalent of a USDA-defined typical diet followed by a PDC-reduced diet to compare blood levels of hsCRP. This proof-of-concept investigation is the first to use an easily accessible, medically-accepted clinical laboratory test to directly measure human health effects of PDC reduction.

Unexpected phenomena discovered during the investigation offer study protocol modifications to enhance widespread replicability, and economically practical expansion to a substantial proportion of the approximately 84,000 mostly unregulated chemicals found in the human environment. In addition, our LC/MS-MS results offer the first direct quantitative human clinical evidence (of which we are aware) confirming the existence of regrettable substitutions in which product manufacturers have reduced BPA usage while substituting Bisphenol analogues that appear to equal or exceed BPA human toxicity. Bolstered by the unexpected results in this proof-of-concept investigation, novel lessons and techniques described herein may further specific and improved methods and best practices that can enable future dietary interventions to produce replicable, causal human results.
Recombination shapes 2022 monkeypox outbreak
Authors: Yeh Ting-Yu , Hsieh Zih-Yu , Feehley Michael C. , Feehley Patrick J. , Contreras Gregory P. , Su Ying-Chieh , Hsieh Shang-Lin , Lewis Dylan A.
Published: August 2022

Background

On July 23, 2022, the WHO declared monkeypox outbreak a global health emergency. Here we analyze monkeypox virus (MPXV) sequences during 2022 pandemic to investigate whether the virus is adapting for better survival and transmission among the human population.

Methods

By studying tandem repeats (TRs) and linkage disequilibrium (LD), we analyzed 415 MPXV sequences from January 1 to July 20, 2022 worldwide.

Finding

The 2022 MPXV population has diverged into 4 lineages and 11 subgroups based on various TRs and their copy numbers. LD analysis also shows that virus has evolved into 3 new lineages. We identify 8 new recombinants (six from Slovenia, one from Australia, one from Italy) using TR analysis and 3 recombinants (two from Germany, one from Spain) using LD analysis.

Conclusion

Our results indicate that the MPXV genome is evolving and expanding quickly during the 2022 pandemic. We conclude that in combination with genomic surveillance, TR analysis, as well as LD analysis, are useful tools with which to monitor and track phylogenetic dynamics and recombination of monkeypox transmission.
Human photoreceptor cell transplants integrate into human retina organoids
Authors: Wagner Felix , Carrera Roberto , Kurth Thomas , Michalakis Stylianos , Naumann Ronald , Zuzic Marta , Neumann Katrin , Gourau Olivier , Busskamp Volker , Karl Mike O.
Published: August 2022

Cell transplantation is a promising therapeutic approach to recover loss of neurons and vision in patient retinas. So far, human photoreceptor transplants restored some visual function in degenerating mouse retina. Whether retinal cell transplants also integrate into human retina, and how to optimize this for different pathologies are still unknown. Here, we sought to determine if human retina organoids generated from pluripotent stem cells might assist cell replacement therapy development in a human-to-human setting. Models for intra- and subretinal cell transplantation strategies were explored: Photoreceptor donor cells carrying a transgenic fluorescent reporter were enriched from acutely dissociated human retinal organoids. Donor cells were precisely transplanted by microinjection into the retina of host organoids, but high cell numbers might require multiple injections posing potential damage. Alternatively, donor cells were transplanted in large numbers by placing them in subretinal-like contact to the apical organoid surface. Using postmitotic retinal organoids (age >170-days) as a source for donor cells and as hosts, we show that six weeks after subretinal-like transplantation, large clusters of photoreceptors reproducibly incorporate into the host retina. Transplanted clusters frequently are located within or across the host photoreceptor layer, include cone and rod photoreceptors, and become infiltrated by cell processes of host Müller glia, indicative of structural integration. Histological and ultrastructural data of virally-labeled photoreceptor transplants show characteristic morphological and structural features of polarized photoreceptors: inner segments and ribbon synapses, and donor-host cell contacts develop contributing to the retinal outer limiting membrane. These results demonstrate that human retinal organoids provide a preclinical research system for cell replacement therapies.

Graphical abstract
Odor identification task actually measures global cognition, but with 70% error
Authors: Tractenberg Rochelle E. , Yumoto Futoshi
Published: August 2022

Objective: To study the reliability and validity of an odor identification test.
Methods: The data come from an epidemiological cohort including 1146 non-Hispanic Caucasian, 86 Hispanic, and 12 other participants at the baseline visit (73.4% female). We tested the fit of each of three neurobiologically plausible models (validity) for responding on a 12-item odor identification task using confirmatory factor analyses (CFA); five model fit indices were assessed for each run. CFA testing fit over time (reliability) was planned for the measurement model that was found to fit across groups at the baseline visit. If a model was not found for the baseline visit, the test would be deemed 'not invariant' over group, and not tested over time. In this case, we planned a post hoc Rasch analysis to further study test validity; and a multi-trait, multi-method analysis (MTMM) of the entire test battery to study reliability in terms of other, valid, cognitive and neuropsychological functional assessments.
Results: Nearly 70% of the variability in odor identification scores is error, a result that was replicated over four independent samples at the baseline visit. A core of 30% of 'signal' from the task was identified over time (via Rasch modeling) but was explained fully by global cognition (replicated over time).
Conclusions: 'Odor identification' as a construct cannot be reliably or validly measured over time or group. Multiple hypothesis-driven methods and replications show that this test provides no information that a global cognition score does not also (more validly and reliably) provide.
Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model
Authors: Kandaswamy Surabhi , Zobel Lena , John Bina , Santhiya Sathiyaveedu Thyagarajan , Bogedein Jacqueline , Przemeck Gerhard K.H. , Gailus-Durner Valérie , Fuchs Helmut , Biel Martin , de Angelis Martin Hrabĕ , Graw Jochen , Michalakis Stylianos , Amarie Oana Veronica
Published: August 2022

Retinitis pigmentosa is a group of progressive inherited retinal dystrophies that may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. In a family suffering from retinitis pigmentosa, we identified a missense variation in CNGA1 affecting the cyclic nucleotide binding domain (CNBD) and characterized a mouse model developed with mutated CNBD. A gene panel analysis comprising 105 known RP genes was used to analyze a family with autosomal-recessive retinitis pigmentosa (arRP) and revealed that CNGA1 was affected. From sperm samples of ENU mutagenesis derived F1 mice, we re-derived a mutant with a Cnga1 mutation. Homozygous mutant mice, developing retinal degeneration, were examined for morphological and functional consequences of the mutation. In the family, we identified a rare CNGA1 variant (NM_001379270.1) c.1525G>A; (p.Gly509Arg), which co-segregated among the affected family members. Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526A>G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on. This study supports a role for CNGA1 as a disease gene for arRP and provides new insights on the pathobiology of cGMP-binding domain mutations in CNGA1-RP.
PeTriBERT : Augmenting BERT with tridimensional encoding for inverse protein folding and design
Authors: Dumortier Baldwin , Liutkus Antoine , Carré Clément , Krouk Gabriel
Published: August 2022

Protein is biology workhorse. Since the recent break-through of novel folding methods, the amount of available structural data is increasing, closing the gap between data-driven sequence-based and structure-based methods. In this work, we focus on the inverse folding problem that consists in predicting an amino-acid primary sequence from protein 3D structure. For this purpose, we introduce a simple Transformer model from Natural Language Processing augmented 3D-structural data. We call the resulting model PeTriBERT: Proteins embedded in tridimensional representation in a BERT model. We train this small 40-million parameters model on more than 350 000 proteins sequences retrieved from the newly available AlphaFoldDB database. Using PetriBert, we are able to in silico generate totally new proteins with a GFP-like structure. These 9 of 10 of these GFP structural homologues have no ressemblance when blasted on the whole entry proteome database. This shows that PetriBert indeed capture protein folding rules and become a valuable tool for de novo protein design.
Pelagibacter phage Skadi - An abundant polar specialist that exemplifies ecotypic niche specificity among the most abundant viruses on Earth
Authors: Buchholz Holger H. , Bolaños Luis M. , Bell Ashley G. , Michelsen Michelle L. , Allen Michael J. , Temperton Ben
Published: August 2022

Bacteria in the SAR11 clade are the most abundant members of surface marine bacterioplankton and are a critical component of global biogeochemical cycles. Similarly, pelagiphages that predate SAR11 are both ubiquitous and highly abundant in the oceans. These viruses are predicted to shape SAR11 community structures and increase carbon turnover throughout the oceans. Yet, ecological drivers of host and niche specificity of pelagiphage populations are poorly understood. Here we report the global distribution of a novel pelagiphage called Skadi isolated from the Western English Channel using a cold-water ecotype of SAR11 (HTCC1062) as bait. Skadi is closely related to the globally dominant pelagiphage HTVC010P. We show that, along with other HTVC010P-type viruses, Skadi belongs to a distinct viral family within the order Caudovirales for which we propose the name Ubiqueviridae. Metagenomic read recruitment identifies Skadi as one of the most abundant pelagiphages on Earth. Skadi is a polar specialist, replacing HTVC010P at high latitudes. Experimental evaluation of Skadi host-range against cold- and warm-water SAR11 ecotypes supported cold-water specialism. Read mapping from the Global Ocean Viromes project (GOV2) showed that relative abundance of Skadi correlated negatively with temperature, and positively with nutrients, available oxygen and chlorophyll concentrations. In contrast, relative abundance of HTVC010P correlated negatively with oxygen and positively with salinity, with no significant correlation to temperature. The majority of other pelagiphages were scarce in most marine provinces, with a few representatives constrained to discrete ecological niches. Our results suggest that pelagiphage populations persist within a global viral seed-bank, with environmental parameters and host availability selecting for a few ecotypes that dominate ocean viromes.
DeepIFC: virtual fluorescent labeling of blood cells in imaging flow cytometry data with deep learning
Authors: Timonen Veera A. , Kerkelä Erja , Impola Ulla , Penna Leena , Partanen Jukka , Kilpivaara Outi , Arvas Mikko , Pitkänen Esa
Published: August 2022

Imaging flow cytometry (IFC) combines flow cytometry with microscopy, allowing rapid characterization of cellular and molecular properties via high-throughput single-cell fluorescent imaging. However, fluorescent labeling is costly and time-consuming. We present a computational method called DeepIFC based on the Inception U-Net neural network architecture, able to generate fluorescent marker images and learn morphological features from IFC brightfield and darkfield images. Furthermore, the DeepIFC workflow identifies cell types from the generated fluorescent images and visualizes the single-cell features generated in a 2D space. We demonstrate that rarer cell types are predicted well when a balanced data set is used to train the model, and the model is able to recognize red blood cells not seen during model training as a distinct entity. In summary, DeepIFC allows accurate cell reconstruction, typing and recognition of unseen cell types from brightfield and darkfield images via virtual fluorescent labeling.
Cellular and computational models reveal environmental and genetic interactions in MMUT-type methylmalonic aciduria
Authors: Ramon Charlotte , Traversi Florian , Bürer Céline , Froese D. Sean , Stelling Jörg
Published: August 2022

MMUT-type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the methylmalonyl-CoA mutase (MMUT) enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT-KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose-based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT-deficient BJ5ta cell lines showed a reduced viability in glutamine-free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared to controls on purine- and glutamine-based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl-CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3-hydroxyisobutytyl-CoA hydrolase (HIBCH) in the secondary propionyl-CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway, which may have therapeutic relevance.

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By perturbing metabolic pathways through genetic and environmental interventions in cellular and computational models of MMUT-type methylmalonic aciduria, we identified glutamine and secondary oxidative propionyl-CoA oxidation pathways as being important in the disease.
Protein Fold Classification using Graph Neural Network and Protein Topology Graph
Authors: Sayeed Suri Dipannita , Wolf Jan Niclas , Koch Ina , Song Guang
Published: August 2022

Protein fold classification reveals key structural information about proteins that is essential for understanding their function. While numerous approaches exist in the literature that classifies protein fold from sequence data using machine learning, there is hardly any approach that classifies protein fold from the secondary or tertiary structure data using deep learning. This work proposes a novel protein fold classification technique based on graph neural network and protein topology graphs. Protein topology graphs are constructed according to definitions in the Protein Topology Graph Library from protein secondary structure level data and their contacts. To the best of our knowledge, this is the first approach that applies graph neural network for protein fold classification. We analyze the SCOPe 2.07 data set, a manually and computationally curated database that classifies known protein structures into their taxonomic hierarchy and provides predefined labels for a certain number of entries from the Protein Data Bank. We also analyze the latest version of the CATH data set. Experimental results show that the classification accuracy is at around 82% − 100% under certain settings. Due to the rapid growth of structural data, automating the structure classification process with high accuracy using structural data is much needed in the field. This work introduces a new paradigm of protein fold classification that meets this need. The implementation of the model for protein fold classification and the datasets are available here https://github.com/SuriDipannitaSayeed/ProteinFoldClassification.git

Author summary

Classification of protein structures is traditionally done using manual curation, evolutionary relationship, or sequence comparison-based methods. Applying machine learning and deep learning to protein structure classification is a comparatively new trend that holds great promises for automating the structure classification process. Advance deep learning technique like Graph Neural Network is still unexplored in this respect. SCOP and CATH are two traditional databases that provide the hierarchical taxonomic classification of protein structures. This work provides a novel computational approach that classifies protein folds in SCOP and CATH with graph neural network, performing a graph classification task.
Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson’s disease
Authors: Frigerio Irene , Laansma Max A , Lin Chen-Pei , Hermans Emma JM , Bouwman Maud MA , Bol John GJM , Galis-de Graaf Yvon , Hepp Dagmar H , Rozemuller Annemieke JM , Barkhof Frederik , van de Berg Wilma DJ , Jonkman Laura E
Published: August 2022

Increased neurofilament levels in biofluids, commonly used as a proxy for axonal degeneration in the brain, have been found in Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB), and correlate with MRI biomarkers. The aim of the current study was to unravel the regional distribution of cortical neurofilaments and their association with pathology load and MRI measures of atrophy and diffusivity in the post-mortem brain.

Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3Tin-situMRI. After autopsy, pSer129 alpha-synuclein (pSer129-αSyn), p-tau, and amyloid-beta, together with neurofilament light-chain (NfL) and phosphorylated neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in 7 cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.

Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was mainly increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. Increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.

Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increasing pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.
A contractile injection system mediates developmentally regulated intra-strain cell death in Streptomyces coelicolor
Authors: Vladimirov Maria , Zhang Ruo , Mak Stefanie , Nodwell Justin R. , Davidson Alan R.
Published: August 2022

Extracellular contractile injection systems (eCIS) are encoded in diverse clades of bacterial species. Although closely related to contractile phage tails, these entities can inject toxic proteins into eukaryotic cells. The roles of eCIS in mediating cytotoxic activities has led to a view of them as defense mechanisms that are not central to normal bacterial lifecycles. Here, we provide evidence that eCIS play an entirely distinct role in Streptomyces coelicolor (Sco), where they appear to participate in the complex developmental process of this species. In particular, we have shown that Sco produces eCIS particles as a part of its normal growth cycle and that strains lacking functional eCIS particles exhibit pronounced alterations in their developmental program. Most intriguingly, eCIS-deficient mutants display significantly reduced levels of cell death and altered morphology during liquid growth. These data suggest that Sco eCIS function by inducing intra-strain lethality rather than by attacking foreign species.
HIV-1 latent infection triggers broader epigenomic and transcriptional changes in protein-coding and long non-coding RNAs than active infection of SupT1 cells
Authors: Lê-Bury Gabrielle , Chen Yao , Rhen Jordan M. , Grenier Jennifer K. , Singhal Amit , Russell David G. , Boliar Saikat
Published: August 2022

Latent HIV-1 infection poses a major challenge in complete viral remission and cure. HIV-1 latency is a multi-dimensional, dynamic process and many aspects of how the viral latency is established and maintained still remains incompletely characterized. Here, we have investigated the host chromatin organization and transcriptomic changes in active- and latently-infected SupT1 cells. We employed an in vitro model of HIV-1 latency in SupT1 cells using a dual-reporter virus, HIVGKO, which enables high purity sorting and characterization of active- and latently-infected cells. We found a significant divergence in chromatin organization and gene expression pattern between active and latent infection compared to uninfected cells. Latent infection results in a repressive reorganization of the host chromatin, while active infection leads to an overall increase in chromatin accessibility. A stronger correlation was also observed between chromatin accessibility and gene expression in latent infection, which was manifested in a greater alteration of the cellular transcriptome in latent than active infection, for both protein-coding and long-non-coding RNAs (lncRNAs). We identified a number of novel lncRNAs associated with either active and latent infection. A reversal in expression pattern of latency-associated lncRNAs following PMA-induced reactivation indicated their infection-state-specific expression and potential roles in HIV-1 latency. Taken together, this integrated, comparative study revealed that latent HIV-1 infection requires a substantially greater alteration in cellular epigenome and transcriptome. Understanding of the distinct cellular states conducive to active and latent infection may support devising strategies for specific modulation of host cellular functions as a curative intervention for HIV-1.