bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements
Authors: Ridderbusch Isabelle C. , Wroblewski Adrian , Yang Yunbo , Richter Jan , Hollandt Maike , Hamm Alfons O. , Wittchen Hans-Ulrich , Ströhle Andreas , Arolt Volker , Margraf Jürgen , Lueken Ulrike , Herrmann Martin J. , Kircher Tilo , Straube Benjamin
Published: October 2020

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

Clinical Trials Registration

Registry names: Deutsches Register Klinischer Studien (DRKS) – German Clinical Trails Register

ClinicalTrials.gov

Registration ID-numbers: DRKS00008743

DRKS00009687

ClinicalTrials.gov Identifier: NCT02605668

URLs: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008743

https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00009687

https://clinicaltrials.gov/ct2/show/NCT02605668
Social inequalities in human mobility during the Spanish lockdown and post-lockdown in the Covid-19 pandemic of 2020
Authors: Hernando Alberto , Mateo David , barrios Ignacio , Plastino Angelo
Published: October 2020

Many countries established strong population lockdowns as a response to the pandemic of COVID-19 in 2020. While these measures proved efficient in stopping the spreading of the virus, they also introduced collateral effects in the economies of these countries. We report in this work that the imprints in mobility of both the lockdown and post-lockdown on the Spanish population are measurable by means of the daily radius of gyration using mobile phone data. We cross mobility with economic data segmented by average salary per person so as to find large inequalities between low- and high-income populations. Indeed, low-income populations typically show a 17% higher radius of gyration than high-income ones during pre-lockdown (8.1 km vs. 6.9 km). However, this relative difference grows to a maximum during lock-down (3.3 km vs. 900 m) since most of the essential workers (carriers, nurses, supermarket cashiers, farmworkers, etc.) belong to the first segment. Post-lockdown shows reversed inequality in the weeks during summer vacations as high-income populations multiplied their pre-lockdown radius by 70% as a rebound effect driven by leisure, while low-income populations recovered their normal pre-lockdown radius. This period is correlated with an extraordinary increase in the number of new Covid cases, which stabilized after the holyday weeks once at the so-called new normal. We find that this new normal emphasizes the pre-lockdown inequalities in mobility between low- and high-income population, increasing the inequality up to a 47%. These results show the relevance of devising measures that could account for potential collateral inequalities.
Modelling the impact of COVID-19-related programme interruptions on visceral leishmaniasis in India
Authors: Le Rutte Epke A , Coffeng Luc E , Muñoz Johanna , de Vlas Sake J
Published: October 2020

Background

In March 2020, India declared a nationwide lockdown to control the spread of COVID-19. As a result, control efforts against visceral leishmaniasis (VL) were interrupted.

Methods

Using an established age-structured deterministic VL transmission model, we predicted the impact of a 6 to 24-month programme interruption on the timeline towards achieving the VL elimination target, as well as on the increase of VL cases. We also explored the potential impact of a mitigation strategy after the interruption.

Results

Delays towards the elimination target are estimated to range between 0 to 9 years. Highly endemic settings where control efforts have been ongoing for 5-8 years are most affected by an interruption, for which we identified a mitigation strategy to be most relevant. However, more importantly, all settings can expect an increase in the number of VL cases. This increase is substantial even for settings with a limited expected delay in achieving the elimination target.

Conclusion

Besides implementing mitigation strategies, it is of great importance to try and keep the duration of the interruption as short as possible, to prevent new individuals from becoming infected with VL, and continue the efforts towards VL elimination as a public health problem in India.
Risk Factors for Mild, Moderate, and Severe Alcohol Use Disorder (AUD) in a sample of adult substance users: Implications for DSM-5 AUD Classification
Authors: Mannes Zachary L. , Shmulewitz Dvora , Livne Ofir , Stohl Malka , Hasin Deborah
Published: October 2020

Though risk factors of Alcohol Use Disorder (AUD) have been well-studied, information is lacking on whether clinical characteristics differentiate between the three levels of severity (mild, moderate, severe) that were established for the first time in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). Therefore, in this study, we examined the association between alcohol consumption, mental and physical health, and functional impairment with the three DSM-5 AUD severity levels among adults age 18+ (N=588) pre-screened for problems with at least one substance. Participants recruited between 2016-2019 completed measures of AUD, harmful alcohol use, psychiatric conditions, and mental, physical, and social functional impairment. For each predictor, a multinomial logistic regression model was used to evaluate the association with a four-level AUD outcome (mild, moderate, severe, vs none), controlling for sociodemographic characteristics and other substance use. Twelve-month prevalence of none, mild, moderate, and severe DSM-5 AUD was 34.0%, 12.2%, 13.4%, and 40.3%, respectively. Participants reported a mean of 11.3 (SD=9.90) days of alcohol use in the past month, nearly half (48.0%) perceived to have a major problem with alcohol, and 61.4% met the threshold for harmful drinking. Multinomial logistic regression demonstrated that compared to the reference group (no AUD), all three AUD severity levels were associated with drinking frequency, problematic, and harmful alcohol use. However, only severe AUD was associated with personality disorders: (AOR=1.91, 95% CI=1.28, 2.86), MDD (AOR= 2.44, 95% CI= 1.62, 3.66) or PTSD (AOR= 1.65, 95% CI= 1.00, 2.71),. Similarly, only severe AUD was associated with impaired physical (AOR= 1.63, 95% CI= 1.01, 2.61), mental (AOR= 1.80, 95% CI= 1.16, 2.79), and social functioning (AOR= 1.87, 95% CI= 1.39, 2.51). This study adds to existing literature on clinical correlates of AUD by further elucidating the risk factors of the different AUD severity groups, while also highlighting an important, differential observation wherein measures of psychiatric disorders and functional impairment were only associated with severe AUD. The study suggests that the DSM-5 category of severe AUD most closely corresponds to AUD cases often found in secondary or tertiary treatment settings, and that cases of mild or moderate AUD may warrant less intensive treatment approaches. Future investigations should seek to examine the validity of the DSM-5 AUD three-level severity distinction by using longitudinal designs to evaluate change in mental health and functioning over time, along with their association with AUD severity classification.
Phenome-wide HLA association landscape of 235,000 Finnish biobank participants
Authors: Ritari Jarmo , Koskela Satu , Hyvärinen Kati , FinnGen  , Partanen Jukka
Published: October 2020

The human leukocyte antigen (HLA) system is the single most important genetic susceptibility factor for many autoimmune diseases and immunological traits. However, in a range of clinical phenotypes the impact of HLA alleles or their combinations on the disease risk are not comprehensively understood.

For systematic population-level analysis of HLA-phenotype associations we imputed the alleles of classical HLA genes in a discovery cohort of 146,630 and replication cohort of 89,340 Finns of whom SNP genotype data and 3,355 disease phenotypes were available as part of the FinnGen project.

The results suggest HLA associations in phenotypes not reported previously and highlight interactions between HLA genes and alleles in autoimmune diseases. Furthermore, shared HLA alleles in autoimmune and infectious diseases support a genetic link between these diseases.
Prognostic value of early leukocyte fluctuations for recovery from traumatic spinal cord injury
Authors: Jogia T , Lübstorf T , Jacobson E , Scriven E , Atresh S , Liebscher T , Schwab JM , Kopp MA , Walsham J , Campbell KE , Ruitenberg MJ
Published: October 2020

Background

Acute traumatic spinal cord injury (SCI) induces a systemic immune response involving circulating white blood cells (WBC). How this response is influenced by overall trauma severity, the neurological level of injury and/or correlates with patient outcomes is poorly understood. The objective of this study was to identify relationships between early changes in circulating WBCs, injury characteristics, and long-term patient outcomes in individuals with traumatic SCI.

Methods

We retrospectively analysed data from n=161 SCI patients admitted to Brisbane’s Princess Alexandra Hospital (exploration cohort). Logistic regression models in conjunction with receiver-operator characteristic (ROC) analyses were used to assess the strength of specific links between the WBC response, respiratory infection incidence and neurological outcomes (American Spinal Injury Association Impairment Scale (AIS) grade conversion). An independent validation cohort from the Trauma Hospital Berlin, Germany (n=49) was then probed to assess the robustness of effects and to disentangle centre effects.

Results

We find that the extent of acute neutrophilia in human SCI patients is positively correlated with New Injury Severity Scores (NISS) but inversely with the neurological outcome (AIS grade). Multivariate analysis demonstrated that acute SCI-induced neutrophilia is an independent predictor of AIS grade conversion failure, with an odds ratio (OR) of 4.16 and ROC area under curve (AUC) of 0.82 (p<0.0001). SCI-induced lymphopenia was separately identified as an independent predictor of better recovery (OR = 24.15; ROC AUC = 0.85, p<0.0001). Acute neutrophilia and increased neutrophil-lymphocyte ratios were otherwise significantly associated with respiratory infection presentation in both patient cohorts.

Conclusions

Our findings demonstrate the prognostic value of modelling early circulating neutrophil and lymphocyte counts with patient characteristics for predicting the longer-term recovery after SCI.
Proximal arm non-use optimises movement when the shoulder is weak: consequences for stroke patients
Authors: Faity Germain , Mottet Denis , Pla Simon , Froger Jérôme
Published: October 2020

Most stroke patients do not use their paretic limb whereas they are able to. The Constraint-Induced Movement Therapy (CIMT) is effective to reverse this non-use behaviour in some patients but is inapplicable or unsuccessful on others. Here, we investigate how much non-use could come from shoulder weakness instead of the behavioural conditioning treated by the CIMT. We asked 26 healthy participants to reach a target while holding a dumbbell. We found that 18/26 participants exhibit proximal arm non-use when loaded and that non-use reduces shoulder torque of final posture. We either found that non-use improves accuracy in a high gravity field. Following optimal control policy, we explain how the non-use could be an adaptative solution when the shoulder is weak. Our results show the need to include muscular strength into cost function used to model human movement. The framework presented here suggests that psychological non-use could be treated effectively with CIMT, while physiological non-use, resulting from shoulder weakness, might respond better to anti-gravity muscles strengthening.
Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody
Authors: Rosenfeld Ronit , Noy-Porat Tal , Mechaly Adva , Makdasi Efi , Levy Yinon , Alcalay Ron , Falach Reut , Aftalion Moshe , Epstein Eyal , Gur David , Chitlaru Theodor , Vitner Einat B. , Melamed Sharon , Politi Boaz , Zauberman Ayelet , Lazar Shirley , Beth-Din Adi , Evgy Yentl , Yitzhaki Shmuel , Shapira Shmuel C. , Israely Tomer , Mazor Ohad
Published: October 2020

Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterized and further evaluated the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6-9 days post-infection while administration of the MD65 antibody as late as 3 days after exposure, rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data unprecedentedly demonstrate, the therapeutic value of human monoclonal antibodies as a life-saving treatment of severe COVID-19 infection.
Not so optimal: The evolution of mutual information in potassium voltage-gated channels
Authors: Durán Alejandra , Marzen Sarah
Published: October 2020

Potassium voltage-gated (Kv) channels need to detect and respond to rapidly changing ionic concentrations in their environment. With an essential role in regulating electric signaling, they would be expected to be optimal sensors that evolved to predict the ionic concentrations. To explore these assumptions, we use statistical mechanics in conjunction with information theory to model how animal Kv channels respond to changes in potassium concentrations in their environment. By estimating mutual information in representative Kv channel types across a variety of environments, we find two things. First, under a wide variety of environments, there is an optimal gating current that maximizes mutual information between the sensor and the environment. Second, as Kv channels evolved, they have moved towards decreasing mutual information with the environment. This either suggests that Kv channels do not need to act as sensors of their environment or that Kv channels have other functionalities that interfere with their role as sensors of their environment.
Survey, Identification and Evaluation of biodiversity ofSeabuckthorn(Hippophae salicifolia) in hills of Uttarakhand
Authors: Singh Ranjit , Dwivedi S.K. , Bala Madhu
Published: October 2020

Extensive studies were carried out during 2017-2019 to evaluate theHippophae salicifolia(Seabuckthorn) biodiversity in Uttarakhand for their physico-chemical/biochemical parameters of ripe fruits like acidity (1.78-3.01 %), pH (2.15-2.87), Vitamin ‘C’ (271-494mg/100g), Total soluble solids (5.1-9.8) etc. Variation was also observed in fruit color (light yellow, yellow, light yellow orange, orange and orange red), fruit size (length 6.29-8.77mm, width 4.80-7.59mm), Juice (44.23-76.18%), Pomace (8.01-28.30%) and seed (6.8-21.1%). On the basis of above parameters, promising morphotypes were identified and conserved at field gene bank at DIBER field station, Auli (Joshimath) 3142m AMSL.
Proteomic and transcriptomic analysis ofMicroviridaeφXI74 infection reveals broad up-regulation of host membrane damage and heat shock responses
Authors: Wright Bradley W , Logel Dominic Y , Mirzai Mehdi , Pascovici Dana , Molloy Mark P , Jaschke Paul R
Published: October 2020

Measuring host-bacteriophage dynamics is an important approach to understanding bacterial survival functions and responses to infection. The modelMicroviridaebacteriophage φX174 is endemic to the human gut and has been studied for over seventy years but the host response to infection has never been investigated in detail. To address this gap in our understanding of this important interaction within our microbiome we have measured hostEscherichia coliC proteomic and transcriptomic response to φX174 infection. We used mass spectrometry and RNA-seq to identify and quantify all 11 φX174 proteins and over 1,700E. coliproteins, enabling us to comprehensively map host pathways involved in φX174 infection. Most notably, we see significant host responses centered on membrane damage and remodeling, cellular chaperone and translocon activity, and lipoprotein processing, which we speculate is due to the peptidoglycan-disruptive effects of the φX174 lysis protein E on MraY activity. We also observe the massive upregulation of small heat-shock proteins IbpA/B, along with other heat shock pathway chaperones, and speculate on how the specific characteristics of holdase protein activity may be beneficial for viral infections. Together, this study enables us to begin to understand the proteomic and transcriptomic host responses ofE. colitoMicroviridaeinfections and contributes insights to the activities of this important model phage.

IMPORTANCE

A major part of the healthy human gut microbiome are theMicroviridaebacteriophage, exemplified by the model φX174 phage. Although much has been learned from studying φX174 over the last half century, until this work, theE. colihost response to infection has never been investigated in detail. We reveal the proteomic and transcriptomic pathways differentially regulated during the φX174 infection cycle, and uncover the details of a coordinated cellular response to membrane damage that results in increased lipoprotein processing and membrane trafficking, likely due to the phage antibiotic-like lysis protein. We also reveal that small heat shock proteins IbpA/B are massively upregulated during infection and that these holdase chaperones are highly conserved across the domains of life, indicating that reliance on them is likely widespread across viruses.
Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling
Authors: Hayn Manuel , Blötz Andrea , Rodríguez Armando , Vidal Solange , Preising Nico , Ständker Ludger , Wiese Sebastian , Stürzel Christina M. , Harms Mirja , Groß Rüdiger , Jung Christoph , Kiene Miriam , Hahn Beatrice H. , Jacob Timo , Pöhlmann Stefan , Forssmann Wolf-Georg , Münch Jan , Sparrer Konstantin M. J. , Seuwen Klaus , Kirchhoff Frank
Published: October 2020

GPR15 is a G protein-coupled receptor proposed to play a role in mucosal immunity that also serves as entry cofactor for HIV and SIV. To discover novel endogenous GPR15 ligands, we screened a hemofiltrate-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of Cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2 and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that Cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4+ T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this G protein-coupled receptor.
Positive outcomes of COVID-19 research-related gender policy changes
Authors: Witteman Holly O. , Haverfield Jenna , Tannenbaum Cara
Published: October 2020

The COVID-19 pandemic has exposed and exacerbated gender biases in science, technology, engineering, mathematics, and medicine. Accumulating evidence suggests that female scientists’ productivity dropped during the initial lockdown period. With more time being spent on caregiving responsibilities, women may be struggling to collaborate on grant applications and launch new experiments. Scientists with disabilities or who belong to Indigenous nations or communities of color may have less time to devote to research due to health, family, or community needs. Collateral damage in this situation, the appropriate integration of sex, gender, and other identity characteristics in research content may also suffer. Sex and gender are better attended to when female scientists form part of the research team. Research funding agencies have a role to play in mitigating these effects by putting in place gender equity policies that support all applicants and ensure research quality. Accordingly, a national health research funder implemented gender policy changes that included extending deadlines and factoring sex and gender into COVID-19 grant requirements. Following these changes, the funder received more applications from female scientists, awarded a greater proportion of grants to female compared to male scientists, and received and funded more grant applications that considered sex and gender in the content of COVID-19 research. Whether or not these strategies will be sufficient in the long-term to prevent widening of the gender gap in science, technology, engineering, mathematics and medicine requires continued monitoring and oversight. Further work is urgently required to mitigate inequities associated with identity characteristics beyond gender.
Di(2-ethylhexyl) adipate (DEHA), A NEW HOPE! A sustainable and promising process for the plasticisers industry
Authors: Acciaretti Federico , Pasquale Andrea
Published: October 2020

Plasticisers are commonly incorporated in plastic materials in order to improve their physico-chemicals properties. In particular, Poly-(vinyl chloride) (PVC) is a polymer which has excellent plasticiser compatibility characteristics. The demand for plasticized-PVC is steadily increasing and its synthesis need to be more sustainable, considering the interest in developing a circular economy in the next years. In order to achieve these goals, a bio-based process to synthesize di(2-ethylhexyl) adipate (DEHA), a widely used plasticiser, could be an interesting approach. The most important starting material for the process is adipic acid, but its synthesis from petrochemical sources is not sustainable. An alternative is using waste materials as substrates for fermentation in a totally green process. Among many strategies, the reverse adipate degradation pathway (RADP) inE. coliseems to be the most interesting one, considering the highest titer of 68 g/L and the yield of 93.1%. The next step is the enzyme-catalysed esterification of adipic acid and 2-ethylhexanol to produce DEHA, using an immobilized lipase fromCandida antarctica. Applying a solvent-free system under vacuum condition is convenient as it guarantees a conversion to DEHA of 100 mol%.
An interplay of population size and environmental heterogeneity explains why fitness costs are rare
Authors: Chavhan Yashraj , Malusare Sarthak , Dey Sutirth
Published: October 2020

Theoretical models of ecological specialization commonly assume that adaptation to one environment leads to fitness reductions (costs) in others. However, empirical studies often fail to detect such costs. We addressed this conundrum using experimental evolution withEscherichia coliin several homogeneous and heterogeneous environments at multiple population sizes. We found that in heterogeneous environments, smaller populations paid significant costs, but larger ones avoided them altogether. Contrastingly, in homogeneous environments, larger populations paid more costs than the smaller ones. Overall, large population sizes and heterogeneous environments led to cost avoidance when present together but not on their own. Whole-genome whole-population sequencing revealed that the enrichment of multiple mutations within the same lineage (and not subdivision into multiple distinct specialist subpopulations) was the mechanism of cost avoidance. Since the conditions revealed by our study for avoiding costs are widespread, it explains why the costs expected in theory are rarely detected in experiments.
The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey
Authors: Makovac Elena , Venezia Alessandra , Hohenschurz-Schmidt David , Dipasquale Ottavia , Jackson Jade B , Medina Sonia , O’Daly Owen , Williams Steve CR , McMahon Stephen B , Howard Matthew A
Published: October 2020

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored.

Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded.

Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes.

Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.
LINE-1 retrotransposons facilitate horizontal gene transfer into poxviruses
Authors: Julhasur Rahman M. , Haller Sherry L. , Stoian Ana M. M. , Li Jie , Brennan Greg , Rothenburg Stefan
Published: October 2020

There is ample phylogenetic evidence that many critical virus functions, like immune evasion, evolved by the acquisition of genes from their hosts through horizontal gene transfer (HGT). However, the lack of an experimental system has prevented a mechanistic understanding of this process. We developed a model to elucidate the mechanisms of HGT into vaccinia virus, the prototypic poxvirus. All identified gene capture events showed signatures of long interspersed nuclear element-1 (LINE-1)-mediated retrotransposition, including spliced-out introns, polyadenylated tails and target site duplications. In one case, the acquired gene integrated together with a polyadenylated host U2 small nuclear RNA. Integrations occurred across the genome, in some cases knocking out essential viral genes. These essential gene knockouts were rescued through a process of complementation by the parent virus followed by non-homologous recombination during serial passaging to generate a single competent virus. This work links multiple evolutionary mechanisms into one adaptive cascade and identifies host retrotransposons as major drivers for virus evolution.
Resveratrol reduces COMPopathy in mice through activation of autophagy
Authors: Hecht Jacqueline T. , Coustry Francoise , Veerisetty Alka C. , Hossain Mohammad G. , Posey Karen L.
Published: October 2020

Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within in ER of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation and oxidative stress which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant COMP, dampens cellular stress and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mTORC1 (mammalian target of rapamycin complex 1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild type or mutant COMP (MT-COMP), resveratrol significantly increased the number of large LC3 vesicles, directly demonstrating that resveratrol stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of MT-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of pAKT and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant COMP retention, decreased mTORC1 signaling and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to one week of age in MT-COMP mice, translating to birth to approximately 2 years of age in PSACH children. These results clearly demonstrate that resveratrol stimulates clearance of mutant COMP by an autophagy-centric mechanism.
In vivotwo-photon imaging and parasympathetic neuromodulation of pancreatic microvascular dynamics in rats
Authors: Canzano Joseph S. , Subramanian Narayan , Castro Rebeca , Siddiqi Abdurahman , Oweiss Karim G.
Published: October 2020

The pancreas has long been known to be densely innervated with parasympathetic, sympathetic, and visceral afferent fibers that are believed to exert significant influence on local endocrine activity and vascular function. Yet the extent to which these interactions depend on neurovascular dynamics in the normal and pathological states remain largely unknown. Herein we describe a new method for high resolution functional imaging of the rat pancreasin vivo. The method comprises a number of elements: a stability-optimized preparation in dorsal recumbency immobilizing several square centimeters of intact pancreas for upright fluorescent imaging while leaving access for concurrent manipulation of abdominal nerves, a full-frame two-photon imaging protocol and analysis pipeline supporting high-throughput (100+) monitoring of islet and acinar microvessel diameter dynamics simultaneously, and a first adaptation of random-access linescan imaging to the pancreas capable of tracking internal blood flow speeds up to 5 mm/s at 20 Hz across multiple microvessels. These methods were then deployed in concert to characterize the capacity of parasympathetic fibers to modulate pancreatic microvascular dynamics with compartment specificity. Electrical stimulation was repeatedly applied to the abdominal vagal trunks at various current magnitudes while imaging islet and acinar microvascular populations in the pancreas. Vagal stimulation consistently elicited increases in both islet and acinar capillary population motility in a current-dependent manner, with only acinar responsive vessels trending toward dilation. Further, we found vagal stimulation to profoundly and reversibly disrupt all traces of fast-wave vasomotor oscillation across a lobular arteriole-venule pair, and this was associated with a significant increase in average flow speed. Together, these findings add to mounting evidence that vagal projections exert tangible reversible influence on pancreatic microvascular activity and underscore the potential for new neuromodulation-based strategies to address diabetes, pancreatitis, or other diseases of the pancreas under autonomic nervous influence.
Physiological and ecological warnings that Dodder pose an exigent threat to farmlands in Eastern Africa
Authors: Masanga Joel , Mwangi Beatrice Njoki , Kibet Willy , Sagero Philip , Wamalwa Mark , Oduor Richard , Ngugi Mathew , Alakonya Amos , Ojola Patroba , Bellis Emily S. , Runo Steven
Published: October 2020

Invasive holoparasitic plants of the genusCuscuta(dodder) threaten Africa’s ecosystems, due to their rapid spread and attack on various host plant species. MostCuscutaspecies cannot photosynthesize, hence rely on host plants for nourishment. After attachment through a peg-like organ called a haustorium, the parasites deprive hosts of water and nutrients leading to their death. Despite their rapid spread in Africa, dodders have attracted limited research attention, although data on their taxonomy, host range and epidemiology are critical for their management. Here, we combine taxonomy and phylogenetics to reveal presence of field dodder (Cuscuta campestris) andC. kilimanjari(both either naturalized or endemic to East Africa), and for the first time in continental Africa, presence of the giant dodder (C. reflexa) a south Asian species. These parasites have a wide host range, parasitizing species across 13 angiosperm orders. Evaluating the possibility ofC. reflexato expand this host range to tea, coffee, and mango, crops of economic importance to Africa, revealed successful parasitism, following haustorial formation and vascular bundle connections in all three crops. However, only mango mounted a successful post-attachment resistance response. Furthermore, species distribution models predicted high habitat suitability for all threeCuscutaspecies across major tea- and coffee-growing regions of Eastern Africa, suggesting an imminent risk to these crops. Our findings provide relevant insights into a little-understood threat to biodiversity and economic wellbeing in Eastern Africa, and providing critical information to guide development of management strategies to avert their spread.

Sentence Summary

Microscopy and habitat suitability modeling provide an early warning that dodder’s invasion in Eastern Africa poses a threat to important cash crops
Comprehensive and scalable quantification of splicing differences with MntJULiP
Authors: Yang Guangyu , Sabunciyan Sarven , Florea Liliana
Published: October 2020

Alternative splicing of mRNA is an essential gene regulatory mechanism with important roles in development and disease. We present MntJULiP, a method for comprehensive and accurate quantification of splicing differences between two or more conditions. MntJULiP implements novel Dirichlet-multinomial and zero-inflated negative binomial models within a Bayesian framework to detect both changes in splicing ratios and in absolute splicing levels of introns with high accuracy, and can find classes of variation overlooked by reference tools. Additionally, a mixture model allows multiple conditions to be compared simultaneously. Highly scalable, it processed hundreds of GTEx samples in <1 hour to reveal splicing constituents of tissue differentiation.
Pausing after clap reduces power required to fling wings apart at low Reynolds number
Authors: Kasoju Vishwa T. , Santhanakrishnan Arvind
Published: October 2020

The smallest flying insects such as thrips (body length < 2 mm) are challenged with needing to move in air at chord-based Reynolds number (Rec) on the order of 10. Pronounced viscous dissipation at such lowRecrequires considerable energetic expenditure for tiny insects to stay aloft. Free-flying thrips flap their densely bristled wings at large stroke amplitudes, bringing both wings in close proximity of each other at the end of upstroke (‘clap’) and moving their wings apart at the start of downstroke (‘fling’). From high-speed videos of free-flying thrips, we observed that their forewings remain clapped for approximately 10% of the wingbeat cycle before start of fling. We sought to examine if there are aerodynamic advantages associated with pausing wing motion after clap and before fling atRec=10. A dynamically scaled robotic clap-and-fling platform was used to measure lift and drag forces generated by physical models of non-bristled (solid) and bristled wing pairs for pause times ranging between 0% to 41% of the cycle. In both solid and bristled wings, varying pause time showed no effect on average force coefficients generated within each half-stroke. This was supported by nearly identical time-variation of circulation of the leading and trailing edge vortices for different pause times. At smaller pause times, bristled wings showed larger reduction of cycle-averaged drag coefficient as compared to that of solid wings. For a given wing design (solid or bristled), the ratio of cycle-averaged lift coefficient to cycle-averaged drag coefficient was unchanged across different pause times. We observed 13.5% drop in cycle-averaged power coefficient and 3% drop in cycle-averaged lift coefficient when moving from 0% pause to 9% pause duration. Our results suggest that pausing at the end of clap can be beneficial for reducing the power required to fling, with a small reduction in lift.
Management of Acute Appendicitis in Children during Coronavirus Disease-2019, a Perspective of Pediatric Surgeons from South Asia
Authors: Hannan Md Jafrul , Parveen Mosammat Kohinoor , Hoque Md Mozammel , Chowdhury Tanvir Kabir , Hasan Md Samiul , Nandy Alak
Published: October 2020

Background

Non-operative treatment (NOT) of pediatric appendicitis as opposed to surgery elicits great debate and is potentially influenced by physician preferences. Owing to the effects of the COVID pandemic on healthcare, the practice of NOT has generally increased by necessity and may, in a post-COVID world, change surgeons’ perceptions of NOT.

Objective

The objective was to determine whether the use of NOT has increased in usage in South Asia and whether these levels of practice would be sustained after the pandemic subside.

Methods

A survey was conducted by pediatric surgeons regarding their position, institute, country, number of appendicitis cases managed, and their mode of treatment between identical time periods in 2019 and 2020 (April 1 to August 31). It also directly posed the question as to whether they would continue with the COVID imposed level of NOT after the effect of pandemic diminishes.

Results

A total of 134 responses were collected. A significant increase in the practice of NOT was observed for the entire cohort, although no effect was observed when grouped by country or institute. When grouped by position, seniors increased the practice of NOT the most, while juniors reported the least change. The data suggests that only professors would be inclined to maintain the COVID level of NOT practice after the pandemic.

Conclusions

Increased practice of NOT during the COVID pandemic was observed in South Asia, particularly by senior surgeons. Only professors appear inclined to consider maintaining this increased level of practice in the post-COVID world.
HybPhaser: a workflow for the detection and phasing of hybrids in target capture datasets
Authors: Nauheimer Lars , Weigner Nicholas , Joyce Elizabeth , Crayn Darren , Clarke Charles , Nargar Katharina
Published: October 2020

Premise of the study

Hybrids contain divergent alleles that can confound phylogenetic analyses but can provide insights into reticulated evolution when identified and phased. We developed a workflow to detect hybrids in target capture datasets and phase reads into parental lineages using a similarity and phylogenetic framework.

Methods

We used Angiosperms353 target capture data forNepenthesincluding known hybrids to test the novel workflow. Reference mapping was used to assess heterozygous sites across the dataset, detect hybrid accessions and paralogous genes. Hybrid samples were phased by mapping reads to multiple references and sorting reads according to similarity. Phased accessions were included in the phylogenetic framework.

Results

All knownNepentheshybrids and nine more samples had high levels of heterozygous sites, reads associated with multiple divergent clades, and were phased into accessions resembling divergent haplotypes. Phylogenetic analysis including phased accessions increased clade support and confirmed parental lineages of hybrids.

Discussion

HybPhaser provides a novel approach to detect and phase hybrids in target capture datasets, which can provide insights into reticulations by revealing origins of hybrids and reduce conflicting signal leading to more robust phylogenetic analyses.
Meta-Analysis Identifies Pleiotropic Loci Controlling Phenotypic Trade-offs in Sorghum
Authors: Mural Ravi V. , Grzybowski Marcin , Miao Chenyong , Damke Alyssa , Sapkota Sirjan , Boyles Richard E. , Fernandez Maria G. Salas , Schnable Patrick S. , Sigmon Brandi , Kresovich Stephen , Schnable James C.
Published: October 2020

Community association populations are composed of phenotypically and genetically diverse accessions. Once these populations are genotyped, the resulting marker data can be reused by different groups investigating the genetic basis of different traits. Because the same genotypes are observed and scored for a wide range of traits in different environments, these populations represent a unique resource to investigate both pleiotropy and genotype by environment interactions. Here we assembled a set of 234 separate trait datasets for the Sorghum Association Panel, a group of 406 sorghum genotypes widely employed by the sorghum genetics community. Comparison of genome wide association studies conducted with two independently generated marker sets for this population demonstrate that existing genetic marker sets do not saturate the genome and likely capture only 35-43% of potentially detectable loci controlling variation for traits scored in this population. While limited evidence for pleiotropy was apparent in cross-GWAS comparisons, a multivariate adaptive shrinkage approach recovered both known pleiotropic effects of existing loci and new pleiotropic effects, particularly significant impacts of known dwarfing genes on root architecture. In addition, we identified new loci with pleiotropic effects consistent with known trade-offs in sorghum development. These results demonstrate the potential for mining existing trait datasets from widely used community association populations to enable new discoveries from existing trait datasets as new, denser genetic marker datasets are generated for existing community association populations.
The Regulatory Evolution of the Primate Fine-Motor System
Authors: Wirthlin Morgan , Kaplow Irene M. , Lawler Alyssa J. , He Jing , Phan BaDoi N. , Brown Ashley R. , Stauffer William R. , Pfenning Andreas R.
Published: October 2020

In mammals, fine motor control is essential for skilled behavior, and is subserved by specialized subdivisions of the primary motor cortex (M1) and other components of the brain’s motor circuitry. We profiled the epigenomic state of several components of the Rhesus macaque motor system, including subdivisions of M1 corresponding to hand and orofacial control. We compared this to open chromatin data from M1 in rat, mouse, and human. We found broad similarities as well as unique specializations in open chromatin regions (OCRs) between M1 subdivisions and other brain regions, as well as species- and lineage-specific differences reflecting their evolutionary histories. By distinguishing shared mammalian M1 OCRs from primate- and human-specific specializations, we highlight gene regulatory programs that could subserve the evolution of skilled motor behaviors such as speech and tool use.
TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo
Authors: Chen Lu , Roake Caitlin M. , Maccallini Paolo , Bavasso Francesca , Dehghannasiri Roozbeh , Santonicola Pamela , Mendoza-Ferreira Natalia , Scatolini Livia , Rizzuti Ludovico , Esposito Alessandro , Gallotta Ivan , Francia Sofia , Cacchione Stefano , Galati Alessandra , Palumbo Valeria , Tartaglia Gian Gaetano , Colantoni Alessio , Proietti Gabriele , Wu Yunming , Hammerschmidt Matthias , De Pittà Cristiano , Sales Gabriele , Salzman Julia , Pellizzoni Livio , Wirth Brunhilde , Schiavi Elia Di , Gatti Maurizio , Artandi Steven E. , Raffa Grazia D.
Published: October 2020

Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5’ mono-methylguanosine cap of snRNAs to a trimethylguanosine cap. Here, we show that loss of TGS1 in C. elegans, D. melanogaster and D. rerio results in neurological phenotypes similar to those caused by Survival Motor Neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3’ tails that are often uridylated. snRNAs with defective 3’ terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.