bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing and Validating an Effective Pediatric and Adolescent HIV Testing Eligibility Screening Tool for High-Volume Entry Points in Uganda
Authors: Katureebe Cordelia , Ashburn Kim , Machekano Rhoderick , Gill Michelle M. , Gross Jessica , Kazooba Patrick , Kiyonga Angehulha , Taasi Geoffrey , Adler Michelle , Nazziwa Esther , Rivadeneira Emilia D. , Kekitiinwa Adeodata , Magongo Eleanor , Matovu John Bosco , Nantume Sophie , Bitarakwate Edward
Published: October 2021

Introduction:

Because of low pediatric HIV prevalence, more tests are needed to find 1 HIV-positive child compared with adults. In Uganda, the number needed to test (NNT) to find 1 new HIV-positive child was 64 in outpatient departments (OPDs) and 31 through index testing. We aimed to develop and validate a pediatric (1.5–14 years) screening tool to optimize testing approaches.

Methods:

Phase 1 evaluated the performance of 10 screening questions in 14 OPDs using a variable selection algorithm to evaluate combinations of screening questions. Using logistic regression, we identified the number of screening questions with the best predictive accuracy using the receiver operation characteristic curve. Phase 2 validated the proposed tool in 15 OPDs and 7 orphan and vulnerable children programs. We estimated sensitivity, specificity, and NNT accounting for intercluster correlations.

Results:

A total of 3482 children were enrolled. The optimal model included reported HIV-positive maternal status or 2/5 symptoms (sickly in the last 3 months, recurring skin problems, weight loss, not growing well, and history of tuberculosis). The proposed tool had sensitivity of 83.6% [95% confidence interval (CI): 68.1 to 92.4] and specificity of 62.5% (95% CI: 55.0 to 69.4). The tool was validated in a sample of 11,342 children; sensitivity was 87.8% (95% CI: 80.9 to 92.5) and specificity 62.6% (95% CI: 54.8 to 69.7) across OPDs and community sites. In OPDs, sensitivity was 88.1% (95% CI: 80.8 to 92.8) and specificity 69.0% (95% CI: 61.9 to 75.3). The NNT was 43 (95% CI: 28 to 67) across settings and 28 (95% CI: 20 to 38) for OPD.

Conclusions:

This HIV screening tool has high sensitivity and reasonable specificity, increasing testing efficiency and yield for children and adolescents.
Impact of Parental Consanguinity on the Frequency of Orofacial Clefts in Jordan
Authors: Jabaiti Samir , Salah Bareqa , Al-lawama Manar , AlRyalat Saif Aldeen , Jabaiti Omar , Al-Mikhi Bana , Alsmady Danah M. , Al-Basti Habib
Published: October 2021

Orofacial clefts (OFCs) are the most common craniofacial congenital anomalies, and its prevalence is highest among Asian populations. The aim of this retrospective case-control study is to evaluate the effect of parental consanguinity on the frequency of OFCs at Jordan University Hospital over a 15-year-period. The study group consists of all patients with OFCs presented to the major tertiary referral center in Jordan during the last 15 years, along with age and gender-matched controls. The authors analyzed the risk of different predictors, including consanguinity, on the development of OFCs, both cleft lip with or without cleft palate (CL/P) and cleft palate only. A total of 332 participants were included in this study, with a mean age of 74.36 (±48.75) months. The authors included 129 (38.9%) OFCs, and 203 (61.1%) controls. The percentage of parental consanguinity among OFCs group was 41.1%, compared to only 24.1% for controls, a difference that was statistically significant (P = 0.001). On logistic regression analysis, the authors found that parental consanguinity is a significant predictor for the occurrence of OFCs (P = 0.007), where people with consanguineous marriage have 2 times higher risk (odds ratio of 0.504, with 95% confidence interval 0.306–0.830) to have offspring with OFCs. Moreover, lower birth weight babies are also significantly more associated with OFCs (P = 0.014), with an odds ratio of 1.819 (95% confidence interval 1.131 2.926). Among the Jordanian population, the authors found that consanguinity and lower birth weight were the only variables significantly associated with the development of OFCs.
Evaluation of COVID-19 vaccine breakthrough infections among immunocompromised patients fully vaccinated with BNT162b2
Authors: Di Fusco Manuela , Moran Mary M , Cane Alejandro , Curcio Daniel , Khan Farid , Malhotra Deepa , Surinach Andy , Miles Amanda , Swerdlow David , McLaughlin John M , Nguyen Jennifer L
Published: October 2021

Objective

To evaluate COVID-19 vaccine breakthrough infections among immunocompromised (IC) individuals.

Methods

Individuals vaccinated with BNT162b2 were selected from the US HealthVerity database (12/10/2020-7/8/2021). COVID-19 vaccine breakthrough infections were examined in fully vaccinated (≥14 days after 2nddose) IC individuals (IC cohort), 12 mutually exclusive IC condition groups, and a non-IC cohort. IC conditions were identified using an algorithm based on diagnosis codes and immunosuppressive (IS) medication usage.

Results

Of 1,277,747 individuals ≥16 years of age who received 2 BNT162b2 doses, 225,796 (17.7%) were identified as IC (median age: 58 years; 56.3% female). The most prevalent IC conditions were solid malignancy (32.0%), kidney disease (19.5%), and rheumatologic/inflammatory conditions (16.7%). Among the fully vaccinated IC and non-IC cohorts, a total of 978 breakthrough infections were observed during the study period; 124 (12.7%) resulted in hospitalization and 2 (0.2%) were inpatient deaths. IC individuals accounted for 38.2% (N=374) of all breakthrough infections, 59.7% (N=74) of all hospitalizations, and 100% (N=2) of inpatient deaths. The proportion with breakthrough infections was 3 times higher in the IC cohort compared to the non-IC cohort (N=374 [0.18%] vs. N=604 [0.06%]; unadjusted incidence rates were 0.89 and 0.34 per 100 person-years, respectively. Organ transplant recipients had the highest incidence rate; those with >1 IC condition, antimetabolite usage, primary immunodeficiencies, and hematologic malignancies also had higher incidence rates compared to the overall IC cohort. Incidence rates in older (≥65 years old) IC individuals were generally higher versus younger IC individuals (<65).

Limitations

This retrospective analysis relied on coding accuracy and had limited capture of COVID-19 vaccine receipt.

Conclusions

COVID-19 vaccine breakthrough infections are rare but are more common and severe in IC individuals. The findings from this large study support FDA authorization and CDC recommendations to offer a 3rdvaccine dose to increase protection among IC individuals.
Statistical power in clinical trials of interventions for mood, anxiety, and psychotic disorders
Authors: de Vries Ymkje Anna , Schoevers Robert A. , Higgins Julian P. T. , Munafò Marcus R. , Bastiaansen Jojanneke A.
Published: October 2021

Background

Previous research has suggested that statistical power is suboptimal in many biomedical disciplines, but it is unclear whether power is better in trials for particular interventions, disorders, or outcome types. We therefore performed a detailed examination of power in trials of psychotherapy, pharmacotherapy, and complementary and alternative medicine (CAM) for mood, anxiety, and psychotic disorders.

Methods

We extracted data from the Cochrane Database of Systematic Reviews (Mental Health). We focused on continuous efficacy outcomes and estimated power to detect standardized effect sizes (SMD=0.20-0.80, primary effect size SMD=0.40) and the meta-analytic effect size (ESMA). We performed meta-regression to estimate the influence of including underpowered studies in meta-analyses.

Results

We included 216 reviews with 8809 meta-analyses and 36540 studies. Statistical power for continuous efficacy outcomes was very low across intervention and disorder types (overall median [IQR] power for SMD=0.40: 0.33 [0.19-0.54]; for ESMA: 0.15 [0.07-0.44]), only reaching conventionally acceptable levels (80%) for SMD=0.80. Median power to detect the ESMA was higher in TAU/waitlist-controlled (0.54-0.66) or placebo-controlled (0.15-0.40) trials than in trials comparing active treatments (0.07-0.10). Meta-regression indicated that adequately-powered studies produced smaller effect sizes than underpowered studies (B=-0.06, p=0.008).

Conclusions

Power to detect both fixed and meta-analytic effect sizes in clinical trials in psychiatry was low across all interventions and disorders examined. As underpowered studies produced larger effect sizes than adequately-powered studies, these results confirm the need to increase sample sizes and to reduce reporting bias against studies reporting null results to improve the reliability of the published literature.
Hepatitis C virus infection and tobacco smoking - joint health effects and implications for treatment of both: A systematic review
Authors: Taye Belaynew W
Published: October 2021

Background

Tobacco smoking and hepatitis C virus (HCV) infection cause many diseases independently. The interaction of these conditions on health effects has not been widely studied. There is a paucity of information on addressing tobacco smoking in HCV treatment settings. This review examines the relationship between tobacco smoking and HCV infection and health outcomes and discusses opportunities for treating both conditions.

Methods

A systematic review was conducted following the PRISMA 2009 guidelines(Registration No.: CRD42019127771). We searched PubMed, EMBASE, Web of Science, and CINAHL on the health effects of tobacco smoking and HCV infection using keywords and MeSH terms for hepatitis C, tobacco smoking, hepatocellular carcinoma (HCC), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), cardiovascular diseases (CVD), and chronic kidney disease (CKD). We used the Newcastle-Ottawa Scale, a measurement tool to assess systematic reviews (AMSTAR-2), and international narrative systematic assessment (INSA) tools to assess the methodological quality of the included studies.

Findings

Tobacco smoking and HCV infection share similar underlying risk factors and hence it is unsurprising that tobacco smoking prevalence is higher in people living with HCV (PLHCV) than in the general population. Tobacco smoking and HCV infection have additive or multiplicative interaction to cause HCC, COPD, DM, CVD, and CKD. Anti-HCV direct-acting antiviral (DAA) treatment is highly efficacious and widely accessible in many countries, but untreated tobacco smoking addiction may undermine the achievement of optimal health outcomes possible from HCV treatment.

Interpretation

The scale-up of DAA treatment programs globally is an opportunity to address the high prevalence of tobacco smoking in PLHCV by concurrently offering tobacco smoking cessation treatment. Simultaneous initiation of smoking cessation therapy at HCV treatment centres is likely to be cost-effective at maximizing the health gains afforded by DAA treatment. Studies are needed to evaluate the effect of tobacco smoking cessation on the sustained virologic response in DAA treated patients.
Cost-effectiveness analysis of patent foramen ovale closure versus medical therapy alone after cryptogenic stroke
Authors: Shijoh Yoko , Saito Shota , Dai Zhehao , Ohde Sachiko
Published: October 2021

Background

Closure of a patent foramen ovale reduces the risk of recurrent stroke compared with medical therapy alone in young patients with cryptogenic strokes revealed by randomized control trials. Some cost-effectiveness analyses outside Japan have shown that patent foramen ovale closure is cost-effective, but no studies have examined cost-effectiveness in Japan. The objective of this study is to assess cost-effectiveness, from the perspective of a Japanese healthcare payer, of patent foramen ovale closure versus medical therapy alone for the patients with patent foramen ovale related cryptogenic strokes.

Methods

A cost-effectiveness study was conducted by developing a decision tree and a Markov model. Probabilities and a 5.9-year time horizon followed the RESPECT study. Utilities and costs were based upon published studies and assumptions. The model cycle was one month. All assumptions were assessed by experts, including a cardiologist and a statistical expert. The target population comprised patients with cryptogenic stroke and patent foramen ovale, aged 60 years or younger. Incremental cost-effectiveness ratio was evaluated. Then one-way sensitivity analyses and probabilistic sensitivity analyses were conducted to assess robustness.

Results

Incremental cost-effectiveness ratio of patent foramen ovale closure compared with medical therapy was estimated at ¥3,318,152 per quality-adjusted life years gained. One-way sensitivity analysis showed that the stable state utility score difference between patent foramen ovale closure and medical therapy had the largest impact on incremental cost-effectiveness ratio. Patent foramen ovale closure is cost-effective at a stable state utility score difference of >0.051, compared with medical therapy. Probabilistic sensitivity analyses demonstrated that patent foramen ovale closure was 50.3% cost-effective with a willingness-to-pay threshold of ¥5,000,000 / quality-adjusted life years.

Conclusions

From a healthcare payer perspective, patent foramen ovale closure may be cost-effective compared with medical therapy for Japanese patients with cryptogenic stroke who were ≤60 years.
Clinical and genomic epidemiology ofmcr-9-carrying carbapenem-resistant Enterobacterales isolates in Metropolitan Atlanta, 2012-2017
Authors: Babiker Ahmed , Bower Chris , Lutgring Joseph D. , Howard-Anderson Jessica , Ansari Uzma , McAllister Gillian , Adamczyk Michelle , Breaker Erin , Satola Sarah W. , Jacob Jesse T. , Woodworth Michael H.
Published: October 2021

Colistin is a last-resort antibiotic for multidrug-resistant gram-negative infections. Recently, the ninth allele of the mobile colistin resistance (mcr) gene family, designatedmcr-9, was reported. However, its clinical and public health significance remains unclear. We queried genomes of carbapenem-resistant Enterobacterales (CRE) formcr-9from a convenience sample of clinical isolates collected between 2012-2017 through the Georgia Emerging Infections Program, a population- and laboratory-based surveillance program. Isolates underwent phenotypic characterization and whole genome sequencing. Phenotypic characteristics, genomic features, and clinical outcomes ofmcr-9positive and negative CRE cases were then compared. Among 235 sequenced CRE genomes, thirteen (6%) were found to harbormcr-9, all of which wereEnterobacter cloacaecomplex. The median MIC, rates of heteroresistance and inducible resistance to colistin were similar betweenmcr-9positive and negative isolates. However, rates of resistance were higher among mcr-9 positive isolates across most antibiotic classes. All cases had significant healthcare exposures. The 90-day mortality was similarly high in bothmcr-9positive (31%) and negative (7%) CRE cases. Nucleotide identity and phylogenetic analysis did not reveal geo-temporal clustering.mcr-9positive isolates had a significantly higher number of median [range] AMR genes (16 [4-22] vs. 6 [2-15];p<0.001) compared tomcr-9negative isolates. Pan genome tests confirmed a significant association ofmcr-9detection with mobile genetic element and heavy metal resistance genes. Overall, the presence ofmcr-9was not associated with significant changes in colistin resistance or clinical outcomes but continued genomic surveillance to monitor for emergence of AMR genes is warranted.
Sleep health education and a personalized smartphone application improve sleep and productivity and reduce healthcare utilization among employees: Results of a randomized clinical trial
Authors: Robbins Rebecca , Weaver Matthew D. , Quan Stuart F. , Sullivan Jason P. , Qadri Salim , Czeisler Charles A. , Barger Laura
Published: October 2021

Sleep deficiency and undiagnosed or untreated sleep disorders are pervasive among employed adults, yet often ignored in the context of workplace health promotion programs among employers. Smartphone applications (app) are a promising, scalable approach to improving sleep among employees. In this randomized clinical trial, we evaluate the dayzz app, a personalized sleep training program that promotes healthy sleep and sleep disorders awareness through personalized, comprehensive sleep improvement solutions. In a sample of daytime employees affiliated with a large healthcare organization, we evaluated the dayzz app in a parallel-group, randomized, waitlist control trial. Participants were randomly assigned to either use the dayzz app throughout the study or the waitlist control condition where they would receive the dayzz app at the end of the study period. We collected data on employee sleep (e.g., sleep duration, sleep health behavioral changes); workplace outcomes (e.g., employee presenteeism, absenteeism, and performance); and healthcare utilization (e.g., mental health, ambulatory visits, and emergency room visits), throughout the study. Results show that those assigned to the experimental condition exhibited an increase in healthy sleep behaviors; an increase in sleep duration; a trend toward a more regular sleep schedule; and a significant increase in overall sleep quality. Regarding workplace outcomes, results showed that those in the experimental condition also demonstrated a trend toward less absenteeism and significantly lower presenteeism; and those in the experimental condition reported lower healthcare utilization. Results from this randomized clinical trial demonstrate that a workplace sleep wellness program can be beneficial to both the employee and employer.
Genetic diversity loss in the Anthropocene
Authors: Exposito-Alonso Moises , Booker Tom R. , Czech Lucas , Fukami Tadashi , Gillespie Lauren , Hateley Shannon , Kyriazis Christopher C. , Lang Patricia L. M. , Leventhal Laura , Nogues-Bravo David , Pagowski Veronica , Ruffley Megan , Spence Jeffrey P. , Arana Sebastian E. Toro , Weiß Clemens L. , Zess Erin
Published: October 2021

More species than ever before are at risk of extinction due to anthropogenic habitat loss and climate change. But even species that are not threatened have seen reductions in their populations and geographic ranges, likely impacting their genetic diversity. Although preserving genetic diversity is key to maintaining adaptability of species, we lack predictive tools and global estimates of genetic diversity loss across ecosystems. By bridging theories of biodiversity and population genetics, we introduce a mathematical framework to understand the loss of naturally occurring DNA mutations within decreasing habitat within a species. Analysing genome-wide variation data of 10,095 geo-referenced individuals from 20 plant and animal species, we show that genome-wide diversity follows a power law with geographic area (the mutations-area relationship), which can predict genetic diversity loss in spatial computer simulations of local population extinctions. Given pre-21st century values of ecosystem transformations, we estimate that over 10% of genetic diversity may already be lost, surpassing the United Nations targets for genetic preservation. These estimated losses could rapidly accelerate with advancing climate change and habitat destruction, highlighting the need for forecasting tools that facilitate implementation of policies to protect genetic resources globally.
Functional and structural features of L2/3 pyramidal cells continuously covary with pial depth in mouse visual cortex
Authors: Weiler Simon , Nilo Drago Guggiana , Bonhoeffer Tobias , Hübener Mark , Rose Tobias , Scheuss Volker
Published: October 2021

Pyramidal cells of neocortical layer 2/3 (L2/3 PyrCs) integrate signals from numerous brain areas and project throughout the neocortex. Within L2/3, PyrCs show functional and structural specializations depending on their pial depth, indicating participation in different functional microcircuits. However, it is unknown whether these depth-dependent differences result from separable L2/3 PyrC subtypes or whether functional and structural features represent a continuum while correlating with pial depth. Here, we assessed the stimulus selectivity, electrophysiological properties, dendritic morphology, and excitatory and inhibitory synaptic connectivity across the depth of L2/3 in the binocular visual cortex (bV1) of female mice. We find that the structure of the apical but not the basal dendritic tree varies with pial depth, which is accompanied by differences in passive but not active electrophysiological properties. PyrCs in lower L2/3 receive increased excitatory and inhibitory input from L4, while upper L2/3 PyrCs receive a larger proportion of intralaminar input. Complementary in vivo calcium imaging revealed a systematic change in visual responsiveness, with deeper L2/3 PyrCs showing more robust responses than superficial PyrCs. Furthermore, deeper L2/3 PyrCs are more strongly driven by contralateral than ipsilateral eye stimulation. In contrast, orientation- and direction-selectivity of L2/3 PyrCs are not dependent on pial depth. Importantly, the transitions of the various properties are gradual, and cluster analysis does not support the classification of L2/3 PyrCs into discrete subtypes. These results show that L2/3 PyrCs’ multiple functional and structural properties systematically correlate with their depth within L2/3, forming a continuum rather than representing discrete subtypes.

SIGNIFICANCE STATEMENT

Neocortical pyramidal cells in layer 2/3 (L2/3 PyrCs) are crucial for cortical computation and display heterogenous properties. We investigated whether and how these properties vary across the depth of L2/3 and whether L2/3 PyrCs can be subdivided into distinct subtypes. This is important for a better understanding of the coding strategy and information integration processes within L2/3. We find that multiple properties such as morphology, physiology, connectivity, and functional in vivo responses of L2/3 PyrCs correlate with cortical depth in mouse visual cortex. These variations are continuous and do not support classification of L2/3 PyrCs into discrete subtypes. In contrast to L5 and L6, PyrCs in L2/3 therefore process information based on a continuous property space.
Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiovascular and Renal Outcomes: A Meta-Analysis and Meta-Regression Analysis
Authors: Yoshiji Satoshi , Minamino Hiroto , Tanaka Daisuke , Yamane Shunsuke , Harada Norio , Inagaki Nobuya
Published: October 2021

Aims

Cardiovascular and renal effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been inconsistent in cardiovascular outcome trials, and factors associated with the efficacy of GLP-1RAs remain to be clarified. Here, we evaluate the cardiovascular and renal outcomes with GLP-1RAs and associations between these outcomes and HbA1c or weight reduction.

Materials and Methods

We searched PubMed/MEDLINE, EMBASE, and CENTRAL for randomized, placebo-controlled trials of GLP1-RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes.

Results

We extracted data of 60,800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80–0.93; P < 0.001) and secondary outcomes including the composite renal outcome (0.80; 0.73–0.87; P < 0.001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = 0.044; R2 = 0.65) and the composite renal outcome (P = 0.040; R2 = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = 0.390).

Conclusions

The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for cardiovascular and renal benefits of treatment with GLP-1RAs.
Adapting cleft care protocols in low- and middle-income countries during and after COVID-19: a process-driven review with recommendations
Authors: Fell Matthew , Goldwasser Michael , Jayanth B.S , Rodrigues Pereira Rui Manuel , Nawej Christian Tshisuz , Winer Rachel , Daftari Neeti , Brewster Hugh , Goldschmied Karen
Published: October 2021

Objective

A consortium of global cleft professionals, predominantly from low- and middle-income countries, identified adaptions to cleft care protocols during and after COVID as a priority learning area of need.

Design

A multidisciplinary international working group met on a videoconferencing platform in a multi-staged process to make consensus recommendations for adaptions to cleft protocols within resource-constrained settings. Feedback was sought from a roundtable discussion forum and global organisations involved in comprehensive cleft care.

Results

Foundational principles were agreed to enable recommendations to be globally relevant and two areas of focus within the specified topic were identified. First the safety aspects of cleft surgery protocols were scrutinised and COVID adaptions, specifically in the pre and peri-operative periods, were highlighted. Second, surgical operations and access to services were prioritized according to their relationship to functional outcomes and time-sensitivity. The operations assigned the highest priority were emergent interventions for breathing and nutritional requirements and primary palatoplasty. The cleft services assigned the highest priority were new-born assessments, paediatric support for children with syndromes, management of acute dental or auditory infections and speech pathology intervention.

Conclusions

A collaborative, interdisciplinary and international working group delivered consensus recommendations to assist with the provision of cleft care in low- and middle-income countries. At a time of global cleft care delays due to COVID-19, a united approach amongst global cleft care providers will be advantageous to advocate for children born with cleft lip and palate in resource-constrained settings.
Lin28a rejuvenates muscle stem cells via mitochondrial optimization
Authors: Wang Peng , Liu Xupeng , Elwin Tan Jun-Hao , Jason Chua Min-Wen , Benjamin Chua Yan-Jiang , Luo Lanfang , Ma Shilin , Cao Wenhua , Ma Wenwu , Yao Ziyue , Chen Yu , Miao Hefan , Guo Luyao , Zhang Liping , Guang Lu , Liang Kun , Wang Yuefan , Su Jiali , Liu Shuqing , Liu Ruirui , Wang Ruiqi Rachel , Li Chunwei , Ai Na , Li Yun , Jiang Zongming , Liu Taoyan , Teh Bin Tean , Jiang Lan , Yu Kang , Shyh-Chang Ng
Published: October 2021

The well-conserved correlation between juvenility and tissue regeneration was first discussed by Charles Darwin. Ectopic Lin28 is known to play an important role in somatic reprogramming and tissue regeneration, but endogenous Lin28’s role in tissue homeostasis and juvenility had remained unclear. Through lineage tracing, we found that a rare subset of muscle stem cells (MuSCs) expressing Lin28a can respond to acute injury by proliferating as Pax3+ or Pax7+ MuSCs, and contribute to all types of myofibers during muscle regeneration. Compared with conventional Pax7+ MuSCs, Lin28a+ MuSCs express more Pax3 and show enhanced myogenicity in vitro. In terms of the epigenetic clock, adult Lin28a+ MuSCs lie between adult Pax7+ MuSCs and embryonic Pax7+ myoblasts according to their DNA methylation profiles. We found that Lin28a+ MuSCs upregulate several embryonic limb bud mesoderm transcription factors and could maintain a juvenile state with enhanced stem cell self-renewal and stress-responsiveness in vitro and in vivo. When combined with telomerase and TP53 inhibition to biomimic mouse Lin28a+ MuSCs, we found that Lin28a can rejuvenate and dedifferentiate aged human primary myoblasts into engraftable, self-renewing MuSCs. Mechanistic studies revealed that Lin28a activated the HIF1A pathway by optimizing mitochondrial ROS (mtROS), thereby rejuvenating MuSC self-renewal and muscle regeneration. Our findings connect the stem cell factor Lin28, mtROS metabolism and stress response pathways to the process of stem cell rejuvenation and tissue regeneration.
γδ T cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects
Authors: de Vries Natasja L. , van de Haar Joris , Veninga Vivien , Chalabi Myriam , Ijsselsteijn Marieke E. , van der Ploeg Manon , van den Bulk Jitske , Ruano Dina , Haanen John B. , Schumacher Ton N. , Wessels Lodewyk F.A. , Koning Frits , de Miranda Noel F.C.C. , Voest Emile E.
Published: October 2021

DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. However, MMR-d colon cancers that evade CD8+ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation3–6, frequently remain responsive to ICB7 suggesting the involvement of other immune effector cells. Here, we demonstrate that HLA class I-negative MMR-d cancers are highly infiltrated by γδ T cells. These γδ T cells are mainly composed of Vδ1 and Vδ3 subsets, and express high levels of PD-1, activation markers including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors (KIRs). In vitro, PD-1+ γδ T cells, isolated from MMR-d colon cancers, exhibited a cytolytic response towards HLA class I-negative MMR-d colon cancer cell lines and β2-microglobulin (B2M)-knockout patient-derived tumor organoids (PDTOs), which was enhanced as compared to antigen presentation-proficient cells. This response was diminished after blocking the interaction between NKG2D and its ligands. By comparing paired tumor samples of MMR-d colorectal cancer patients obtained before and after dual PD-1 and CTLA-4 blockade, we found that ICB profoundly increased the intratumoral frequency of γδ T cells in HLA class I-negative cancers. Taken together, these data indicate that γδ T cells contribute to the response to ICB therapy in patients with HLA class I-negative, MMR-d colon cancers, and illustrate the potential of γδ T cells in cancer immunotherapy.
Dysregulated Protein Translation Control in Hidradenitis Suppurativa: Implication for Lesion-associated Squamous Cell Carcinoma Development
Authors: Jin Lin , Kashyap Mahendra P. , Chen Yunjia , Guo Yuanyuan , Khan Jasim , Chen Jari Q. , Lee Madison B , Weng Zhiping , Oak Allen , Sinha Rajesh , Mukhtar M. Shahid , Deshane Jessy S. , Raman Chander , Elmets Craig A. , Athar Mohammad
Published: October 2021

Hidradenitis Suppurativa (HS) is a proinflammatory painful skin disorder. This chronic disease is often associated with aggressive squamous cell carcinoma (SCC). The molecular pathogenesis of this disease progression remains undefined. The translation initiation factor eIF4E/4G/4A1 complex is overexpressed in a variety of human malignancies. In this study, we found that the expression of eIF4E/4G/4A1 as well as phosphorylated eIF4E were upregulated in HS skin. In the global transcription profiles derived from two public database, we were able to enrich 734 eIF4F-related genes. GSEA pathway enrichment analysis further demonstrated that RAS/MEK/ERK oncogene signaling pathway associated with inflammation signaling were significantly activated in HS lesion. The increase expression of eIF4 protein components was associated with enhanced eIF4E translation targets Cyclin D1 and c-Myc. Confocal fluorescence microscopy analysis further revealed that Cyclin D1 and c-Myc specifically co-localized in nuclei of certain cells in HS epithelium. We also found that many of the PCNA positive hyperproliferative cells were also positive for c-Myc expression. These data demonstrate that 5’-cap□dependent translation is a potential pathway underlying the SCC pathogenesis in chronic HS lesions. Furthermore, being a druggable target, inhibition of eIF4F may block lesion-associated lethal SCCs in HS patients.
Mutual Regulation between Phosphofructokinase 1 platelet isoform and VEGF Promotes Glioblastoma Tumor Growth
Authors: Lim Je Sun , Shi YuJie , Jeon So Mi , Park Su Hwan , Zhang Chuanbao , Park Yun-Yong , Liu Rui , Li Jing , Cho Wan-Seob , Du Linyong , Lee Jong-Ho
Published: October 2021

Glioblastoma (GBM) is highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, it remains unknown whether PFKP and VEGF are reciprocally regulated during GBM tumor growth. Here, we show that PFKP promotes EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in the AKT/SP1-mediated transcriptional expression ofHIF-1αand in the AKT-mediated β-catenin S552 phosphorylation, to fully enhanceVEGFtranscription and subsequent blood vessel formation and brain tumor growth. The levels of PFKP Y64 phosphorylation in human GBM specimens positively correlate with HIF-1α expression, β-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and provide the therapeutic potential of targeting the PFKP/VEGF regulatory loop for GBM patients.
Interpretable Pairwise Distillations for Generative Protein Sequence Models
Authors: Feinauer Christoph , Meynard-Piganeau Barthelemy , Lucibello Carlo
Published: October 2021

Abstract

Many different types of generative models for protein sequences have been proposed in literature. Their uses include the prediction of mutational effects, protein design and the prediction of structural properties. Neural network (NN) architectures have shown great performances, commonly attributed to the capacity to extract non-trivial higher-order interactions from the data. In this work, we analyze three different NN models and assess how close they are to simple pairwise distributions, which have been used in the past for similar problems. We present an approach for extracting pairwise models from more complex ones using an energy-based modeling framework. We show that for the tested models the extracted pairwise models can replicate the energies of the original models and are also close in performance in tasks like mutational effect prediction.
scSPLAT, a scalable plate-based protocol for single cell WGBS library preparation
Authors: Raine Amanda , Lundmark Anders , Annett Alva , Wiman Ann-Christin , Cavalli Marco , Wadelius Claes , Bergin Claudia , Nordlund Jessica
Published: October 2021

DNA methylation is a central epigenetic mark that has diverse roles in gene regulation, development, and maintenance of genome integrity. 5 methyl cytosine (5mC) can be interrogated at base resolution in single cells by using bisulfite sequencing (scWGBS). Several different scWGBS strategies have been described in recent years to study DNA methylation in single cells. However, there remain limitations with respect to cost-efficiency and yield. Herein, we present a new development in the field of scWGBS library preparation; single cell Splinted Ligation Adapter Tagging (scSPLAT). scSPLAT employs a pooling strategy to facilitate sample preparation at a higher scale and throughput than previously possible. We demonstrate the accuracy and robustness of the method by generating data from 225 single K562 cells and from 309 single liver nuclei and compare scSPLAT against other scWGBS methods.

Motivation

scWGBS library preparation in a one-cell-per-library format presents practical and economical constraints to the number of cells that can be analyzed in a research project. In addition, most of the current scWGBS methods suffer from low read alignment rates. We present a scWGBS protocol which mitigates these issues, empowering single-cell DNA methylation analysis at an increased scale.
Unifying turbulent dynamics framework distinguishes different brain states
Authors: Escrichs Anira , Perl Yonatan Sanz , Uribe Carme , Camara Estela , Türker Basak , Pyatigorskaya Nadya , López-González Ane , Pallavicini Carla , Panda Rajanikant , Annen Jitka , Grosseries Olivia , Laureys Steven , Naccache Lionel , Sitt Jacobo D. , Laufs Helmut , Tagliazucchi Enzo , Kringelbach Morten L. , Deco Gustavo
Published: October 2021

Recently, significant advances have been made by identifying the levels of synchronicity of the underlying dynamics of a given brain state. This research has demonstrated that unconscious dynamics tend to be more synchronous than those found in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that the different brain states are always underpinned by spatiotemporal chaos but with dissociable turbulent dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep, and disorders of consciousness after coma) and were able to distinguish between them using complementary model-free and model-based measures of turbulent information transmission. Our model-free approach used recent advances describing a measure of information cascade across spatial scales using tools from turbulence theory. Complementarily, our model-based approach used exhaustive in silico perturbations of whole-brain models fitted to the empirical neuroimaging data, which allowed us to study the information encoding capabilities of the brain states. Overall, the current framework demonstrates that different levels of turbulent dynamics are fundamental for describing and differentiating between brain states.
The chromatin regulator HMGA1a undergoes phase separation in the nucleus
Authors: Zhu Hongjia , Narita Masako , Joseph Jerelle A. , Krainer Georg , Arter William E. , Olan Ioana , Saar Kadi L. , Ermann Niklas , Espinosa Jorge R. , Shen Yi , Kuri Masami Ando , Qi Runzhang , Welsh Timothy J. , Xu Yufan , Collepardo-Guevara Rosana , Narita Masashi , Knowles Tuomas P. J.
Published: October 2021

The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is critically promoted by protein–DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through cation–π and electrostatic interactions. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.
Oxalic acid binds to gustatory receptor Gr23a and inhibits feeding in the brown planthopper
Authors: Kang Kui , Zhang Mengyi , Yue Lei , Chen Weiwen , Dai Yangshuo , Lin Kai , Liu Kai , Lv Jun , Guan Zhanwen , Xiao Shi , Zhang Wenqing
Published: October 2021

Plants produce diverse secondary compounds as natural protection against microbial and insect attack. Most of these compounds, including bitters and acids, are sensed by insect gustatory receptors (Grs). Acids are potentially toxic to insects, but there are few reports on sour compounds as ligands of insect Grs. Here, using two different heterologous expression systems, the insect Sf9 cell line and the mammalian HEK293T cell line, we started from crude extracts of rice (Oryza sativa) and successfully identified oxalic acid (OA) as a ligand of NlGr23a, a Gr in the brown planthopper Nilaparvata lugens. The antifeedant effect of OA on the brown planthopper was dose dependent, and NlGr23a is essential for OA’s antifeedant activity in both artificial diets and rice plants. NlGr23a is also indispensable for tarsal OA sensing. To our knowledge, OA is the first identified ligand starting from plant crude extracts and the first known strong acid for insect Grs. These findings on rice-planthopper interactions will be of broad interest for pest control in agriculture and also for better understanding of how insects select host plants.

Research organism

Nilaparvata lugens
Intratumoral and extratumoral synapses are required for glioblastoma progression in Drosophila
Authors: Losada-Pérez María , Hernández García-Moreno Mamen , Casas-Tintó Sergio
Published: October 2021

Glioblastoma (GB) is the most aggressive, lethal and frequent primary brain tumor. It originates from glial cells and is characterized by rapid expansion through infiltration. GB cells interact with the microenvironment and healthy surrounding tissues, mostly neurons and vessels. GB cells project tumor microtubes (TMs) that contact with neurons and exchange signaling molecules related to Wingless/WNT, JNK, Insulin or Neuroligin-3 pathways. This cell to cell communication promotes GB expansion and neurodegeneration. Moreover, healthy neurons form glutamatergic functional synapses with GB cells which facilitate GB expansion and premature death in mouse GB xerograph models. Targeting signaling and synaptic components of GB progression may become a suitable strategy against glioblastoma. In a Drosophila GB model, we have determined the post-synaptic nature of GB cells with respect to neurons, and the contribution of post-synaptic genes expressed in GB cells to tumor progression. In addition, we document the presence of intratumoral synapses between GB cells, and the functional contribution of pre-synaptic genes to GB calcium dependent activity and expansion. Finally, we explore the relevance of synaptic genes in GB cells to the lifespan reduction caused by GB advance. Our results indicate that both presynaptic and postsynaptic proteins play a role in GB progression and lethality.
Human enteric viruses shape disease phenotype through divergent innate immunomodulation
Authors: Adiliaghdam Fatemeh , Amatullah Hajera , Digumarthi Sreehaas , Saunders Tahnee L. , Rahman Raza-Ur , Wong Lai Ping , Sadreyev Ruslan , Droit Lindsay , Paquette Jean , Goyette Philippe , Rioux John , Hodin Richard , Mihindukulasuriya Kathie A. , Handley Scot A. , Jeffrey Kate L.
Published: October 2021

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched PicornovirusEnterovirus B,not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential.

One Sentence Summary

Human viromes divergently shape host immunity and disease
Genomic and common garden approaches yield complementary results for quantifying environmental drivers of local adaptation in rubber rabbitbrush, a foundational Great Basin shrub
Authors: Faske Trevor M. , Agneray Alison C. , Jahner Joshua P. , Sheta Lana M. , Leger Elizabeth A. , Parchman Thomas L.
Published: October 2021

The spatial structure of genomic and phenotypic variation across populations reflects historical and demographic processes as well as evolution via natural selection. Characterizing such variation can provide an important perspective for understanding the evolutionary consequences of changing climate and for guiding ecological restoration. While evidence for local adaptation has been traditionally evaluated using phenotypic data, modern methods for generating and analyzing landscape genomic data can directly quantify local adaptation by associating allelic variation with environmental variation. Here, we analyze both genomic and phenotypic variation of rubber rabbitbrush (Ericameria nauseosa), a foundational shrub species of western North America. To quantify landscape genomic structure and provide perspective on patterns of local adaptation, we generated reduced representation sequencing data for 17 wild populations (222 individuals; 38,615 loci) spanning a range of environmental conditions. Population genetic analyses illustrated pronounced landscape genomic structure jointly shaped by geography and environment. Genetic-environment association (GEA) analyses using both redundancy analysis (RDA) and a machine-learning approach (Gradient Forest) indicated environmental variables (precipitation seasonality, slope, aspect, elevation, and annual precipitation) influenced spatial genomic structure, and were correlated with allele frequency shifts indicative of local adaptation at a consistent set of genomic regions. We compared our GEA based inference of local adaptation with phenotypic data collected by growing seeds from each population in a greenhouse common garden. Population differentiation in seed weight, emergence, and seedling traits was associated with environmental variables (e.g., precipitation seasonality) that were also implicated in GEA analyses, suggesting complementary conclusions about the drivers of local adaptation across different methods and data sources. Our results provide a baseline understanding of spatial genomic structure for E. nauseosa across the western Great Basin and illustrate the utility of GEA analyses for detecting the environmental causes and genetic signatures of local adaptation in a widely distributed plant species of restoration significance.
The 4D Nucleome Data Portal: a resource for searching and visualizing curated nucleomics data
Authors: Reiff Sarah B. , Schroeder Andrew J. , Kirli Koray , Cosolo Andrea , Bakker Clara , Mercado Luisa , Lee Soohyun , Veit Alexander D. , Balashov Alexander K. , Vitzthum Carl , Ronchetti William , Pitman Kent M. , Johnson Jeremy , Ehmsen Shannon R. , Kerpedjiev Peter , Abdennur Nezar , Imakaev Maxim , Öztürk Serkan Utku , Çamoğlu Uğur , Mirny Leonid A. , Gehlenborg Nils , Alver Burak H. , Park Peter J.
Published: October 2021

The 4D Nucleome (4DN) Network aims to elucidate the complex structure and organization of chromosomes in the nucleus and the impact of their disruption in disease biology. We present the 4DN Data Portal (https://data.4dnucleome.org/), a repository for datasets generated in the 4DN network and relevant external datasets. Datasets were generated with a wide range of experiments, including chromosome conformation capture assays such as Hi-C and other innovative sequencing and microscopy-based assays probing chromosome architecture. All together, the 4DN data portal hosts more than 1800 experiment sets and 34000 files. Results of sequencing-based assays from different laboratories are uniformly processed and quality-controlled. The portal interface allows easy browsing, filtering, and bulk downloads, and the integrated HiGlass genome browser allows interactive visualization and comparison of multiple datasets. The 4DN data portal represents a primary resource for chromosome contact and other nuclear architecture data for the scientific community.