bluuebunny/crossref_metadata_2025 huggingface dataset:
Robotic-Assisted Proctosigmoidectomy vs. Laparoscopic-Assisted Soave Pull-Through for Hirschsprung’s Disease: Medium-Term Outcomes From a Prospective Multicenter Study
Authors: Zhang Mengxin , Zhang Xi , Chi Shuiqing , Chang Xiaopan , Zeng Jixiao , Bian Hongqiang , Cao Guoqing , Li Shuai , Zhou Ying , Rong Liying , Tang Shao-tao
Published: December 2023

Objective:

To compare the surgical outcomes of robotic-assisted proctosigmoidectomy (RAP) and laparoscopic-assisted Soave pull-through (LAP) for children with Hirschsprung’s disease (HD).

Summary Background Data:

LAP and RAP have been developed for minimally invasive pull-through of HD, but the clinical benefits of robotic-assisted versus laparoscopic-assisted approaches have yet to be proven in a multicenter prospective study.

Methods:

This study was a prospective multicenter clinical trial conducted on children with rectosigmoid/descending HD from July 2015 to June 2022, with registration in the Chinese Clinical Trial Registry (ChiCTR2000035220). The primary outcome was the medium-term functional outcomes in children aged ≥4 years based on bowel functional scores, which were assessed and compared between LAP and RAP.

Results:

A total of 328 consecutive patients (RAP=165, LAP=163) were approached who were considered eligible for elective minimally invasive endorectal pull-through, and 219 patients aged ≥4 years of age completed follow-up (RAP=109, LAP=110). The transanal dissection length and anal traction time were significantly shorter in RAP than those in LAP (0.30 cm vs. 3.70 cm, P <0.001; 45 min vs. 62 min, P <0.001). The RAP group had significantly lower urinary retention rate (0% vs. 5.52%, P=0.006), while other short-term results between two groups were not significantly different. The medium-term overall BFS scores were comparable between two groups; however, among the subgroup of children aged ≤ 3 months at surgery, the RAP group had better anal canal resting pressure at one year postoperatively and amounted to better annual POFC scores at 4-7 years old postoperatively (all P <0.05).

Conclusions:

RAP and LAP should have similar medium-term bowel functional outcomes in HD children, but RAP may be associated with a slight functional benefit in infants operated on below age 3 months, requiring further investigation in larger case cohorts.
Investigation of the Relationship Between Laparoscopic Sleeve Gastrectomy and Gastroesophageal Reflux Disease Using 24-hour Multichannel Intraluminal Impedance With pH Testing According to Current Consensus
Authors: Teke Emre , Esen Bulut Nuriye , Onur Ender , Güneş Yasin , Fersahoglu Mehmet Mahir , Ergin Anil , Taşdelen İksan , Köroğlu Mehmet , Çavuş Bilger , Akyüz Ümit , Akyüz Filiz
Published: December 2023

Background:

Laparoscopic sleeve gastrectomy (LSG) is a popular weight loss procedure with potential effects on gastroesophageal reflux disease (GERD). However, research on the association between LSG and GERD using objective evaluation criteria, such as multichannel intraluminal impedance combined with pH testing (MII-pH), is limited. This study aimed to investigate the impact of LSG on GERD using MII-pH and current consensus guidelines.

Materials and Methods:

It was conducted as a prospective clinical study on 33 patients who underwent LSG between January 2022 and August 2022. MII-pH and high-resolution manometry were performed preoperatively and 3 to 6 months postoperatively. GERD diagnosis was based on MII-pH results using the Lyon and Update Porto consensus guidelines.

Results:

Postoperative MII-pH analysis revealed a significant increase in acid reflux time, acid exposure time, reflux index, esophageal clearance, total reflux time, and longest reflux period. Weak acid reflux episodes decreased, while Demeester score and alkaline reflux showed nonsignificant increases. Pathologic reflux significantly increased postoperatively based on MII-pH diagnosis. High-resolution manometry showed a significant increase in unsuccessful motility.

Conclusion:

Although the Demeester score calculation consists of 6 metrics, including acid exposure time, the acid exposure time is more specific in detecting pathologic reflux. Pathologic GERD increases significantly with LSG in the early period. Therefore, preoperative and postoperative endoscopy and MII-pH can provide valuable information regarding the need for closer follow-up after LSG.
Periodic Discharges in Critically Ill Children: Predictors and Outcome
Authors: Fung France W. , Parikh Darshana S. , Massey Shavonne L. , Fitzgerald Mark P. , Vala Lisa , Donnelly Maureen , Jacobwitz Marin , Kessler Sudha K. , Xiao Rui , Topjian Alexis A. , Abend Nicholas S.
Published: December 2023

Objectives:

We aimed to identify clinical and EEG monitoring characteristics associated with generalized, lateralized, and bilateral-independent periodic discharges (GPDs, LPDs, and BIPDs) and to determine which patterns were associated with outcomes in critically ill children.

Methods:

We performed a prospective observational study of consecutive critically ill children undergoing continuous EEG monitoring, including standardized scoring of GPDs, LPDs, and BIPDs. We identified variables associated with GPDs, LPDs, and BIPDs and assessed whether each pattern was associated with hospital discharge outcomes including the Glasgow Outcome Scale-Extended Pediatric version (GOS-E-Peds), Pediatric Cerebral Performance Category (PCPC), and mortality.

Results:

PDs occurred in 7% (91/1,399) of subjects. Multivariable logistic regression indicated that patients with coma (odds ratio [OR], 3.45; 95% confidence interval [CI]: 1.55, 7.68) and abnormal EEG background category (OR, 6.85; 95% CI: 3.37, 13.94) were at increased risk for GPDs. GPDs were associated with mortality (OR, 3.34; 95% CI: 1.24, 9.02) but not unfavorable GOS-E-Peds (OR, 1.93; 95% CI: 0.88, 4.23) or PCPC (OR, 1.64; 95% CI: 0.75, 3.58). Patients with acute nonstructural encephalopathy did not experience LPDs, and LPDs were not associated with mortality or unfavorable outcomes. BIPDs were associated with mortality (OR, 3.68; 95% CI: 1.14, 11.92), unfavorable GOS-E-Peds (OR, 5.00; 95% CI: 1.39, 18.00), and unfavorable PCPC (OR, 5.96; 95% CI: 1.65, 21.46).

Significance:

Patients with coma or more abnormal EEG background category had an increased risk for GPDs and BIPDs, and no patients with an acute nonstructural encephalopathy experienced LPDs. GPDs were associated with mortality and BIPDs were associated with mortality and unfavorable outcomes, but LPDs were not associated with unfavorable outcomes.
From Patients to Providers: Assessing Impact of Normothermic Machine Perfusion on Liver Transplant Practices in the US
Authors: Wang Benjamin K , Shubin Andrew D , Harvey Jalen A , MacConmara Malcolm M , Hwang Christine S , Patel Madhukar S , Vagefi Parsia A
Published: December 2023

BACKGROUND:

Normothermic machine perfusion (NMP) of livers allows for the expansion of the donor pool and minimization of posttransplant complications. Results to date have focused on both donor and recipient outcomes, but there remains potential for NMP to also impact transplant providers.

STUDY DESIGN:

Using United Network for Organ Sharing Standard Transplant Analysis file data, adult deceased donors who underwent transplantation between January 1, 2016, and December 31, 2022, were identified. Transplanted livers were divided by preservation methods (static cold storage [SCS] and NMP) and case time (day-reperfusion 8 am to 6 pm). Patient factors, transplant characteristics, and short-term outcomes were analyzed between Mahalanobis-metric-matched groups.

RESULTS:

NMP livers represented 742 (1.4%) of 52,132 transplants. NMP donors were more marginal with higher Donor Risk Index scores (1.78 ± 0.50 NMP vs 1.49 ± 0.38 SCS, p < 0.001) and donation after cardiac death frequency (36.9% vs 8.4%, p < 0.001). NMP recipients more often had model for end-stage liver disease (MELD) exception status (29.9% vs 23.4%, p < 0.001), lower laboratory MELD scores (20.7 ± 9.7 vs 24.3 ± 10.9, p < 0.001), and had been waitlisted longer (111.5 [21.0 to 307.0] vs 60.0 [9.0 to 245.0] days, p < 0.001). One-year graft survival (90.2% vs 91.6%, p = 0.505) was similar between groups, whereas length of stay was lower for NMP recipients (8.0 [6.0 to 14.0] vs 10.0 [6.0 to 16.0], p = 0.017) after adjusting for confounders. Notably, peak case volume occurred at 11 am with NMP livers (vs 9 pm with SCS). Overall, a higher proportion of transplants was performed during daytime hours with NMP (51.5% vs 43.0%, p < 0.001).

CONCLUSIONS:

NMP results in increased use of marginal allografts, which facilitated transplantation in lower laboratory MELD recipients who have been waitlisted longer and often have exception points. Importantly, NMP also appeared to shift peak caseloads from nighttime to daytime, which may have significant effects on the quality of life for the entire liver transplant team.
IIaA13G2R1 is the most common Cryptosporidium parvum Subtype among Calves with diarrhea in Türkiye
Authors: Erdem Aynur Zeynep
Published: December 2023

Cryptosporidium spp., an intracellular extra cytoplasmic localized protozoan, is one of the leading infectious agents in the etiology of neonatal diarrheal syndrome of ruminants. Cryptosporidiosis is a common disease seen all over the world. However molecular epidemiologic studies are limited on distribution of Cryptosporidium parvum subtypes in the world. To date, nearly 20 subtypes of C. parvum have been described. Gene sequence analysis of the glycoprotein 60 structural protein (GP60) is used to identify subtypes. It is reported that the GP60 gene sequence shows a high degree of genetic polymorphism among the strains. In this study, it was aimed to determine the subtypes of C. parvum parasite in cow and calf stool samples by using GP60 gene sequence analysis. A total of 109 stool samples from calves (< 30 days) found to be Cryptosporidium spp. positive by Kinyoun Acid Fast staining were further studied for subtyping. Samples were obtained from farms in 2 regions of Türkiye (Burdur/Yesilova and Aydin provinces). DNA isolation from feces was done with the QIAamp Stool Mini Kit. Cryptosporidium specie identification was done by 18S gene sequences analysis. Nested PCR was performed to amplify GP60 gene and sequences of amplicons were used to identify subtypes. The repeat regions at the serine residue in the GP60 sequences were used to define the subtypes. The results of C. parvum subtyping study showed that IIaA13G2R1 subtype was the most common subtype. IIaA13G2R1 was detected in 73% (80/109) of 109 stool samples followed by IIaA14G1R1 with 15 samples (14%), IIaA2R1 with 12 samples (11%), and IIaA16R1 and IIaA5G1R1 subtypes with one sample each (1%). In subtype studies based on the GP60 sequence, IIaA15G2R1 was found to be the most common in the world, however this subtype was not found among our samples. In our study, IIaA13G2R1 subtype was the most common subtype detected, which is also the most common subtype in Türkiye. In our study, two new subtypes were found, IIaA2R1 and IIaA5G1R1 subtypes. These subtypes were defined for the first time in the world. The subtype IIaA16R1 was to be new in Türkiye. Molecular epidemiology studies are important for better understanding the dissemination of subtypes and IIaA13G2R1 is the most common subtype in Türkiye and the IIaA15G2R1 the most common subtype in the world were absent among our samples.
Subinhibitory antibiotic concentrations promote the excision of a genomic island carried by the globally spread carbapenem-resistant Klebsiella pneumoniae sequence type 258
Authors: Piña-Iturbe Alejandro , Hoppe-Elsholz Guillermo , Suazo Isidora D. , Kalergis Alexis M. , Bueno Susan M.
Published: December 2023

The ICEKp258.2 genomic island (GI) has been proposed as an important factor for the emergence and success of the globally spread carbapenem-resistant

Klebsiella pneumoniae

sequence type (ST) 258. However, a characterization of this horizontally acquired element is lacking. Using bioinformatic and experimental approaches, we found that ICEKp258.2 is not confined to ST258 and ST512, but also carried by ST3795 strains and emergent invasive multidrug-resistant pathogens from ST1519. We also identified several ICEKp258.2-like GIs spread among different

K. pneumoniae

STs, other

Klebsiella

species and even other pathogen genera, uncovering horizontal gene transfer events between different STs and bacterial genera. Also, the comparative and phylogenetic analyses of the ICEKp258.2-like GIs revealed that the most closely related ICEKp258.2-like GIs were harboured by ST11 strains. Importantly, we found that subinhibitory concentrations of antibiotics used in treating

K. pneumoniae

infections can induce the excision of this GI and modulate its gene expression. Our findings provide the basis for the study of ICEKp258.2 and its role in the success of

K. pneumoniae

ST258. They also highlight the potential role of antibiotics in the spread of ICEKp258.2-like GIs among bacterial pathogens.
Signalling-state dependent drug-tolerance in head and neck squamous cell carcinoma
Authors: Karjosukarso Dyah W. , Dini Alice , Wingens Laura J.A. , Liu Ruiqi , Joosten Leo A.B. , Bussink Johan , Mulder Klaas W.
Published: December 2023

Intratumor heterogeneity negatively impacts therapeutic response and patient prognosis. Besides the established role of genetic heterogeneity, non-genetic mechanisms of persistence to drug treatment are emerging. Here, we characterise cells selected for their persistence to control, epidermal growth factor inhibition (EGFRi), radiation and combined treatment from low passage head and neck squamous cell carcinoma (HNSCC) cultures. Using a panel of 70 (phospho-)specific DNA-conjugated antibodies we measured activities of 8 signalling pathways, self-renewal, differentiation, DNA damage and cell-cycle, in conjunction with the transcriptional output in single cells, using our RNA and Immuno-Detection (RAID) technology. Six recurrent transcriptional programs reflecting processes including proliferation, differentiation and metabolic activity, as well as protein-based signalling-states, were associated with drug persistence, while copy number variation inference indicated involvement of non-genetic tolerance mechanisms. Projecting RNA velocity onto the antibody-derived signalling-states suggested a key role for integrin-mediated focal-adhesion signalling in drug-persistence in our cell system. Using machine-learning we derived a core transcriptional signature connected to adhesion-based drug-persistence, which was predictive of poor prognosis in a TGCA HNSCC cohort (hazard-ratio 1.87, p<10-5). Furthermore, functional analyses confirmed that cells expressing high levels of integrin alpha-6 (ITGA6) were tolerant to EGFRi treatment, and that forcing cells out of this cell-state through transient targeted inhibition of Focal Adhesion Kinase activity re-instated EGFRi sensitivity in drug persistent cells. Taken together, our single-cell multi-omics analysis identified an actionable adhesion-signalling mediated cell-state driving drug tolerance in HNSCC.
The two key substitutions in the chromophore environment of mKate2 to produce an enhanced FusionRed-like red fluorescent protein
Authors: Ruchkin Dmitry A. , Gavrikov Alexey S. , Kolesov Danila V. , Gorokhovatsky Andrey Yu. , Chepurnykh Tatiana V. , Mishin Alexander S. , Maksimov Eugene G. , Pletneva Nadya V. , Pletnev Vladimir Z. , Pavlova Anastasiia M. , Nikitin Vladimir A. , Lukyanov Konstantin A. , Bogdanov Alexey M.
Published: December 2023

Red fluorescent proteins (RFPs) are often probes of choice for living tissue microscopy and whole-body imaging. When choosing a specific RFP variant, the priority may be focused on fluorescence brightness, maturation rate, monomericity, excitation/emission wavelengths, and low toxicity, which are rarely combined in optimal way in a single protein. If the additional requirements such as prolonged fluorescence lifetime and/or blinking ability are applied, the available probe’s repertoire could become surprisingly narrow. Since the whole diversity of the conventional single-component RFPs belongs to just a few phylogenetic lines (with DsRed-, eqFP578- and eqFP611-derived being the major ones), it is not unexpected that their advantageous properties are split between close homologs. In such cases, a systematic mutagenetic analysis focused on variant-specific amino acid residues can shed light on the origins of sibling RFPs’ distinctness and might be beneficial for consolidation of their strengths in new RFP variants. For instance, the protein FusionRed, although being efficient in the fluorescence labeling due its good monomericity and low cytotoxicity, has undergone a considerable loss in fluorescence brightness/lifetime compared to the parental mKate2. In this contribution, we describe a fast-maturing monomeric RFP designed semi-rationally based on the mKate2 and FusionRed templates, outperforming both its parents in molecular brightness, having extended fluorescence lifetime, and showing spontaneous blinking pattern promising for nanoscopy use.
TML1ANDTML2SYNERGISTICALLY REGULATE NODULATION AND AFFECT ARBUSCULAR MYCORRHIZA INMEDICAGO TRUNCATULA
Authors: Chaulagain Diptee , Schnabel Elise , Kappes Mikayla , Lin Erica Xinlei , Müller Lena Maria , Frugoli Julia A.
Published: December 2023

Two symbiotic processes, nodulation and arbuscular mycorrhiza, are primarily controlled by the plant’s need for nitrogen (N) and phosphorus (P), respectively. Autoregulation of Nodulation (AON) and Autoregulation of Mycorrhization (AOM) both negatively regulate their respective processes and share multiple components - plants that make too many nodules usually have higher AM fungal root colonization. The protein TML (TOO MUCH LOVE) was shown to function in roots to maintain susceptibly to rhizobial infection under low N conditions and control nodule number through AON inLotus japonicus.M. truncatulahas two sequence homologs:MtTML1 andMtTML2. We report the generation of stable single and double mutants harboring multiple allelic variations inMtTML1andMtTML2using CRISPR-Cas9 targeted mutagenesis and screening of a transposon mutagenesis library. Plants containing single mutations inMtTML1 orMtTML2 produced 2-3 times the nodules of wild-type plants whereas plants containing mutations in both genes displayed a synergistic effect, forming 20x more nodules compared to wild type plants. Examination of expression and heterozygote effects suggest genetic compensation may play a role in the observed synergy. Plants with mutations in bothTMLsonly showed mild increases in AM fungal root colonization at later timepoints in our experiments, suggesting these genes may also play a minor role in AM symbiosis regulation. The mutants created will be useful tools to dissect the mechanism of synergistic action ofMtTML1 andMtTML2 inM. truncatulasymbiosis with beneficial microbes.
The socioeconomic gap in life expectancy in Germany: a decomposition of age- and cause-specific mortality contributions, 2003–2021
Authors: Tetzlaff F , Sauerberg M , Grigoriev P , Tetzlaff J , Mühlichen M , Baumert J , Michalski N , Wengler A , Nowossadeck E , Hoebel J
Published: December 2023

Background

Earlier death among people in socioeconomically deprived circumstances has been found internationally and for various causes of death, resulting in a considerable life expectancy gap between socioeconomic groups. This study examines how age- and cause-specific mortality contributions to the socioeconomic gap in life expectancy have changed in Germany over time.

Methods

Official German population and cause-of-death statistics from 2003 to 2021 were linked to the district-level German Index of Socioeconomic Deprivation. Life-table and decomposition methods were applied to calculate life expectancy by deprivation quintile and decompose the life expectancy gap (ΔLE) between the most and least deprived quintiles into age- and cause-specific mortality contributions.

Findings

From 2003 to 2019, the ΔLE between the most and least deprived quintiles of districts increased from 1.1 to 1.8 years among women and from 3.0 to 3.1 years among men. Thereafter, in the COVID-19 pandemic, it increased more rapidly to 2.2 and 3.5 years respectively in 2021. The causes of death contributing most to the ΔLE were cardiovascular diseases (CVD) and cancer, with declining contributions of CVD deaths at age 70 and above and increasing contributions of cancer deaths at ages 40–74 over time. COVID-19 mortality at ages 45+ was the strongest contributor to the increase in ΔLE after 2019.

Interpretation

To reduce the socioeconomic gap in life expectancy, effective efforts are needed to prevent early deaths from CVD and cancer in deprived populations, with cancer prevention and control becoming an increasingly important field of action in this respect.
HIV and viremia prevalence in non-migrating members of migrant households in Rakai region, Uganda: A cross-sectional population-based study
Authors: Young Ruth , Ssekasanvu Joseph , Kagaayi Joseph , Ssekubugu Robert , Kigozi Godfrey , Reynolds Steven J. , Wawer Maria J. , Nonyane Bareng A.S. , Chang Larry W. , Kennedy Caitlin E. , Paina Ligia , Anglewicz Philip A. , Quinn Thomas C. , Serwadda David , Nalugoda Fred , Grabowski M. Kate
Published: December 2023

Introduction

In sub-Saharan Africa, migrants are more likely to be HIV seropositive and viremic than non-migrants. However, little is known about HIV prevalence and viremia in non-migrants living in households with in- or out-migration events. We compared HIV outcomes in non-migrating persons in households with and without migration events using data from the Rakai Community Cohort Study (RCCS), an open population-based cohort in Uganda

Methods

We analyzed RCCS survey data from one survey round collected between August 2016 and May 2018 from non-migrating participants aged 15–49. Migrant households were classified as those reporting ≥1 member moving into or out of the household since the prior survey. A validated rapid test algorithm determined HIV serostatus. HIV viremia was defined as >1,000 copies/mL. Modified Poisson regression was used to estimate associations between household migration and HIV outcomes, with results reported as adjusted prevalence ratios (adjPR) with 95% confidence intervals (95%CI). Analyses were stratified by gender, direction of migration (into/out of the household), and relationship between non-migrants and migrants (e.g., spouse).

Results

There were 14,599 non-migrants (7,654, 52% women) identified in 9,299 households. 4,415 (30%) lived in a household with ≥1 recent migrant; of these, 972(22%) had migrant spouses, 1,102(25%) migrant children, and 875(20%) migrant siblings. Overall, HIV prevalence and viremia did not differ between non-migrants in migrant and non-migrant households. However, in stratified analyses, non-migrant women with migrant spouses were significantly more likely to be HIV seropositive compared to non-migrant women with non-migrant spouses (adjPR:1.44, 95%CI:1.21-1.71). Conversely, non-migrant mothers living with HIV who had migrant children were less likely to be viremic (adjPR:0.34, 95%CI:0.13-0.86). Among non-migrant men living with HIV, spousal migration was associated with a non-significant increased risk of viremia (adjPR:1.37, 95%CI:0.94-1.99). Associations did not typically differ for migration into or out of the household.

Conclusions

Household migration was associated with HIV outcomes for certain non-migrants, suggesting that the context of household migration influences the observed association with HIV outcomes. In particular, non-migrating women with migrating spouses were more likely to have substantially higher HIV burden. Non-migrants with migrant spouses may benefit from additional support when accessing HIV services.
A pilot study of the comparison using a standard and individual altitude exposure protocol in elite gymnasts
Authors: Grushin A.A. , Zelenkova I.E. , Ilin D. , Zotkin S.V. , Korneev P.V. , Koprov S.V. , Almyashev D.Kh. , Badtieva V.A. , Glazachev O.S
Published: December 2023

Aim

Evaluate the effectiveness of the use of altitude training in elite gymnasts and compare two approaches of the altitude exposure protocols.

Materials and methods

The study involved 6 athletes of high qualification specializing in gymnastics (22 (20.5-22.5 years, 166.5 (162.5-169) cm, 63.5 (60-65 kg)). Athletes underwent hypoxic exposure using “Live high - train low” method using standard (18 days) and individual protocol (18 days). The biochemical parameters of blood, total hemoglobin mass, blood volume, hypoxic index, and oxygen saturation of arterial blood were determined.

Results

The tHb-mass values before the standard protocol were 678.5 (664-712.5) g, immediately after 696 (679-752.7) g. Before the start of the individual protocol, the tHb-mass values were 687 (622.7-752) g, immediately after 751.5 (750.2-827) g, (p < 0.05). The tHb-mass shifts after exposure to the unified protocol were 24 (4.8-31) g, and after personified 73.5 (55.5-132.7) g, (p < 0.05). At the same time, ALT, AST, and CPK values did not differ from the baseline, and testosterone values increased after a personalized hypoxic exposure program.

Conclusions

The application of personalized protocol of additional hypoxic impact seems to be more effective than standard protocol in terms of change of hematological parameters.
Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity
Authors: Russell Jamie , Chen Luming , Liu Aijie , Wang Jianhui , Ghosh Subarna , Zhong Xue , Shi Hexin , Beutler Bruce , Nair-Gill Evan
Published: December 2023

Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T cell function. Through forward genetic screening in mice, we discovered that loss-of-function mutations inLDL receptor related protein 10(Lrp10) caused naïve and central memory CD8 T cells to accumulate in peripheral lymphoid organs.Lrp10encodes a conserved cell surface protein of unknown immunological function. Lrp10 was induced with T cell activation and its expression post-translationally suppressed IL7 receptor (IL7R) levels. Accordingly,Lrp10deletion enhanced T cell homeostatic expansion through IL7R signaling.Lrp10-deficient mice were also intrinsically resistant to syngeneic tumors. This phenotype depended on dense tumor infiltration of CD8 T cells that displayed increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
Serotonin Reduces Belief Stickiness
Authors: Conceição Vasco A. , Petzschner Frederike H. , Cole David M. , Wellstein Katharina V. , Müller Daniel , Raman Sudhir , Maia Tiago V.
Published: December 2023

Serotonin fosters cognitive flexibility, but how, exactly, remains unclear. We show that serotonin reduces belief stickiness: the tendency to get “stuck” in a belief about the state of the world despite incoming contradicting evidence. Participants performed a task assessing belief stickiness in a randomized, double-blind, placebo-controlled study using a single dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram. In the escitalopram group, higher escitalopram plasma levels reduced belief stickiness more, resulting in better inference about the state of the world. Moreover, participants with sufficiently high escitalopram plasma levels had less belief stickiness, and therefore better state inference, than participants on placebo. Exaggerated belief stickiness is exemplified by obsessions: “sticky” thoughts that persist despite contradicting evidence. Indeed, participants with more obsessions had greater belief stickiness, and therefore worse state inference. The opposite relations of escitalopram and obsessions with belief stickiness may explain the therapeutic effect of SSRIs in obsessive-compulsive disorder.
Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis
Authors: Mazeaud Clément , Pfister Stefan , Owen Jonathan E. , Pereira Higor Sette , Charbonneau Flavie , Robinson Zachary E. , Anton Anaïs , Bemis Cheyanne L. , Sow Aïssatou Aïcha , Patel Trushar R. , Neufeldt Christopher J. , Scaturro Pietro , Chatel-Chaix Laurent
Published: December 2023

Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication and packaging into new virions, all within virus-induced replication organelles (vRO). In this study, with an RNAi mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescencein situhybridization-based confocal imaging,in vitrobinding assays, and immunoprecipitation coupled to RT-qPCR, showed that IGF2BP2 directly interacts with ZIKV vRNA 3’-nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairsde novoviral organelle biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR, revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.
Quantitative description of six fish species’ gut contents and abundances of their prey in the benthic food web of the Baltic Sea (1968-1978)
Authors: Gauzens Benoit , Kalinkat Gregor , Antunes Ana Carolina , Boy Thomas , O’Gorman Eoin J. , Jacob Ute , Jochum Malte , Kortsch Susanne , Rosenbaum Benjamin , Figueiredo Ludmilla , Brose Ulrich
Published: December 2023

The dataset presents a compilation of stomach contents from six demersal fish species from two functional groups inhabiting the Baltic Sea. It includes detailed information on prey identities, body masses, and biomasses recovered from both the fish’s digestive systems and their surrounding environment. Environmental parameters, such as salinity and temperature levels, have been integrated to enrich this dataset. The juxtaposition of information on prey found in stomachs and in the environment provides an opportunity to quantify trophic interactions across different environmental contexts and investigate how fish foraging behaviour adapts to changes in their environment, such as an increase in temperature. The compilation of body mass and taxonomic information for all species allows approaching these new questions using either a taxonomic (based on species identity) or functional trait (based on body mass) approach.
Explaining tip-of-the-tongue experiences in older adults – contributions of brain function, structure, and perfusion in relation to older adults’ cardiorespiratory fitness
Authors: Rahman Foyzul , Tsvetanov Kamen A. , Feron Jack , Mullinger Karen , Joyce Kelsey , Gilani Ahmed , Fernandes Eunice G. , Wetterlin Allison , Wheeldon Linda , Lucas Samuel J.E. , Segaert Katrien
Published: December 2023

Cognitive decline associated with healthy ageing is complex and multifactorial: brain-based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. We tested 73 (Mage= 65.51) neurologically healthy older adults and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and behavioural performance data to investigate a well-documented, prominent cognitive challenge for older adults: word-finding failures. We aimed to uncover associations between predictors, which have previously been theoretically-implicated, in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness levels. Age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongue states. Our findings can be interpreted in the context of the classic models of neurocognitive ageing suggesting compensation. Our findings moreover suggest that brain health indices in concordance with cardiorespiratory fitness measures have the potential to provide a more holistic explanation of individual differences in age-related cognitive decline.

Highlights

The incidence of word-finding failures is associated with brain health and cardiorespiratory fitness factors

Language network activation associated with word-finding failures is linked to age and cardiorespiratory fitness levels

Distinct contribution of brain structure and perfusion are also associated with word-finding

Brain health indices in concordance with cardiorespiratory fitness measures have the potential to provide a more holistic explanation of individual differences in age-related cognitive decline
Microbial metabolic specificity controls pelagic lipid export efficiency
Authors: Behrendt Lars , Alcolombri Uria , Hunter Jonathan E. , Smriga Steven , Mincer Tracy , Lowenstein Daniel P. , Yawata Yutaka , Peaudecerf François J. , Fernandez Vicente I. , Fredricks Helen F. , Almblad Henrik , Harrison Joe J. , Stocker Roman , Van Mooy Benjamin A. S.
Published: December 2023

Lipids comprise more than 20% of sinking organic matter in the ocean and play a crucial role in the carbon cycle. Despite this, our understanding of the processes that control lipid degradation is limited. Here we combined nano-lipidomics and imaging to study the bacterial degradation of diverse algal lipid droplets. Bacteria isolated from natural marine particles exhibited distinct dietary preferences, ranging from selective to promiscuous degraders. Dietary preference was associated with a distinct set of lipid degradation genes rather than with taxonomic origin. The top degrader,Pseudomonas zhaodongensis,rapidly consumed triacylglycerols (TAGs) from lipid extracts while promoting colonization of kin by chemotaxis toward glycerol, the TAG degradation product. Using synthetic communities composed of isolates with distinct dietary preferences, we demonstrated that lipid degradation is modulated by microbial interactions. A particle export model incorporating these dynamics suggests that metabolic specialization and community dynamics influences lipid transport efficiency in the ocean’s mesopelagic zone.
Spatial Patterning Analysis of Cellular Ensembles (SPACE) discovers complex spatial organization at the cell and tissue levels
Authors: Schrom Edward C. , McCaffrey Erin F. , Sreejithkumar Vivek , Radtke Andrea J. , Ichise Hiroshi , Arroyo-Mejias Armando , Speranza Emily , Arakkal Leanne , Thakur Nishant , Grant Spencer , Germain Ronald N.
Published: December 2023

Spatial patterns of cells and other biological elements drive both physiologic and pathologic processes within tissues. While many imaging and transcriptomic methods document tissue organization, discerning these patterns is challenging, especially when they involve multiple elements in complex arrangements. To address this challenge, we present Spatial Patterning Analysis of Cellular Ensembles (SPACE), an R package for analysis of high-plex spatial data. SPACE is compatible with any data collection modality that records values (i.e., categorical cell/structure types or quantitative expression levels) at fixed spatial coordinates (i.e., 2d pixels or 3d voxels). SPACE detects not only broad patterns of co-occurrence but also context-dependent associations, quantitative gradients and orientations, and other organizational complexities. Via a robust information theoretic framework, SPACE explores all possible ensembles of tissue elements – single elements, pairs, triplets, and so on – and ranks the most strongly patterned ensembles. For single images, rankings reflect patterns that differ from random assortment. For sets of images, rankings reflect patterns that differ across sample groups (e.g., genotypes, treatments, timepoints, etc.). Further tools then thoroughly characterize the nature of each pattern for intuitive interpretation. We validate SPACE and demonstrate its advantages using murine lymph node images for which ground truth has been defined. We then use SPACE to detect new patterns across varied datasets, including tumors and tuberculosis granulomas.
ATAT: Automated Tissue Alignment and Traversal in Spatial Transcriptomics with Self-Supervised Learning
Authors: Song Steven , Mohsin Emaan , Zhang Renyu , Kuznetsov Andrey , Shen Le , Grossman Robert L. , Weber Christopher R. , Khan Aly A.
Published: December 2023

Spatial transcriptomics (ST) has enhanced RNA analysis in tissue biopsies, but interpreting these data is challenging without expert input. We present Automated Tissue Alignment and Traversal (ATAT), a novel computational framework designed to enhance ST analysis in the context of multiple and complex tissue architectures and morphologies, such as those found in biopsies of the gastrointestinal tract. ATAT utilizes self-supervised contrastive learning on hematoxylin and eosin (H&E) stained images to automate the alignment and traversal of ST data. This approach addresses a critical gap in current ST analysis methodologies, which rely heavily on manual annotation and pathologist expertise to delineate regions of interest for accurate gene expression modeling. Our framework not only streamlines the alignment of multiple ST samples, but also demonstrates robustness in modeling gene expression transitions across specific regions. Additionally, we highlight the ability of ATAT to traverse complex tissue topologies in real-world cases from various individuals and conditions. Our method successfully elucidates differences in immune infiltration patterns across the intestinal wall, enabling the modeling of transcriptional changes across histological layers. We show that ATAT achieves comparable performance to the state-of-the-art method, while alleviating the burden of manual annotation and enabling alignment of tissue samples with complex morphologies.

Availability

ATAT is available at:https://github.com/StevenSong/tissue-alignment
Bone quality following peripubertal growth in a mouse model of transmasculine gender-affirming hormone therapy
Authors: Henry Brandon W. , Cruz Cynthia Dela , Goulet Robert W. , Nolan Bonnie T. , Locke Conor , Padmanabhan Vasantha , Moravek Molly B. , Shikanov Ariella , Killian Megan L.
Published: December 2023

During peri-puberty, bone growth and the attainment peak bone mass is driven predominantly by sex steroids. This is important when treating transgender and gender diverse youth, who have become increasingly present at pediatric clinics. Analogues of gonadotropin-releasing hormone (GnRH) are commonly prescribed to transgender and gender diverse youth prior to starting gender-affirming hormone therapy (GAHT). However, the impact of GnRH agonists on long bones with the addition of GAHT is relatively unknown. To explore this, we developed a trans-masculine model by introducing either GnRHa or vehicle treatment to female-born mice at a pre-pubertal age. This treatment was followed by male GAHT (testosterone, T) or control treatment three weeks later. Six weeks after T therapy, bone quality was compared between four treatment groups: Control (vehicle only), GnRHa-only, GnRHa + T, and T-only. Bone length/size, bone shape, mechanical properties, and trabecular morphology were modulated by GAHT. Independent of GnRHa administration, mice treated with T had shorter femurs, larger trabecular volume and increased trabecular number, higher trabecular bone mineral density, and wider superstructures on the surface of bone (e.g., third trochanters) when compared to control or GnRHa-only mice. In conclusion, prolonged treatment of GnRHa with subsequent GAHT treatment directly affect the composition, parameters, and morphology of the developing long bone. These findings provide insight to help guide clinical approaches to care for transgender and gender diverse youth.
All-cause, circulatory disease and cancer mortality in the population of a large Italian area contaminated by perfluoroalkyl and polyfluoroalkyl substances (1980-2018)
Authors: Biggeri Annibale , Stoppa Giorgia , Facciolo Laura , Fin Giuliano , Mancini Silvia , Manno Valerio , Minelli Giada , Zamagni Federica , Zamboni Michela , Catelan Dolores , Bucchi Lauro
Published: December 2023

Background

Perfluoroalkyl substances (PFAS) are associated with many adverse health conditions. Among the main effects is carcinogenicity in humans, which deserves to be further clarified. A clear association has been reported for kidney cancer and testicular cancer. In 2013, a large episode of surface, ground and drinking water contamination with PFAS was uncovered in three provinces of the Veneto Region (north-eastern Italy) involving 30 municipalities and a population of about 150,000. We report on the temporal evolution of all-cause mortality and selected cause-specific mortality by calendar period and birth cohort in the local population between 1980 and 2018.

Methods

The Italian National Institute of Health and the Italian National Institute of Statistics made available the anonymous records of death certificates of residents of the provinces of Vicenza, Verona and Padova (males, n=29,629; females, n=29,518) who died between 1980 and 2018. Calendar period analysis was done by calculating standardized (European standard population 2013) mortality ratios using the total population of the three provinces in the same calendar period as a reference. The birth cohort analysis was performed using cumulative risks for ages 20-84 years.

Results

During the 33 years between 1985 (assumed as beginning date of water contamination) and 2018 (last year of available cause-specific mortality), in the resident population of theRed area(the municipalities being connect to the contaminated water plant) we observed 51,621 deaths as compared to 47,731 expected (age-sex SMR: 108; 90% CI: 107-109). We found evidence of raised mortality for diseases of the circulatory system (in particular, heart disease and ischemic heart disease) and malignant neoplastic diseases, including kidney cancer and testicular cancer.

Conclusions

For the first time, an association of PFAS exposure with mortality from circulatory disease mortality was formally demonstrated. Circumstantial evidence regarding kidney cancer and testicular cancer is consistent with previously reported data.
A Fast Interferometric Beam Shaper for Multi-Emitter 3D MINFLUX
Authors: Geismann Maximilian K. , Gomez-Segalas Alba , Passera Alessandro , Shirzadian Mehrta , Balzarotti Francisco
Published: December 2023

Beams of light that feature an intensity zero are essential to a variety of optical microscopy methods. Super-resolution techniques like STED and RESOLFT, together with localization strategies like MINFLUX and MINSTED, rely on accurate and fast displacements of such beams and their zeros. Extending these methods to the third dimension requires axial deflection, which, in contrast to lateral deflection, remains technologically challenging on the microsecond scale. Here, we present a fast general-purpose beam-shaping polarization interferometer that, instead of displacing the entire beam, enables such axial deflections by deforming the beam shape to deflect its zero. Based on this approach, we showcase a four-channel dual-color excitation system for three-dimensional MINFLUX imaging and tracking. We include first demonstrations of improved MINFLUX localization schemes that utilize the combination of distinct beam shapes and three-dimensional multi-emitter tracking. We believe that the presented approach will facilitate the broader adoption of three dimensional MINFLUX and provides a versatile basis for future implementations of advanced single-molecule localization methods.
Tissue stiffness mapping by light sheet elastography
Authors: Zhu Min , Zhang Kaiwen , Thomas Evan C. , Xu Ran , Ciruna Brian , Hopyan Sevan , Sun Yu
Published: December 2023

Tissue stiffness plays a crucial role in regulating morphogenesis. The ability to measure and monitor the dynamic progression of tissue stiffness is important for generating and testing mechanistic hypotheses. Methods to measure tissue propertiesin vivohave been emerging but present challenges with spatial and temporal resolution especially in 3D, by their reliance on highly specialised equipment, and/or due to their invasive nature. Here, introduce light sheet elastography, a noninvasive method that couples low frequency shear waves with light sheet fluorescence microscopy by adapting commercially available instruments. With this method, we achievedin totostiffness mapping of organ-stage mouse and zebrafish embryos at cellular resolution. Versatility of the method enabled time-lapse stiffness mapping during tissue remodelling and of the beating embryonic heart. This method expands the spectrum of tools available to biologists and presents new opportunities for uncovering the mechanical basis of morphogenesis.
A novel nested geneAff3irparticipates in vascular remodelling by enhancing endothelial cell differentiation in mice
Authors: Zhao Yue , Ehteramyan Mazdak , Li Yi , Bai Xuefeng , Huang Lei , Gao Yingtang , Angbohang Angshumonik , Yang Xiaoping , Lynham Steven , Margariti Andriana , Shah Ajay M , Tao Yaling , Cai Ting , Li Tong , Zhang Min , Zeng Lingfang
Published: December 2023

Endothelial integrity in the vasculature is critically maintained by vascular stem/progenitor cells (SPCs) giving rise to endothelial cells (ECs). However, the genes significantly activated during differentiation remain incompletely understood. Based on mouse aorta and vein cDNA library, we unearthed a hitherto unidentified gene nested residing within intron 6 ofAff3, christened asAff3intron resident (Aff3ir), upregulated during laminar shear stress-induced ECs differentiation in mouse. Proteomic analysis substantiated the presence of a 45-amino acid(aa) peptide (AFF3IR-ORF1) and 109-aa or 151-aa protein (AFF3IR-ORF2) encoded from two transcript variants. During embryonic development, AFF3IR-ORF1 peaked at E14.5, while AFF3IR-ORF2 displayed a continuous increase until E19.5. In adult mice, AFF3IR-ORF1 was detected in the lung, liver, spleen, and kidney, while AFF3IR-ORF2 was most abundant in the aorta. Furthermore, Western blot and immunofluorescence analyses revealed a specific upregulation of AFF3IR-ORF2, but not AFF3IR-ORF1, three days after femoral artery injury or hindlimb ischemiain vivo. Overexpression of AFF3IR-ORF2 enhanced, while its knockdown attenuated, SPCs differentiation into ECs induced by shear stress or vascular endothelial growth factorin vitro. Notably, the upregulated AFF3IR-ORF2 hindered SPCs proliferation by sequestering minichromosome maintenance complex component 3 in the cytoplasm, thereby shifting the status of SPCs from a pro-proliferation to a pro-differentiation state. In conclusion, our discoveries unveil the novel protein-coding geneAff3iras a participant in ECs differentiation, providing fresh insights into the regulation of vascular endothelial integrity.