bluuebunny/crossref_metadata_2025 huggingface dataset:
Maxillary Reconstruction with Free Vascularized Fibula: 15-Year Experience
Authors: Cho Min-Jeong , Padilla Pablo L. , Skoracki Roman J. , Hanasono Matthew M.
Published: August 2024

Background:

Reconstruction of the midface after maxillectomy is extremely challenging because of the need to reestablish the contour of the midface, maintain oronasal separation, support the orbit, and to restore the dentition. In this study, the authors present their specific technique, surgical and functional outcomes, and pitfalls to avoid for reconstruction of the midface with the fibula osteocutaneous free flap.

Methods:

A retrospective review of patients who underwent maxillary reconstruction with a fibula osteocutaneous free flap was performed.

Results:

Eighty-five flaps were performed in 73 patients (61 patients received a fibula flap only; 12 patients received an additional soft-tissue free flap). Reconstructions were performed for Cordeiro type 2 (82.2%) and Cordeiro type 3a (18.8%) defects. Osseointegrated dental implants were placed in 95.9% of patients, 13.7% of whom underwent immediate implant placement. Concurrent orbital floor reconstruction was performed in 16.2% of patients. The rate of operative take-back was 18.9%, and total flap loss occurred in 2.7%. Hardware exposure occurred in 11.0% at a mean of 4.4 years postoperatively and palatal fistulas occurred in 5.5%, usually within the first 3 weeks following reconstruction. Functionally, 79.5% demonstrated excellent speech and 80.9% had unrestricted diet postoperatively. The mean follow-up period was 3.4 years.

Conclusions:

The present study shows that maxillary reconstruction with free fibula flap provides reliable reconstruction that restores dental, orbital, and midfacial support. Modifications and nuances to the reconstructive technique learned over time to avoid complications and improve outcomes are described herein.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Cultural Influences on the Receipt of Breast Reconstruction: A Scoping Review
Authors: Liang Joey , Flusche Ann Marie , Kaplan Samantha , Rezak Kristen , Sisk Geoffroy C. , Patel Ash
Published: August 2024

Background:

Postmastectomy breast reconstruction can provide breast cancer patients with lasting psychosocial, functional, and body image benefits. Although sociodemographic factors affecting the receipt of breast reconstruction have been well studied, the cultural factors influencing patients’ decisions to undergo breast reconstruction remain unclear. There are currently no reviews on cultural factors influencing breast reconstruction decision-making. This scoping review aimed to broadly evaluate the current literature on cultural factors that influence the receipt of breast reconstruction in breast cancer patients who have undergone mastectomies.

Methods:

A combination of keywords and subject headings was used to search for articles related to breast reconstruction and decision-making. Databases were searched from inception to November 20, 2023. Screening was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines, and quantitative studies examining the receipt of breast reconstruction in breast cancer patients following mastectomy were evaluated for inclusion.

Results:

Of the 4520 studies that were screened, 61 were included in the final review. The majority of studies included in the review were retrospective and performed in the United States. Included studies were evaluated for cultural influences on the receipt of breast reconstruction. Six themes emerged across the included studies: race and ethnicity, language and communication barriers, education and literacy, cultural competency, patient perceptions, and family and relationships.

Conclusion:

In addition to well-established influences on breast reconstruction such as race and ethnicity, this review broadly identified additional cultural factors that influence patients’ decisions to undergo breast reconstruction.
Biomechanical Evaluation of the Osseointegration Levels of Implants Placed Simultaneously With Tibia, Femur, and Jaw Allogeneic Bone Grafts
Authors: Ozcan Erhan Cahit , Sokmen Kevser , Karasu Necmettin , Bal Ali , Tanrisever Murat , Istek Ozmen , Kirtay Mustafa , Bozoglan Alihan , Dundar Serkan
Published: August 2024

In implant-supported prosthetic treatments, the jaw bones may not always have enough bone to accommodate implants. Allogeneic grafts can also be preferred as an alternative to autogenous grafts in cases of vertical and horizontal bone deficiencies. The aim of this study is to evaluate the osseointegration levels of lathe-faced titanium implants placed together with allogeneic bone tissue transplants obtained from tibia, femur, and mandible bones using a biomechanical method. Twenty-eight female Sprague Dawley rats were included in the study. The subjects were divided into groups where bone transplantations were performed together with implant placement from the tibia (n=7), femur (n=7), and lower jaw (n=7) regions. Four rats (left and right) were used as donors. Grafts, along with implants, were surgically placed in the corticocancellous part of the metaphyseal parts of the tibia bones of rats. At the end of the 2-week experimental setup, all rats were killed, and the implants and surrounding bone tissues were subjected to biomechanical reverse torque analysis (N/cm), no statistical difference was detected in terms of bone-implant fusion between the groups in which the femur and tibia bones were transplanted (P>0.05), while the bone-implant fusion value in the group in which the lower jaw bone was transplanted was found to be statistically higher than the femur and tibia bones (P<0.05). Based on the limited results of this study, it can be thought that the lower jaw allogeneic jawbone has a higher osseointegration potential than allogeneic grafts obtained from the femur and tibia.
Evaluation of Prognostic Factors in Adult Chemical Corneal Injury
Authors: Eröz Pinar , Özer Ömer , Güçlü Emin Serbülent , Baysal Zeki , Doğan Levent
Published: August 2024

Objective:

The aim of this study was to evaluate prognostic factors that may be useful in predicting final visual acuity in patients admitted to the clinic with chemical corneal injuries.

Methods:

Data on age, sex, time to admission, irrigation solutions (balanced salt solution or phosphate buffered saline) and type of substance causing chemical injury were recorded. On admission, all patients were evaluated according to Roper Hall and Dua classifications. At the twelfth month after treatment, all measurements were repeated.

Results:

A total of 131 patients with chemical corneal injuries [group 1 (acid, n = 73) and group 2 (alkaline, n = 58)] were included. The initial best corrected visual acuity (BCVA) level was “20/40 and above” in 32 patients (43.8%) in group 1 and 14 patients (24.1%) in group 2. According to Roper Hall classification, the mean grade was 1.92 ± 0.9 in group 1 and 2.27 ± 1.1 in group 2. According to Dua classification, the mean grade of the patients in group 1 was 2.16 ± 0.9 and 2.58 ± 1.2 in group 2. Posttreatment BCVA level improved to “1/200 to 19/200” in 8 (66.7%) of the patients with an initial BCVA level of “perception of light or hand movements.” In univariate analysis, initial visual acuity and posttreatment visual acuity were statistically significant (P < 0.001). It was also statistically significant in multivariate analysis adjusted for sex and age (P < 0.001).

Conclusion:

In conclusion, the treatment of chemical corneal injuries is a long and exhausting process. The use of initial visual acuity and Dua classification in prognosis prediction may provide high success.
Small versus large-bore thoracostomy for traumatic hemothorax: A systematic review and meta-analysis
Authors: Lyons Nicole B. , Abdelhamid Mohamed O. , Collie Brianna L. , Ramsey Walter A. , O’Neil Christopher F. , Delamater Jessica M. , Cobler-Lichter Michael D. , Shagabayeva Larisa , Proctor Kenneth G. , Namias Nicholas , Meizoso Jonathan P.
Published: August 2024

BACKGROUND

Traumatic hemothorax (HTX) is common, and while it is recommended to drain it with a tube thoracostomy, there is no consensus on the optimal catheter size. We performed a systematic review to test the hypothesis that small bore tube thoracostomy (SBTT) (≤14 F) is as effective as large-bore tube thoracostomy (LBTT) (≥20F) for the treatment of HTX.

METHODS

Pubmed, EMBASE, Scopus, and Cochrane review were searched from inception to November 2022 for randomized controlled trials or cohort studies that included adult trauma patients with HTX who received a tube thoracostomy. Data was extracted and Critical Appraisal Skills Program checklists were used for study appraisal. The primary outcome was failure rate, defined as incompletely drained or retained HTX requiring a second intervention. Cumulative analysis was performed with χ2 test for dichotomous variables and an unpaired t-test for continuous variables. Meta-analysis was performed using a random effects model.

RESULTS

There were 2,008 articles screened, of which nine were included in the analysis. The studies included 1,847 patients (714 SBTT and 1,233 LBTT). The mean age of patients was 46 years, 75% were male, average ISS was 20, and 81% had blunt trauma. Failure rate was not significantly different between SBTT (17.8%) and LBTT (21.5%) (p = 0.166). Additionally, there were no significant differences between SBTT vs. LBTT in mortality (2.9% vs. 6.1%, p = 0.062) or complication rate (12.3% vs. 12.5%, p = 0.941), however SBTT had significantly higher initial drainage volumes (753 vs. 398 mL, p < 0.001) and fewer tube days (4.3 vs. 6.2, p < 0.001). There are several limitations. Some studies did not report all the outcomes of interest, and many of the studies are subject to selection bias.

CONCLUSION

SBTT may be as effective as LBTT for the treatment of traumatic HTX.

LEVEL OF EVIDENCE

Systematic Review/Meta-Analysis; Level IV.
The effect of whole blood resuscitation on in-hospital mortality: A propensity score weighted analysis of patients treated at a Level I trauma center
Authors: Acharya Pawan , Garwe Tabitha , Vesely Sara K. , Janitz Amanda , Peck Jennifer D. , Celii Amanda
Published: August 2024

BACKGROUND

Whole blood (WB) transfusion, compared with blood component therapy (CT), has been shown to have superior outcomes in the military population. However, whether this translates to the civilian population remains understudied. This study sought to determine the effect of WB on short-term in-hospital outcomes.

METHODS

This retrospective cohort study included trauma patients at a Level I trauma center who received either WB or CT upon massive transfusion protocol activation between January 2021 and June 2023. The primary outcome was in-hospital mortality, and secondary outcomes included 24-hour mortality, 7-day mortality, 30-day mortality, trauma-induced coagulopathy, and the number of transfusion events required. The effect of transfusion type on patient outcomes was evaluated using a propensity-weighted modified Poisson regression.

RESULTS

Of 1,027 massive transfusion protocol–activated patients, 480 (46.8%) received any WB. The propensity score weighting balanced the covariate distribution between the transfusion groups. Significant effect modification (p < 0.05) by injury type (blunt vs. penetrating) on mortality outcomes was observed. Compared with CT recipients, penetrating trauma patients who received WB had a significantly lower adjusted risk of in-hospital (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.15–0.89), 7-day (RR, 0.37; 95% CI, 0.15–0.94), and 30-day (RR, 0.36; 95% CI, 0.15–0.89) mortality but not significantly different 24-hour mortality (RR, 0.39; 95% CI, 0.15–1.00; p = 0.05). An elevated risk of trauma-induced coagulopathy was observed among WB recipients than CT recipients with blunt trauma (RR, 1.59; 95% CI, 1.07–2.36) but not among patients with penetrating injury (RR, 0.65; 95% CI, 0.30–1.40). Compared with CT recipients, WB recipients had reduced transfusion rates for both penetrating (RR, 0.59; 95% CI, 0.36–0.95) and blunt-related injuries (RR, 0.73; 95% CI, 0.58–0.91).

CONCLUSION

The effect of WB on in-hospital mortality is modified by injury type, suggesting the need to consider penetrating injury as an important indication for WB resuscitation. In addition, WB reduces transfusion requirements across both injury types, decreasing patient exposure to transfusion events.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Stronger together: harnessing natural algal communities as potential probiotics for inhibition of aquaculture pathogens
Authors: Smahajcsik Dóra , Roager Line , Strube Mikael Lenz , Zhang Sheng-Da , Gram Lone
Published: August 2024

Intensive fish rearing in aquaculture is challenged by infectious diseases, and although vaccines have been successfully developed for mature fish, alternative disease control measures are needed for fish larvae and juveniles. Probiotics offer a promising alternative to antibiotics, with the potential to reduce the risk of antibiotic resistance. Probiotics are typically isolated and used as pure cultures, however, in natural environments it is the concerted effort of the complex microbiome that keeps pathogens at bay. Here, we developed anin vitroassay to evaluate the anti-pathogen efficacy of mixed algal microbiomes from the live-feed microalgaeTetraselmis suecicaandIsochrysis galbana.The inhibition of a GFP-taggedVibrio anguillarum, a key fish pathogen, by microbial communities, was measured and quantified as reduction in fluorescence. TheIsochrysis galbanamicrobiome was more inhibitory toV. anguillarumthan theTetraselmis suecicamicrobiome. During co-culture with the pathogen, the bacterial density of theIsochrysismicrobiomes increased whilst the diversity was reduced as determined by metataxonomic analyses. Bacteria isolated from the fully inhibitory microbiomes were members ofAlteromonadaceae, Halomonadaceae, Rhodobacteraceae, Vibrionaceae, Flavobacteriaceae,andErythrobacteraceae. Although some strains individually inhibited the pathogen, these were not the key members of the microbiome and enhanced inhibition was observed whenSulfitobacter pontiacusD3 andHalomonas campaniensisD2 were co-cultured, even though neither were inhibitory as monocultures. Thus, this study demonstrates that microbial communities derived from natural algal microbiomes can have anti-pathogen effects, and that bacterial co-cultures may offer synergistic advantages over monocultures as probiotics, highlighting their promise for aquaculture health strategies.

IMPORTANCE

Aquaculture is the fastest growing food protein producing sector and sustainable disease control measures are required. Probiotics have gained interest as a promising solution for combating fish pathogens and using mixtures of microorganisms rather than pure cultures may represent a more stable pathogen control. We developed an assay using GFP-tagging of a fish pathogen, enabling the quantitative assessment of the anti-pathogen effects of complex microbiomes. We show that the efficiency of pathogen suppression can be increased with co-cultures compared to monocultures, thus emphasising the potential in using mixtures of bacteria as probiotics.
Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer
Authors: Mahat Dig B. , Kumra Heena , Castro Sarah A. , Metcalf Emily , Nguyen Kim , Morisue Ryo , Ho William W. , Chen Ivy , Sullivan Brandon , Yim Leon K. , Singh Arundeep , Fu Jiayu , Waterton Sean K. , Cheng Yu-Chi , Roberge Sylvie , Moiso Enrico , Chauhan Vikash P. , Silva Hernandez Moura , Spranger Stefani , Jain Rakesh K. , Sharp Phillip A.
Published: August 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53R172Hestablishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53R172H. Mechanistically, we show that p53R172Hassociates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53R172Hoccupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB’s role in recruiting p53R172Hto the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

Graphical Abstract
Control of Physical and Biochemical Parameters Influencing Exogeneous Cargo Protein association to Extracellular Vesicle using Lipid Anchors Enables High Loading and Effective Intracellular Delivery
Authors: Marquant Antonin , Berthelot Jade , Bich Claudia , Elfekih Zeineb Ibn , Simon Laurianne , Robin Baptiste , Chopineau Joël , Wang David Tianpei , Emerson Samuel Jay , Wang Aijun , Benedetti Clément , Langlois Simon , Guglielmi Laurence , Martineau Pierre , Aubert-Pouëssel Anne , Morille Marie
Published: August 2024

Despite biomolecule delivery is a natural function of Extracellular Vesicles (EVs), loading of exogenous macromolecules such as proteins into EVs remains a major challenge limiting their interest as convincing protein delivery systems for health applications. In this context, lipid-anchorage of exogenous cargo into EV membrane recently emerged as a promising option to enable their vectorization into cells. Nevertheless, this option was not explored for protein intracellular delivery, and further characterization of the critical parameters governing the association of a lipid-anchored cargo protein to EVs is still needed to confirm the relevance of this anchorage strategy. Therefore, in this work, we have sought to identify these parameters in a precise and quantitative manner, working with bulk and single nanoparticle analysis methods to identify protein loading capacity and subsequent intracellular delivery. Incubation temperature, cargo concentration and Lipid Anchor (LA) structure (lipid nature and PEG size) appeared as critical factors influencing maximal EV loading capacity. Precise control of these parameters enabled to load cargo protein close to EV saturation without hindering cellular delivery. Interestingly, we evidenced that EV isolation process influenced this association. Structural properties of LA influenced not only cargo protein/EV association, but also its intracellular delivery into different carcinoma cell lines. By thoroughly characterizing Lipid-PEG-protein anchorage, this study evidences the interest of this tunable and controllable approach for efficient EV protein delivery.

Graphical abstract
TGF-β signaling promotes the expression of proviral circular RNA ciTRAN in HIV-1 infection
Authors: Choudhary Aditi , Mallick Katyayani , Dalavi Rishikesh , Chande Ajit
Published: August 2024

Circular RNA (circRNA) expression is widespread in immune cells infected by HIV-1, but the crosstalk between circRNA expression and various cellular signaling pathways remains unclear. We report that HIV-1 Vpr triggers TGF-β signaling, which we linked to the increased expression of ciTRAN, a proviral circRNA encoded bySMARCA5. Consistent with this finding, we observed that the essential intracellular TGF-β receptor signaling component SMAD2/3 was recruited to theSMARCA5promoter in a Vpr-dependent manner.SMARCA5promoter analysis and functional assays further revealed that the SAMD2/3 binding motif is crucial for ciTRAN upregulation. In response to treatment with DNA-damaging agents or the exogenous addition of recombinant TGF-β, the TGF-β-SMAD axis upregulated the expression of ciTRAN as well as the parentalSMARCA5mRNA. Finally, pharmacological targeting of TGF-β signaling or genetic ablation ofTGFBR1can reduce the ability of HIV-1 Vpr to induce the expression of ciTRAN and viral genes. These results offer crucial mechanistic insights into the regulation of ciTRAN expression by TGF-β signaling and suggest a strategy to inhibit circRNA expression during infection by small molecules.
Auditory feedback effect of self-pacing treadmill walking in comparison to overground walking
Authors: Evans Trevor V. , Reissman Megan E. , Reissman Timothy , Shelhamer Mark , Chaudhari Ajit M. W.
Published: August 2024

Self-pacing treadmills provide advantages for assessing locomotion, but there are differences between gait patterns in overground and treadmill paradigms. A potential explanation could be that the variable auditory sound from the treadmill belt motors when changing speed provides artificial sensory feedback to walkers that may influence their motor output while on the self-pacing treadmill. We hypothesized that there would be significantly different temporal measures between the sound and no-sound conditions, and these same measures from the no-sound condition would be similar to overground walking. Participants (n=29) walked under three different conditions for five-minute periods each: on the self-pacing treadmill with sound inclusion, on the self-pacing treadmill with sound exclusion, and overground walking. Significant differences were found in the variability of all temporal walking measurements between the overground and both treadmill conditions (p < 0.05). Effects of sound on temporal walking measurements were not observed. The lack of difference between the two treadmill conditions suggests that self-pacing treadmill walkers may not utilize the variable belt motor sounds available to them. Additionally, overground walking still has different gait patterns compared to self-pacing treadmill walking, so other potential sources of differences should be explored in future work. Given that both treadmill conditions had different temporal gait patterns from overground, considerations for using the self-pacing treadmill as an alternative for overground walking should be taken when studying human locomotion.
Using in vivo calcium imaging to examine joint neuron spontaneous activity and home cage analysis to monitor activity changes in mouse models of arthritis
Authors: Goodwin George L , Marin Alina-Cristina , Walker Julia Vlachaki , Hobbs Carl , Denk Franziska
Published: August 2024

Background

Studying pain in rodent models of arthritis is challenging. For example, assessing functional changes in joints neurons is challenging due to their relative scarcity amongst all sensory neurons. Additionally, studying pain behaviors in rodent models of arthritis poses its own set of difficulties. Commonly used tests, such as static weight-bearing, often require restraint, which can induce stress and consequently alter nociception. The aim of this study was to evaluate two emerging techniques for investigating joint pain in mouse models of rheumatoid and osteoarthritis:In vivocalcium imaging to monitor joint afferent activity and group-housed home cage monitoring to assess pain-like behaviors. Specifically, we examined whether there was increased spontaneous activity in joint afferents and reduced locomotor activity following induction of arthritis.

Methods

Antigen induced arthritis (AIA) was used to model rheumatoid arthritis and partial medial meniscectomy (PMX) was used to model osteoarthritis. Group-housed home cage monitoring was used to assess locomotor behavior in all mice, and weight bearing was assessed in PMX mice.In vivocalcium imaging with GCaMP6s was used to monitor spontaneous activity in L4 ganglion joint neurons retrogradely labelled with fast blue 2 days following AIA and 13-15 weeks following PMX model induction. Cartilage degradation was assessed in knee joint sections stained with Safranin O and fast green in PMX mice.

Results

Antigen induced arthritis produced knee joint swelling and PMX caused degeneration of articular cartilage in the knee. In the first 46 hours following AIA, mice travelled less distance and were less mobile compared to their control cage mates. In contrast, no such differences were found between PMX and sham mice when measured between 4-12 weeks post-surgery. A larger fraction of joint neurons showed spontaneous activity in AIA but not PMX mice. Spontaneous activity was mostly displayed by medium-sized neurons in AIA mice and was not correlated with any of the home cage behaviors.

Conclusion

Group-housed home cage monitoring revealed locomotor changes in AIA mice, but not PMX mice (with n=10/group).In vivocalcium imaging can be used to assess activity in multiple retrogradely labelled joint afferents and revealed increased spontaneous activity in AIA but not PMX mice.
Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing
Authors: Carrozzo Irene , Maule Giulia , Gentile Carmelo , Umbach Alessandro , Ciciani Matteo , Guidone Daniela , De Santis Martina , Petris Gianluca , Galietta Luis Juan Vicente , Arosio Daniele , Cereseto Anna
Published: August 2024

Cystic Fibrosis (CF) is a life-shortening autosomal recessive disease caused by mutations in theCFTRgene, resulting in functional impairment of the encoded ion channel. F508del mutation, a trinucleotide deletion, is the most frequent cause of CF affecting approximately 80% of patients. Even though current pharmacological treatments alleviate the F508del-CF disease symptoms there is no definitive cure. Here we leveraged revertant mutations (RMs) inciswith F508del to rescue CFTR protein folding and restore its function. We developed CRISPR base editing strategies to efficiently and precisely introduce the desired mutations in the F508del locus. Both editing and CFTR function recovery were verified in CF cellular models including primary epithelial cells derived from CF patients. The efficacy of the CFTR recovery strategy was validated in cultures of pseudostratified epithelia from patients’ cells showing full recovery of ion transport. Additionally, we observed an additive effect by combining our strategy with small molecules that enhance F508del activity, thus paving the way to combinatorial therapies.
Ethylene sensitivity assay for medicinal and fiber-typeCannabisseedlings reveals a triple-response-like phenotype
Authors: Monthony Adrian S. , Ledeuil Marilou , Torkamaneh Davoud
Published: August 2024

As evidence mounts for ethylene’s important role in sex determination, understanding ethylene signaling inCannabis sativaL. (cannabis) has become increasingly vital. This study investigated the response of hemp-type and drug-typeCannabis sativaseedlings to ethylene, revealing a unique ‘paired response’ phenotype under dark conditions and ethephon treatment, suggesting a more specialized variation of the triple response distinct from that observed in other species. Employing a novel ethephon-based assay, this research bypassed the complexities of using gaseous ethylene, providing a more accessible method for examining ethylene responses. The results showedC. sativaseedlings exhibit marked sensitivity to ethephon at concentrations (125 mg/L, 250 mg/L, and 500 mg/L) lower than those previously reported to influence mature plants, indicating a broad ethylene responsiveness across various genetic backgrounds. Furthermore, the reversal of ethylene-induced phenotypic changes by silver thiosulfate (STS) at all concentrations tested (1, 2, and 3 mM) suggests the conservation of ethylene signaling pathways inC. sativa. Importantly these phenotypic responses were observed in both drug and hemp type cannabis. However, the absence of an exaggerated apical hook in treated seedlings potentially points to a unique regulatory mechanism in response to ethylene in achene-bearing plants. These findings, highlighted by the successful induction of ethylene-sensitive phenotypes, underscore the conserved nature of ethylene signaling inC. sativa. The results highlight the need for further investigations into the regulatory mechanisms of ethylene in cannabis, especially concerning sexual development, opening new pathways for optimized breeding and cultivation practices aimed at enhancing plant growth and reproductive strategies.
Direct causal variable discovery leveraging the invariance principle: application in biomedical studies
Authors: Yin Liangying , Liu Menghui , Shi Yujia , Qiu Jinghong , So Hon-cheong
Published: August 2024

Accurate identification of direct causal(parental) variables for a target is of primary interest in many applications, especially in biomedicine. It could promote our understanding of the underlying pathophysiological mechanism and facilitate the discovery of new biomarkers and therapeutic targets for studied clinical outcomes. However, many researchers are inclined to resort to association-based machine learning methods to identify outcome-associated variables. And many of the identified variables may prove to be irrelevant. On the other hand, there is a lack of an efficient method for reliable parental set identification, especially in high-dimensional settings (e.g., biomedicine).

Here, we proposed a novel and efficient two-stage approach (I-GCM) to discover the direct causal variables (including genetic and clinical variables) for various outcomes. Variable selection was first performed by the PC-simple algorithm. Then it exploited the invariance of causal relations in different (experimental) settings, which was represented by generalized covariance measure calculated from gradient-boosted trees, for efficient and reliable causal variable discovery.

We first verified the proposed method through extensive simulations. This approach constantly yielded high precision (a.k.a., positive predictive value) and specificity while maintaining satisfactory sensitivity in general, and consistently outperformed a standard Notably, the precision was larger than 90% in our simulated scenarios, even in high-dimensional settings. We then applied the proposed method to 4 clinical traits to uncover the corresponding direct causal variables. Encouragingly, many identified clinical variables, genes and pathways were supported by the literature. Our proposed method constantly achieved superior performance in identifying actual direct causal variables, making it particularly useful in selecting what (genetic/clinical) risk factors to follow up. Importantly, our work represents one of the first applications of the invariance principle for causal inference in biomedical or clinical studies, and suggests a new avenue for causal discovery in these settings.
Overdoses with Xylazine and Fentanyl Recorded in Pennsylvania’s Overdose Information Network: An Analysis of Law Enforcement/First Responder-reported Overdose Response
Authors: Cano Manuel , Zhu David T. , Aponte-Meléndez Yesenia , Mateu-Gelabert Pedro , Bennett Alex S.
Published: August 2024

This study explored whether law enforcement/first responder-reported fentanyl overdose response actions (such as administration of the opioid overdose reversal agent naloxone) differed between overdoses in which xylazine was, versus was not, suspected to be co-involved. Data were drawn from the Pennsylvania State Police’s Overdose Information Network (ODIN) for 11,478 suspected fentanyl-involved overdoses, 137 reportedly co-involving xylazine, recorded across Pennsylvania, excluding Philadelphia, January 2018-January 16, 2025. We used relative frequencies, Fisher’s exact tests, and binomial logistic regression to compare first responders’ overdose response actions in suspected fentanyl overdoses cases in which xylazine was, versus was not, reportedly co-involved. Naloxone was administered at the scene of 46.0% of the overdoses reportedly involving fentanyl and xylazine, vs. 67.3% of the reported fentanyl-no-xylazine overdoses. Multivariable regression results (among the suspected fentanyl overdoses in ODIN, adjusting for age, sex, race/ethnicity, year, county rurality, and other drugs suspected to be involved) indicated that suspected xylazine co-involvement was associated with 60% lower odds of naloxone administration (Adjusted Odds Ratio, 0.40; 95% Confidence Interval, 0.28-0.57). Observed differences in overdose response based on suspected xylazine co-involvement support the importance of equipping first responders with the tools and training to recognize/manage the distinct challenges of xylazine-fentanyl-involved overdose.
A multi-omics analysis ofArabidopsis thalianaroot tips under Cd exposure: A role of HY5 in limiting accumulation
Authors: Richtmann Ludwig , Thiébaut Noémie , Ranjan Alok , Sarthou Manon , Boutet Stéphanie , Hanikenne Marc , Clemens Stephan , Verbruggen Nathalie
Published: August 2024

Cadmium (Cd) is a major environmental pollutant with high toxicity potential. Even though a reduction of growth, including the primary root, is a clear consequence of Cd exposure, a profound understanding of the impact of Cd on the root apical meristem (RAM) and the elongation/differentiation zone (EDZ) is still lacking.

In this study,Arabidopsis thalianaroots were subjected to Cd and divided into root tips (RT) and remaining roots (RR) to separately assess the effect of Cd using transcriptomics, ionomics and metabolomics.

Elemental profiling revealed lower Cd accumulation in RT and differences in mineral contents between RT and RR. Transcriptomic analysis demonstrated distinct gene expression patterns in RT and RR, with Cd having less impact in RT. Functional enrichment analysis revealed genes associated with iron and sulfur homeostasis as well as the response to light in both RR and RT. RT-specific responses to Cd included several genes regulated by the transcription factor ELONGATED HYPOCOTYL 5 (HY5) and notably, thehy5mutant showed increased Cd sensitivity and accumulation compared to the wild type.

This study provides comprehensive insights into the inhibitory effects of Cd on primary root growth, elucidating molecular mechanisms involved, particularly highlighting the role of HY5 in Cd accumulation.
Investigating the p21 Ubiquitin-Independent Degron Reveals a Dual Degron Module Regulating p21 Degradation and Function
Authors: Riutin Marianna , Erez Pnina , Adler Julia , Biran Assaf , Myers Nadav , Shaul Yosef
Published: August 2024

A group of intrinsically disordered proteins (IDPs) are subjected to 20S proteasomal degradation in a ubiquitin-independent manner. Recently, we have reported that many IDP/IDR are targeted to the 20S proteasome via interaction with the C-terminus of PSMA3 subunit, termed the PSMA3 Trapper. In this study, we investigated the biological significance of the IDP-Trapper interaction using the IDP p21. Using split luciferase reporter assay and conducting detailed p21 mutagenesis, we first identified the p21 RRLIF box, localized at the C-terminus, as mediating the Trapper interaction in cells. To demonstrate the role of this box in p21 degradation, we edited the genome of HEK293 and HeLa cell lines using a CRISPR strategy. We found that the p21 half-life increased in cells with either a deleted or mutated p21 RRLIF box. The edited cell lines displayed an aberrant cell cycle pattern under normal conditions and in response to DNA damage. Remarkably, these cells highly expressed senescence hallmark genes in response to DNA damage, highlighting that the increased p21 half-life, not its actual level, regulates senescence. Our findings suggest that the p21 RRLIF box, which mediates interaction with the PSMA3 Trapper, acts as a ubiquitin-independent degron. This degron is positioned adjacent to the previously identified ubiquitin-dependent degron, forming a dual degron module that functionally regulates p21 degradation and its physiological outcomes.
ONE-STEP tagging: a versatile method for rapid site-specific integration by simultaneous reagent delivery
Authors: Migliori Valentina , Bruntraeger Michaela B. , Guylev Ivan S. , Burgold Thomas , Lichou Florence , Trinh Andrew L. , Washer Sam J. , Jones Carla P , Trynka Gosia , Bassett Andrew R.
Published: August 2024

Site-specific integration of DNA sequences into the genome is an important tool in fundamental research, synthetic biology and cell therapeutic applications. It can be used for protein tagging to investigate expression, localisation, and interactions as well as for expression of transgenes either under endogenous regulatory elements or at consistent safe harbour loci. Here we develop and optimise a simple and effective method for site specific integration in a single step that combines CRISPR-Cas9 mediated homology directed repair using single stranded oligonucleotide templates with the site-specific recombinase Bxb1 to allow large cargos to be integrated at any location in the genome. Our technology requires off the shelf Cas9 and oligonucleotide reagents combined with a set of cargo plasmids that are universal to any integration site. We demonstrate the methods adaptability by tagging at multiple sites and in multiple cell types including induced pluripotent stem cells and primary T cells. We show that our method can integrate large (up to 14 kb) cargos and that it is possible to simultaneously tag two genes or edit two sites with combination of integration and Cas9-mediated knockouts or other HDR events.
Global brain asymmetry and its variations in aging and related diseases
Authors: Hu Haoyu , Pu Yi , Abuduaini Yilamujiang , Wang Xichunwang , Francks Clyde , Thompson Paul M. , Kong Xiang-Zhen
Published: August 2024

Functional lateralization is a cardinal feature of human brain, and deviations from typical lateralization are observed in various brain disorders. Although this phenomenon has been widely acknowledged in the field of human neuroscience, decades of research have shown that it is a challenge to bridge the gap between (a)typically lateralized functions and hemispheric differences in structure (termed structural asymmetry). To address this important question, the present study employed the state-of-the-art machine learning techniques to investigate the brain structural asymmetry and its associations with cognitive functions, aging, and aging-related diseases, by integrating large-scale datasets. Our proposed multivariate approach revealed previously unknown and substantial structural differences between the left and right hemispheres, and established the associations between the global brain asymmetry and lateralized functions including hand motor and emotion processing. Furthermore, at the population level we mapped the aging trajectories of the global brain asymmetry, and unveiled significant diagnosis-specific variations in patients with Alzheimer’s disease and Parkinson’s disease, and individuals carrying a relevant genetic risk for atypical brain aging (i.e., APOE4 carriers). These results demonstrated left-hemisphere-linked changes in aging, which has challenged the traditional “right hemi-aging” model, and offered a promising approach for assessing brain aging and related diseases. Overall, our study with a novel approach presents one of the largest-scale investigation of global brain asymmetry, and takes an important step forward in understanding the intricate interplay between structural asymmetry, lateralized functions, and brain aging in health and disease.

Significance statement

Functional lateralization is fundamental to the human brain, with deviations linked to various brain disorders. Bridging the gap between functional lateralization and structural asymmetry has been a long-standing challenge. Using advanced machine learning and large-scale datasets, this study introduced a multivariate global brain asymmetry approach and revealed previously unidentified structural differences between the brain hemispheres, correlating these with cognitive functions, aging, and diseases like Alzheimer’s and Parkinson’s. Contrary to the traditional “right hemi-aging” model, we found left-hemisphere-linked aging changes. This work provides new insights into brain asymmetry, lateralized functions, and aging, offering a promising approach for assessing brain health and disease.

Classifications:Biological Sciences (Psychological and Cognitive Sciences);
Experimental capture of genomic islands defines a widespread class of genetic element capable of non-autonomous transfer
Authors: Zhao Yansong , Ma Yue , Farr Andrew D. , Rogers David W. , Rainey Paul B.
Published: August 2024

Bacteria acquire new genes by horizontal gene transfer (HGT). Acquisition is typically mediated by mobile genetic elements (MGEs), however, beyond plasmids, bacteriophages and certain integrative conjugative elements (ICEs), the nature and diversity of MGEs is poorly understood. The bacteriumPseudomonas fluorescensSBW25 was propagated by serial transfer in the presence of filtrate obtained from garden compost communities. Genome sequencing of derived colonies revealed acquisition of three different mobile elements, each integrated immediately downstream oftmRNA. All are flanked by direct repeats and harbour a tyrosine integrase (intY), followed by a cargo of accessory genes including putative phage defence systems. Although characteristic of genomic islands, MGE-classifiers showed no matches to mobile elements. Interrogation of DNA sequence databases showed that similar elements are widespread in the genusPseudomonasand beyond, withVibrioPathogenicity Island-1 (VPI-1) fromV. choleraebeing a notable example. Bioinformatic analyses demonstrate frequent transfer among diverse hosts. With focus on a single 55 kb element (I55) we show thatintYis necessary for excision and circularisation, that the element is incapable of autonomous horizontal transfer, but is mobilizable – in the absence of direct cell-cell contact – upon addition of community filtrate. Further analyses demonstrate that I55 enhances host fitness in the presence of community filtrate, which stems in part from ability to defend against phages.

Significance Statement

The impact of horizontal gene transfer on the evolution of bacteria outpaces that driven by spontaneous mutation, but knowledge of the range of mediators, the genes mobilised, and the mechanisms of movement have largely depended on inferences stemming from bioinformatics. Here we describe a real-time evolution experiment in which a single focal strain propagated with filtrate from a complex microbial community captures genetic elements carrying a diverse cargo of genes whose mobility was previously unknown. The elements are representative of a class of mobile DNA that depend on nothing other than a tyrosine integrase that targets a highly conserved gene. The elements encode phage resistance, require the integrase to excise from the genome, confer a significant fitness advantage, and depend on a secondary element for transfer.
Matrix analysis of high-density arrayed waveguides: Crosstalk suppression by bending
Authors: Hildén Panu , Shevchenko Andriy
Published: August 2024

For many photonic devices, crosstalk between densely packed waveguides poses a major problem leading to unreliable or inefficient operation of the device. In this work, a general method for modeling the crosstalk, not only in straight waveguide arrays but also in curved ones, is introduced. The method is based on a matrix analysis of electromagnetic field coupling between closely spaced waveguides. As an example, we show how bending of waveguides in an array reduces the crosstalk. The approach can help overcome the crosstalk problem in a variety of photonic integrated devices, including phased waveguide arrays, arrayed waveguide gratings, optical multiplexers, and high-density interconnects between optical and electronic components.

Published by the American Physical Society
2024
Crystal structure and Hirshfeld surface analysis of 1-[6-bromo-2-(3-bromophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one
Authors: Pronina Anastasia A. , Kutasevich Alexandra G. , Grigoriev Mikhail S. , Hasanov Khudayar I. , Sadikhova Nurlana D. , Javadzade Tahir A. , Akkurt Mehmet , Bhattarai Ajaya
Published: August 2024

This study presents the synthesis, characterization and Hirshfeld surface analysis of 1-[6-bromo-2-(3-bromophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one, C19H18Br2N2O. In the title compound, the pyrrolidine ring adopts a distorted envelope configuration. In the crystal, molecules are linked by intermolecular N—H...O, C—H...O and C—H...Br hydrogen bonds, forming a three-dimensional network. In addition, pairs of molecules along the c axis are connected by C—H...π interactions. According to a Hirshfeld surface study, H...H (36.9%), Br...H/H...Br (28.2%) and C...H/H...C (24.3%) interactions are the most significant contributors to the crystal packing.
Crystal structure of propane-1,3-diaminium squarate dihydrate
Authors: Seidel Rüdiger W. , Kolev Tsonko M.
Published: August 2024

Propane-1,3-diaminium squarate dihydrate, C3H12N2
2+·C4O4
2−·2H2O, results from the proton-transfer reaction of propane-1,3-diamine with squaric acid and subsequent crystallization from aqueous medium. The title compound crystallizes in the tetragonal crystal system (space group P4bm) with Z = 2. The squarate dianion belongs to the point group D
4h
and contains a crystallographic fourfold axis. The propane-1,3-diaminium dication exhibits a C
2v
-symmetric all-anti conformation and resides on a special position with mm2 site symmetry. The orientation of the propane-1,3-diaminium ions makes the crystal structure polar in the c-axis direction. The solid-state supramolecular structure features a triperiodic network of strong hydrogen bonds of the N—H...O and O—H...O types.
Synthesis, crystal structure and Hirshfeld surface analysis of a new copper(II) complex based on diethyl 2,2′-(4H-1,2,4-triazole-3,5-diyl)diacetate
Authors: Vynohradov Oleksandr S. , Vashchenko Oleksandr V. , Khomenko Dmytro M. , Doroshchuk Roman O. , Raspertova Ilona V. , Lampeka Rostyslav D. , Stoica Alexandru-Constantin
Published: August 2024

The title compound, bis[μ-2,2′-(4H-1,2,4-triazole-3,5-diyl)diacetato]bis[diaquacopper(II)] dihydrate, [Cu2(C6H5N3O4)2(H2O)4]·2H2O, is a dinuclear octahedral CuII triazole-based complex. The central copper atoms are hexa-coordinated by two nitrogen atoms in the equatorial positions, two equatorial oxygen atoms of two carboxylate substituents in position 3 and 5 of the 1,2,4-triazole ring, and two axial oxygen atoms of two water molecules. Two additional solvent water molecules are linked to the title molecule by O—H...N and O...H—O hydrogen bonds. The crystal structure is built up from the parallel packing of discrete supramolecular chains running along the a-axis direction. Hirshfeld surface analysis suggests that the most important contributions to the surface contacts are from H...O/O...H (53.5%), H...H (28.1%), O...O (6.3%) and H...C/C...H (6.2%) interactions. The crystal studied was twinned by a twofold rotation around [100].
Crystal structure, Hirshfeld surface analysis, DFT and the molecular docking studies of 3-(2-chloroacetyl)-2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one
Authors: Divyabharathi Sivagnanam , Karthiga Anjalai Ramachandran , Shalo Rajans Reshwen , Rajeswari Krishnan , Vidhyasagar Thankakan , Selvanayagam Sivashanmugam
Published: August 2024

In the title compound, C33H29ClN2O2, the two piperidine rings of the diazabicyclo moiety adopt distorted-chair conformations. Intermolecular C—H...π interactions are mainly responsible for the crystal packing. The intermolecular interactions were quantified and analysed using Hirshfeld surface analysis, revealing that H...H interactions contribute most to the crystal packing (52.3%). The molecular structure was further optimized by density functional theory (DFT) at the B3LYP/6–31 G(d,p) level and is compared with the experimentally determined molecular structure in the solid state.
Bis(2-carboxyquinolinium) hexachloridostannate(IV) dihydrate
Authors: Benhamada Mohamed Siradj Eddine , Benlatreche Tarek , Ghallab Rochdi , Dénès George , Merazig Hocine
Published: August 2024

In the hydrated title salt, (C10H8NO2)2[SnCl6]·2H2O, the tin(IV) atom is located about a center of inversion. In the crystal structure, the organic cation, the octahedral inorganic anion and the water molecule of crystallization interact through O—H...O, N—H...O and O—H...Cl hydrogen bonds, supplemented by weak π–π stacking between neighboring cations, and C—Cl...π interactions.