bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Apical Vertebra Position on Growing Rod Treatment: A Clinical and Finite Element Study
Authors: Dursun Gokay , Cetik Riza M. , Guzel Dilek , Demirkiran Halil Gokhan , Ramazanov Rafik , Dede Ozgur , Gurses Ercan , Yazici Muharrem
Published: March 2022

Background:

Growing rods (GRs) is a commonly utilized technique for the management of early-onset scoliosis. The significance of the position of the apical vertebrae relative to the rods is not known. The purpose of this study is to analyze the potential effects of the position of the apical vertebrae in relation to the GRs on deformity control through plain radiographs and finite element analysis (FEA) modeling.

Methods:

We identified 140 patients treated with GR between 2000 and 2018. Patients who had a congenital vertebral anomaly or <2-year follow-up were excluded. Curve magnitude, traction radiograph under general anesthesia (TRUGA) flexibility, apical rotation, the lengths of T1-12, T1-S1, and the instrumented segments were recorded. Patients were divided into 3 groups according to the apical position on the postoperative radiographs: group 1 (both pedicles are between the rods), group 2 (convex rod is between the apical vertebra pedicles), group 3 (both pedicles are lateral to the convex rod). FEA models were created simulating the 3 groups. Both radiographic and FEA data were analyzed to compare the deformity control and growth in each group.

Results:

Fifty-eight patients were included in the final analyses (mean age 84 mo; range: 38 to 148). Ten patients (17%) were in group 1, 34 (59%) in group 2, and 14 (24%) in group 3. Difference between TRUGA flexibilities was statistically insignificant. Group 3 was the least successful in terms of both height gain and rotational control. FEA showed a decrease in rotation and displacement for every group, however, the residual rotation and displacement was highest in group 3.

Conclusions:

Bringing the apex in line with the GR increases the capacity of growth preservation as it results in largest height gain and better deformity control. FEA model demonstrated that distraction alone is inadequate for controlling rotation, and with increasing apical translation, residual rotation after distraction also increases.

Level of Evidence:

Level III.
Lower Eyelid Reconstruction Using a Myotarsocutaneous Flap while Considering the Superior and Inferior Palpebral Sulci
Authors: Takasu Hiroyuki , Yagi Sasagu , Taguchi Sawa , Furukawa Soichi , Ono Nao , Shimomura Yutaka
Published: March 2022

Various reconstructive procedures have been reported for full-thickness defects of the lower eyelid after tumor excision or trauma. In eyelid reconstruction, not only functionality but also cosmetic results are important; furthermore, making scars inconspicuous is challenging. The purpose of this study is to make the scars less noticeable in lower eyelid reconstruction. We reconstructed the anterior lamella using a myotarsocutaneous flap and the posterior lamella of the donor site using a palatal mucosal graft in a 61-year-old man with basal cell carcinoma of the lower eyelid. In designing the myotarsocutaneous flap, we matched the upper edge of the flap with the superior palpebral sulcus, and the lower edge with the inferior palpebral sulcus. The flap length was the same as the width of the defect. The lateral side of the postoperative scar was hidden by the excess skin of the upper eyelid, while the caudal side of the scar and the trapdoor deformity was covered with a tear trough. After movement, the flap was not located outside the lateral canthus, and good cosmetic results were obtained. This report describes our surgical procedure.
A Rare Presentation of Hand TB Extending to the Space of Parona
Authors: Al Lahham Salim , Aljassem Ghanem , Asnaf Ayman , Omari Rand Y. , Alyazji Zaki , Sada Ruba
Published: March 2022

Most cases of hand infections are caused by gram-positive cocci and gram-negative bacilli. Atypical hand infections are rare and are caused by uncommon pathogens like Mycobacterium tuberculosis (TB). Musculoskeletal tuberculosis accounts for 20% of TB cases, and only 2% of these cases involve the hand and foot. In this article, we describe a case of hand TB that had spread from the thenar space to the space of Parona. The patient was treated with a combined surgical and medical approach. A 29-year-old male patient presented to our clinic with the complaint of pain and swelling of the right hand that had been worsening for 4 months before presentation. It was associated with mild weakness and night sweats. On physical examination, he had two separate swellings: one at the thenar eminence and one at the volar side of the wrist. He was taken for incision, which showed caseous material on both sites. It was sent for culture that revealed mycobacterium tuberculosis. The patient was placed on anti-TB medications for a total of 6 months. Tuberculous infection of the hand is a rare condition; the most common musculoskeletal sites are the spine, hip, and knee. Early diagnosis and treatment of TB infection in hand are essential for retaining optimal function. The diagnosis usually depends on the clinical presentation supported by laboratory tests and imaging studies. Treatment consists of medical, surgical, or combined treatment. Surgical intervention should aim to remove all the infected material in addition to debridement of the involved tissues.
Facial Feminization Surgery: A Systematic Review of Perioperative Surgical Planning and Outcomes
Authors: Tirrell Abigail R. , Abu El Hawa Areeg A. , Bekeny Jenna C. , Chang Brian L. , Del Corral Gabriel
Published: March 2022

Background:

Facial feminization is a critical step in a transfeminine patient’s surgical transition. However, the existing literature on the various types of feminization surgeries suffers from inadequate reporting on perioperative aspects of care, such as preoperative evaluation and postoperative outcomes. The aim of this study is to evaluate facial feminization surgery (FFS), preoperative planning, and patient reported outcomes after various types of procedures.

Methods:

An electronic database search of Ovid MEDLINE was completed according to PRISMA guidelines for articles pertaining to FFS. Study characteristics, operative information, and patient demographics were collected. Data concerning preoperative imaging, virtual simulation, postoperative complications, and patient-reported outcome measures (PROMs) were collected and analyzed for patterns.

Results:

A total of 22 papers representing 1302 patients were included for analysis. The most commonly discussed operations included upper face procedures, particularly of the forehead (17 studies, 77%). When discussed, preoperative planning for FFS included standard photography in 19 (86%) studies, advanced imaging, such as cephalometry or computed tomography, in 12 (55%) studies, and virtual simulation of surgical outcomes in four (18%) studies. Patient-centered outcomes, such as postoperative satisfaction, were described in 17 (77%) studies. Standardized PROMs were heterogenous across included studies with only 11 (50%) including at least one PROM.

Conclusions:

FFS is common, safe, and highly satisfying for transfeminine patients seeking surgical intervention for identity actualization. Future research concerning transgender care must evaluate advanced surgical planning and 3D simulation combined with more standardized assessment of PROMs to ensure high-quality analysis of patient satisfaction.
Corrective Tendon Repair with Local Anesthesia following Wrist-level Replantation
Authors: Lu Yi , Hsieh Chi-Ying , Chang Che-Ning , Chang Ke-Chung , Chang Dun-Hao
Published: March 2022

Wide-awake local anesthesia with no tourniquet has become a popular method to ensure correct tendon condition intraoperatively. We report the case of a 17-year-old man who underwent nearly total left wrist amputation and successful replantation. The misconnection of flexor tendons between the thumb, index, and middle finger was found postoperatively. At 1.5 months postreplantation, simultaneous tenolysis and corrective tendon repair were performed under local anesthesia. The proximal tendon origins were confirmed intraoperatively with the patient awake. Six months after replantation, the patient underwent extensor pollicis longus tendon shortening and pulley reconstruction under wide-awake local anesthesia with no tourniquet for thumb extension lag. After adequate rehabilitation, the functional outcome was satisfactory. This case report demonstrates that local anesthesia is a judicious method to intraoperatively facilitate correct tendon repair, tension adjustment, and direct conversation between the surgeon and the patient.
A Description of ICNIRP’S Independent, Best Practice System of Guidance on the Protection of People and the Environment from Exposure to Non-Ionizing Radiation
Authors:   International Commission on Non-Ionizing Radiation Protection
Published: March 2022

In this statement, the International Commission on Non-Ionizing Radiation Protection (ICNIRP) presents its structure, its activities, and general approach to providing guidance on NIR protection. The statement highlights ICNIRP’s independence and presents the principle and requirements of no commercial or other vested interests. ICNIRP’s funding arrangements and collaboration with other advisory bodies and radiation protection authorities are also described. The statement also presents the types of guidance documents that are produced by ICNIRP and the general approach in assessing scientific evidence.
Placebo's invisible brother: a restricted scoping review of the biomedical literature on the nocebo effect
Authors: Sweeney Owen J. , Parepalli Sai Arathi , Mirtorabi Neginsadat , Loo Yong Kee Kimberley , Feakins Benjamin G. , Aronson Jeffrey K. , Wartolowska Karolina A.
Published: March 2022

Placebos and their beneficial clinical and psychological effects are well-researched, but nocebo effects receive far less attention, despite being highly undesirable. The aim of this restricted scoping review was to examine how nocebo effects are represented in the biomedical literature and to identify the trends and gaps in existing knowledge. After searching 5 biomedical databases and 2 clinical trials registries (from their inception to December 23, 2020) for articles on nocebo effects or negative placebo effects, 1161 eligible publications were identified. The 2 main publication types were nonsystematic reviews (37.7%) and primary research studies (35.6%); only 85 publications (7.3%) were systematic reviews and meta-analyses. The nonsystematic reviews, many of them heavily opinion-based, may contribute to the amplification of narratives, attitudes, and beliefs about nocebo effects that do not objectively reflect the primary research. The primary research articles often used nocebo effects to explain results, rather than as the primary phenomenon under investigation. Most publications were concerned with both positive and negative placebo effects, rather than just nocebo effects. Over half of the abstracts were in the field of neurology, psychiatry, psychology, or neuroscience (52.8%). The nocebo effect was most frequently investigated in the context of pain. Studies were almost exclusively in adults and more often in healthy participants than in patients. In conclusion, in the biomedical literature, there is an overabundance of nonsystematic reviews and expert opinions and a lack of primary research and high-quality systematic reviews and meta-analyses specifically dealing with nocebo effects.
Novel canine high-quality metagenome-assembled genomes, prophages and host-associated plasmids provided by long-read metagenomics together with Hi-C proximity ligation
Authors: Cuscó Anna , Pérez Daniel , Viñes Joaquim , Fàbregas Norma , Francino Olga
Published: March 2022

The human gut microbiome has been extensively studied, yet the canine gut microbiome is still largely unknown. The availability of high-quality genomes is essential in the fields of veterinary medicine and nutrition to unravel the biological role of key microbial members in the canine gut environment. Our aim was to evaluate nanopore long-read metagenomics and Hi-C (high-throughput chromosome conformation capture) proximity ligation to provide high-quality metagenome-assembled genomes (HQ MAGs) of the canine gut environment. By combining nanopore long-read metagenomics and Hi-C proximity ligation, we retrieved 27 HQ MAGs and 7 medium-quality MAGs of a faecal sample of a healthy dog. Canine MAGs (CanMAGs) improved genome contiguity of representatives from the animal and human MAG catalogues – short-read MAGs from public datasets – for the species they represented: they were more contiguous with complete ribosomal operons and at least 18 canonical tRNAs. Both canine-specific bacterial species and gut generalists inhabit the dog’s gastrointestinal environment. Most of them belonged toFirmicutes, followed byBacteroidotaandProteobacteria. We also assembled oneActinobacteriotaand oneFusobacteriotaMAG. CanMAGs harboured antimicrobial-resistance genes (ARGs) and prophages and were linked to plasmids. ARGs conferring resistance to tetracycline were most predominant within CanMAGs, followed by lincosamide and macrolide ones. At the functional level, carbohydrate transport and metabolism was the most variable within the CanMAGs, and mobilome function was abundant in some MAGs. Specifically, we assigned the mobilome functions and the associated mobile genetic elements to the bacterial host. The CanMAGs harboured 50 bacteriophages, providing novel bacterial-host information for eight viral clusters, and Hi-C proximity ligation data linked the six potential plasmids to their bacterial host. Long-read metagenomics and Hi-C proximity ligation are likely to become a comprehensive approach to HQ MAG discovery and assignment of extra-chromosomal elements to their bacterial host. This will provide essential information for studying the canine gut microbiome in veterinary medicine and animal nutrition.
‘‘Now, I know my life is not over!’: Introduction and Adaptation of the RESPECT HIV Intervention, OraQuick, and Trauma-Informed Care for Female Victims of Non-Partner Sexual Violence in Haiti
Authors: Rahill Guitele J. , Joshi Manisha , Blaise Berlande , Carrington Cherelle , Paul Phycien , Zlotnick Caron
Published: March 2022

Introduction

In the Cite Soleil (CS) shantytown of Haiti, non-partner sexual violence (NPSV) is widespread, involves multiple assailants who do not use condoms and inflict intentional coital injuries. HIV prevalence in Haiti is 2.2%, CS HIV prevalence is 3.6% shame, guilt, self-blame and societal stigma impede access to HIV testing/treatment in a context of low confidentiality. In that context, NPSV victims often succumb to AIDS. Culturally adapted evidence-based HIV interventions (EBIs) can increase HIV awareness and reduce HIV risk.

Methods

Following the ADAPT-ITT model, we used purposive sampling to recruit and interview key stakeholders (age 18 and older) in four focus groups (Victims and health providers, as part of adaptation of an EBI HIV (RESPECT) with an orally administered RAPID HIV antibody test (OraQuick) to increase HIV awareness and testing and to reduce HIV risk for victims of NPSV (N=32, 8/focus group). We also introduced trauma-informed care (TIC) to address the post-assault trauma of NPSV victims. Stakeholders were introduced to RESPECT, participated in RESPECT role plays, interpreted OraQuick HIV screen results after viewing a demonstration of a sample collection, and provided feedback on TIC. ATLAS.ti facilitated thematic content analysis of focus group transcripts.

Results

Participants unanimously (100%) reported that RESPECT, OraQuick, and TIC were acceptable, feasible, and useful for increasing HIV awareness, reducing shame, guilt, and trauma, and empowering NPSV victims to reduce the risk of HIV acquisition/transmission in future consensual relationships.

Conclusion

Establishing the acceptability, feasibility and effectiveness of RESPECT, OraQuick, and TIC in CS is a crucial first step towards responding to the HIV prevention and trauma needs of NPSV victims.
A novel automated morphological analysis of microglia activation using a deep learning assisted model
Authors: Lucas Stetzik , Gabriela Mercado , Lindsey Smith , Sonia George , Emmanuel Quansah , Katarzyna Luda , Emily Schulz , Lindsay Meyerdirk , Allison Lindquist , Alexis Bergsma , Jones Russell G , Lena Brundin , Henderson Michael X , Andrew Pospisilik John , Patrik Brundin
Published: March 2022

There is growing evidence for the key role of microglial activation in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements, and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools (Aiforia® Cloud (Aifoira Inc., Cambridge, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinson’s disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are shared within the Aiforia® platform and are available for study-specific adaptation and validation.
A low-power communication scheme for wireless, 1000 channel brain-machine interfaces
Authors: Costello Joseph T. , Nason Samuel R. , An Hyochan , Lee Jungho , Mender Matthew J. , Temmar Hisham , Wallace Dylan M. , Lim Jongyup , Willsey Matthew S. , Patil Parag G. , Jang Taekwang , Phillips Jamie D. , Kim Hun-Seok , Blaauw David , Chestek Cynthia A.
Published: March 2022

Objective

Brain-machine interfaces (BMIs) have the potential to restore motor function but are currently limited by electrode count and long-term recording stability. These challenges may be solved through the use of free-floating “motes” which wirelessly transmit recorded neural signals, if power consumption can be kept within safe levels when scaling to thousands of motes. Here, we evaluated a pulse-interval modulation (PIM) communication scheme for infrared (IR)-based motes that aims to reduce the wireless data rate and system power consumption.

Approach

To test PIM’s ability to efficiently communicate neural information, we simulated the communication scheme in a real-time closed-loop BMI with non-human primates. Additionally, we performed circuit simulations of an IR-based 1000-mote system to calculate communication accuracy and total power consumption.

Main Results

We found that PIM at 1kb/s per channel maintained strong correlations with true firing rate and matched online BMI performance of a traditional wired system. Closed-loop BMI tests suggest that lags as small as 30 ms can have significant performance effects. Finally, unlike other IR communication schemes, PIM is feasible in terms of power, and neural data can accurately be recovered on a receiver using 3mW for 1000 channels.

Significance

These results suggest that PIM-based communication could significantly reduce power usage of wireless motes to enable higher channel-counts for high-performance BMIs.
Improved basic cytogenetics challenges holocentricity of butterfly chromosomes
Authors: Dutrillaux Bernard , Dutrillaux Anne-Marie , McClure Mélanie , Gèze Marc , Elias Marianne , Bed’hom Bertrand
Published: March 2022

Mitotic chromosomes of butterflies, which look like dots or short filaments in most published data, are generally considered to lack localised centromeres and thus to be holokinetic. This particularity, observed in a number of other invertebrates, is associated with meiotic particularities known as “inverted meiosis”, in which the first division is equational, i.e., centromere splitting-up and segregation of sister chromatids instead of that of homologous chromosomes. However, the accurate analysis of butterfly chromosomes is difficult. 1) Their size is very small, equivalent to a single band of a mammalian metaphase chromosome. 2) They lack satellite DNA/heterochromatin in putative centromere regions and therefore marked primary constrictions. Our improved conditions for chromosome preparations in six butterfly species belonging to the Nymphalidae and Pieridae families challenges the holocentricity of their chromosomes: in spite of the absence of primary constriction, sister chromatids are recurrently held together at definite positions during mitotic metaphase, which makes possible to establish karyotypes composed of acrocentric and sub-metacentric chromosomes. The total number of chromosomes per karyotype is roughly inversely proportional to that of non-acrocentric chromosomes, which suggests the occurrence of frequent Robertsonian-like fusions or fissions during evolution. Furthermore, the behaviour and morphological changes of chromosomes along the various phases of meiosis do not differ much from those of canonical meiosis. In particular at metaphase II, chromosomes clearly have two sister chromatids, which refutes that anaphase I was equational. Thus, we propose an alternative mechanism to holocentricity for explaining the large variations in chromosome numbers in butterflies: 1) in the ancestral karyotype, composed of about 60-62 acrocentric chromosomes, the centromeres, devoid of centromeric heterochromatin/satellite DNA, were located at contact with telomeric heterochromatin; 2) the instability of telomeric heterochromatin largely contributed to drive the multiple chromosome rearrangements, which occurred during butterfly evolution.
DeepSCM: an efficient convolutional neural network surrogate model for the screening of therapeutic antibody viscosity
Authors: Lai Pin-Kuang
Published: March 2022

Predicting high concentration antibody viscosity is essential for developing subcutaneous administration. Computer simulations provide promising tools to reach this aim. One such model is the spatial charge map (SCM) proposed by Agrawal and coworkers (mAbs. 2015, 8(1):43–48). SCM applies molecular dynamics simulations to calculate a score for the screening of antibody viscosity at high concentrations. However, molecular dynamics simulations are computationally costly and require structural information, a significant application bottleneck. In this work, high throughput computing was performed to calculate the SCM scores for 6596 nonredundant antibody variable regions. A convolutional neural network surrogate model, DeepSCM, requiring only sequence information, was then developed based on this dataset. The linear correlation coefficient of the DeepSCM and SCM scores achieved 0.9 on the test set (N=1320). The DeepSCM model was applied to screen the viscosity of 38 therapeutic antibodies that SCM correctly classified and resulted in only one misclassification. The DeepSCM model will facilitate high concentration antibody viscosity screening. The code and parameters are freely available at https://github.com/Lailabcode/DeepSCM.
Plakoglobin is a mechanoresponsive regulator of naïve pluripotency
Authors: Kohler Timo N. , De Jonghe Joachim , Ellerman Anna L. , Yanagida Ayaka , Herger Michael , Slatery Erin M. , Fischer Katrin , Mulas Carla , Winkel Alex , Ross Connor , Bergmann Sophie , Franze Kristian , Chalut Kevin , Nichols Jennifer , Boroviak Thorsten E. , Hollfelder Florian
Published: March 2022

Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional programs could provide insight into mechanisms underlying mammalian pre-implantation development. Here, we explore this by exerting microenvironmental control over mouse embryonic stem cells (ESCs). Microfluidic encapsulation of ESCs in agarose microgels stabilized the naïve pluripotency network and specifically induced expression of Plakoglobin (Jup), a vertebrate homologue of β-catenin. Indeed, overexpression of Plakoglobin was sufficient to fully re-establish the naïve pluripotency gene regulatory network under metastable pluripotency conditions, as confirmed by single-cell transcriptome profiling. Finally, we found that in the epiblast, Plakoglobin was exclusively expressed at the blastocyst stage in human and mouse embryos – further strengthening the link between Plakoglobin and naïve pluripotency in vivo. Our work reveals Plakoglobin as a mechanosensitive regulator of naïve pluripotency and provides a paradigm to interrogate the effects of volumetric confinement on cell-fate transitions.

Highlights

3D agarose spheres stabilize the naïve pluripotency network in mouse ESCs.

Volumetric confinement induces expression of Plakoglobin, a vertebrate homologue of β-catenin.

Plakoglobin expression in the epiblast is specific to pre-implantation human and mouse embryos.

Plakoglobin overexpression maintains naïve pluripotency independently of β-catenin.
Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in TNBC
Authors: Ayodeji Saheed , Bao Bin , Teslow Emily A. , Polin Lisa A. , Dyson Greg , Bollig-Fischer Aliccia , Fehl Charlie
Published: March 2022

Enhanced glucose metabolism is a feature of almost all cancers, but downstream functional effects of aberrant glucose flux are difficult to mechanistically determine. The objective of this study is to characterize a mechanism by which elevated glucose level drives a tumorigenic pathway in triple negative breast cancer (TNBC). We used chemical biology methods to track how a metabolite of glucose, N-acetylglucosamine (GlcNAc), is linked to the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1) as an O-linked GlcNAc post translational modification (O-GlcNAc). In this work, we revealed that intracellular protein glycosylation by O-GlcNAc is driven by high glucose levels in TNBC models, including on TET1. A single enzyme, O-GlcNAc transferase (OGT), is responsible for catalyzing protein modification of O-GlcNAc. We showed that OGT activity is higher in TNBC cell lines compared to non-tumor breast cell lines and is associated with hyperglycemia. Furthermore, enhanced OGT activity activated a pathway for cancer stem-like cell (CSC) reprogramming in TNBC cells. In our model, O-GlcNAcylated TET1 upregulated expression of splicing factor TAR-DNA binding protein (TARDBP), which drives CSC induction as well as higher OGT levels. We show that this OGT-TET1-TARDBP axis “feeds-forward” in hyperglycemic conditions both in cell lines and diet-induced obese mice, which displayed higher blood glucose levels and tumor O-GlcNAc levels than lean littermates. This data converges on a novel pathway whereby hyperglycemia drives aberrant OGT activity, activating a pathway for CSC induction in TNBC. Our findings partially explain a key aspect of how obesity is associated with TNBC risk and negative outcomes.

Statement of Implication

This work presents a novel mechanism to explain how obesity is a risk factor for triple-negative breast cancer via elevated sugar-transfer activity by O-GlcNAc transferase in hyperglycemia, leading to the induction of a cancer stem-like cells and revealing a targetable pathway in obesity-associated tumors.
High salinity activates CEF and attenuates state transitions in both psychrophilic and mesophilic Chlamydomonas species
Authors: Kalra Isha , Wang Xin , Zhang Ru , Morgan-Kiss Rachael
Published: March 2022

In the last decade, studies have revealed the importance of PSI-driven cyclic electron flow (CEF) in stress acclimation in model organisms like C. reinhardtii; however, these studies focused on transient, short-term stress. In addition, PSI-supercomplexes are associated with CEF during state transition response to short-term stress. On the other hand, the role of CEF during long-term stress acclimation is still largely unknown. In this study, we elucidate the involvement of CEF in acclimation response to long-term high salinity in three different Chlamydomonas species displaying varying salinity tolerance. We compared CEF rates, capacity for state transitions, and formation of supercomplexes after salinity acclimation in the model mesophile C. reinhardtii and two psychrophilic green algae C. priscuii (UWO241) and C. sp. ICE-MDV. CEF was activated under high salt in all three species, with the psychrophilic Chlamydomonas spp. exhibiting the highest CEF rates. High salt acclimation was also correlated with reduced state transition capacity and a PSI-supercomplex was associated with high CEF. We propose that under long-term stress, CEF is constitutively activated through assembly of a stable PSI-supercomplex. The proteomic composition of the long-term PSI-supercomplex is distinct from the supercomplex formed during state transitions, and its presence attenuates the state transition response.
TopOMetry systematically learns and evaluates the latent dimensions of single-cell atlases
Authors: Sidarta-Oliveira Davi , Domingos Ana , Velloso Licio A.
Published: March 2022

A core task in single-cell data analysis is recovering the latent dimensions encoding the genetic and epigenetic landscapes inhabited by cell types and lineages. However, consensus is lacking for optimal modeling and visualization approaches. Here, we propose these landscapes are ideally modeled as Riemannian manifolds, and present TopOMetry, a computational toolkit based on Laplacian-type operators to learn these manifolds. TopOMetry learns and evaluates dozens of possible representations systematically, eliminating the need to choose a single dimensional reduction methoda priori. The learned visualizations preserve more original information than current PCA-based standards across single-cell and non-biological datasets. TopOMetry allows users to estimate intrinsic dimensionalities and visualize distortions with the Riemannian metric, among other challenging tasks. Illustrating its hypothesis generation power, TopOMetry suggests the existence of dozens of novel T cell subpopulations consistently found across public datasets that correspond to specific clonotypes. TopOMetry is available athttps://github.com/davisidarta/topometry.
HCLC-FC: a novel statistical method for phenome-wide association studies
Authors: Liang Xiaoyu , Cao Xuewei , Sha Qiuying , Zhang Shuanglin
Published: March 2022

The emergence of genetic data coupled to longitudinal electronic medical records (EMRs) offers the possibility of phenome-wide association studies (PheWAS). In PheWAS, the whole phenome can be divided into numerous phenotypic categories according to the genetic architecture across phenotypes. Currently, statistical analyses for PheWAS are mainly univariate analyses, which test the association between one genetic variant and one phenotype at a time. In this article, we derived a novel and powerful multivariate method for PheWAS. The proposed method involves three steps. In the first step, we apply the bottom-up hierarchical clustering method to partition a large number of phenotypes into disjoint clusters within each phenotypic category. In the second step, the clustering linear combination method is used to combine test statistics within each category based on the phenotypic clusters and obtain p-values from each phenotypic category. In the third step, we propose a new false discovery rate (FDR) control approach. We perform extensive simulation studies to compare the performance of our method with that of other existing methods. The results show that our proposed method controls FDR very well and outperforms other methods we compared with. We also apply the proposed approach to a set of EMR-based phenotypes across more than 300,000 samples from UK Biobank. We find that the proposed approach not only can well-control FDR at a nominal level but also successfully identify 1,244 significant SNPs that are reported to be associated with some phenotypes in the GWAS catalog. Our open-access tools and instructions on how to implement HCLC-FC are available at https://github.com/XiaoyuLiang/HCLCFC.

Author summary

As a complementary approach to genome-wide association studies, phenome-wide association studies (PheWAS) have been an efficient tool for testing associations between genetic variations and a wide range of phenotypes utilizing all available phenotypic information. For instance, the first PheWAS has demonstrated that rs3135388 on HLA-DRB1 associated with atrial fibrillation and multiple sclerosis. A challenging step in performing large-scale multiple testing of PheWAS is to control the false discovery rate (FDR). In this work, we propose a novel and powerful multivariate method, HCLC-FC, to test the association between a genetic variant with a large number of phenotypes simultaneously controlling FDR. Within each phenotypic category, a newly proposed method clusters phenotypes into different groups and the combined test statistic within each category based on the phenotypic clusters has an asymptotic distribution which avoids the computational burden of simulation. Furthermore, the newly developed FDR controlling process is based on p-values and does not depend on test statistics. Therefore, it is more general and can be applied to other multiple testing procedures to control FDR.
Individualized Gaussian Process-based Prediction of Memory Performance and Biomarker Status in Ageing and Alzheimer’s disease
Authors: Nemali A. , Vockert N. , Berron D. , Maas A. , Yakupov R. , Peters O. , Gref D. , Cosma N. , Preis L. , Priller J. , Spruth E. , Altenstein S. , Lohse A. , Fliessbach K. , Kimmich O. , Vogt I. , Wiltfang J. , Hansen N. , Bartels C. , Schott B.H. , Maier F. , Meiberth D. , Glanz W. , Incesoy E. , Butryn M. , Buerger K. , Janowitz D. , Ewers M. , Perneczhy R. , Rauchmann B. , Burow L. , Teipel S. , Kilimann I. , Göerß D. , Dyrba M. , Laske C. , Munk M. , Sanzenbacher C. , Müller S. , Spottke A. , Roy N. , Heneka M. , Brosseron F. , Roeske S. , Dobisch L. , Ramirez A. , Ewers M. , Dechent P. , Scheffler K. , Kleineidam L. , Wolfsgruber S. , Wagner M. , Jessen F. , Duzel E. , Ziegler G.
Published: March 2022

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as informative covariates, vascular risks, brain activity, neuropsychological test etc.,) might provide useful predictions of clinical outcomes during progression towards Alzheimer’s disease (AD). The Bayesian approach aims to provide a trade-off by employing relevant features combinations to build decision support systems in clinical settings where uncertainties are relevant. We tested the approach in the MRI data across 959 subjects, aged 59-89 years and 453 subjects with available neuropsychological test scores and CSF biomarker status (amyloid-beta (Aβ)42/40 & and phosphorylated tau (pTau)) from a large sample multi-centric observational cohort (DELCODE). In order to explore the beneficial combinations of information from different sources, we presented a MRI-based predictive modelling of memory performance and CSF biomarker status (positive or negative) in the healthy ageing group as well as subjects at risk of Alzheimer’s disease using a Gaussian process multikernel framework. Furthermore, we systematically evaluated predictive combinations of input feature sets and their model variations, i.e. (A) combinations of brain tissue classes and feature type (modulated vs. unmodulated), choices of filter size of smoothing (ranging from 0 to 15 mm full width at half maximum), and image resolution (1mm, 2mm, 4mm and 8mm); (B) incorporating demography and covariates (C) the impact of the size of the training data set (i.e., number of subjects); (D) the influence of reducing the dimensions of data and (E) choice of kernel types. Finally, the approach was tested to reveal individual cognitive scores at follow-up (up to 4 years) using the baseline features. The highest accuracy for memory performance prediction was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF-biomarkers explaining 57% of outcome variance in out of sample predictions. The best accuracy for Aβ42/40 status classification was achieved for combination demographics, ApoE4 and memory score while usage of structural MRI improved the classification of individual patient’s pTau status.
Sharp wave ripples in macaque V1 and V4 are modulated by top-down visual attention
Authors: Doostmohammadi Jafar , Gieselmann Marc Alwin , van Kempen Jochem , Lashgari Reza , Yoonessi Ali , Thiele Alexander
Published: March 2022

Sharp-wave ripples (SWRs) are highly synchronous neuronal activity events. They have been predominantly observed in the hippocampus during offline states such as pause in exploration, slow-wave sleep and quiescent wakefulness. SWRs have been linked to memory consolidation, spatial navigation, and spatial decision-making. Recently, SWRs have been reported during visual search, a form of remote spatial exploration, in macaque hippocampus. However, the association between SWRs and multiple forms of awake conscious and goal-directed behavior is unknown. We report that ripple activity occurs in macaque visual areas V1 and V4 during focused spatial attention. The frequency of ripples is modulated by characteristics of the stimuli, by spatial attention directed toward a receptive field, and by the size of the attentional focus. Critically, the monkey’s reaction times in detecting behaviorally relevant stimulus changes was affected on trials with SWRs. These results show that ripple activity is not limited to hippocampal activity during offline states, rather they occur in the neocortex during active attentive states and vigilance behaviors.
The chemical basis of metabolic interdependence in microbial communities
Authors: Goyal Akshit , Krishna Sandeep
Published: March 2022

Microbial communities play a crucial role in determining the dynamics of soil and marine ecosystems. They strongly influence the physiological functioning of plants and animals, for instance, nutrient uptake, stress tolerance, immune responses in the gut, lung, skin, etc. The diverse species in such communities interact both competitively as well as cooperatively. Cross-feeding, the exchange of metabolites between a pair of microbial species for mutual benefit is a common interaction that probably explains why 99% of natural bacterial species are unculturable on their own in the laboratory. Here, we provide a theoretical, network-level understanding of the conditions under which cross-feeding between a pair of microbial species can be beneficial to both. Using the known microbial repertoire of metabolic reactions, as represented in the KEGG database, we construct a large ensemble of metabolic networks designed to synthesize a set of biomass precursors from specified nutrients. We construct both autonomous networks, that can perform this task on their own, as well as pairs of cross-feeding networks that can only perform this task together but not alone. Surprisingly, we find that there exist cross-feeding pairs that produce higher biomass or energy yields than even the best autonomous networks. We show that such “outperforming” cross-feeding pairs exist only because of certain nonlinearities in the way metabolic flux is distributed in these networks. By analyzing patterns in our ensemble of networks, we propose a set of necessary and (almost) sufficient conditions that the metabolic networks have to satisfy for cross-feeding to be beneficial. These conditions are based partly on the structure of the networks and partly on the chemical and thermodynamic properties of the underlying chemical reactions, phenomenologically quantified in terms of the effect of donating or accepting metabolites on the yield of our constructed networks. Our analysis not only provides a mechanistic understanding of why cross-feeding is prevalent in microbial communities, but also provides a theoretical basis for understanding the benefit of compartmentalization of chemical reactions in a variety of contexts, for instance with mitochondrial vs. cytoplasmic metabolism in eukaryotic cells, or multi-enzyme cascade reactions in industrial contexts.
A novel single layer microfluidic device for dynamic stimulation, culture and imaging of mammalian cells
Authors: Mustafa Adil , Pedone Elisa , La Regina Antonella , Erten Ahmet , Marucci Lucia
Published: March 2022

The possibility to tightly control the cellular microenvironment within microfluidic devices represents an important step forward precision analysis of cellular phenotypes in vitro. In particular, microfluidic platforms that allow both long-term mammalian cell culture and dynamic modulation of the culture environment can support quantitative studies of cells’ responses to drugs. Here, we report the design and testing of a novel microfluidic device of easy production (single Polydimethylsiloxane layer), which integrates a micromixer with vacuum-assisted cell loading for long-term mammalian cell culture and dynamic mixing of 4 different culture media. Finite element modelling was used to predict the flow rates and device dimensions to achieve diffusion-based fluid mixing. The device showed efficient mixing and dynamic exchange of media in the cell trapping chambers. This work represents the first attempt to integrate single layer microfluidic mixing devices with vacuum-assisted cell loading systems for mammalian cell culture and dynamic stimulation.
Neuroligin-3 in Dopaminergic Circuits Promotes Behavioral and Neurobiological Adaptations to Chronic Morphine Exposure
Authors: Brandner Dieter D. , Retzlaff Cassandra L. , Kocharian Adrina , Stieve Bethany J. , Mashal Mohammed A. , Mermelstein Paul G. , Rothwell Patrick E.
Published: March 2022

Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 (NL3) is an X-linked postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of NL3 alters responses to chronic morphine in male mice. Constitutive NL3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure and changed in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of NL3 from cells expressing the Drd1 dopamine receptor, whereas reduced psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. Without NL3 expression, dopamine neurons in the ventral tegmental area exhibited diminished activation following chronic morphine exposure, by measuring in vivo calcium signals with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of NL3: dopamine neurons lacking NL3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that NL3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.
Genetic affinities and adaptation of the South West coast populations of India
Authors: Kumar Lomous , Chowdhari Anuhya , Sequeira Jaison J. , Mustak Mohammed S. , Banerjee Moinak , Thangaraj Kumarasamy
Published: March 2022

Evolutionary event has not only transformed the genetic structure of human populations but also associated with social and cultural transformation. South Asian populations were formed as a result of such evolutionary events of migration and admixture of genetically and culturally distinct groups. Most of the genetic studies pointed to large-scale admixture event between Ancestral North Indian (ANI) and Ancestral South Indian (ASI) groups, also additional layers of recent admixture. In the present study we have analyzed 213 individuals inhabited in South West coast India with traditional warriors and feudal lord status and historically associated with recent migrations events and possible admixture with Indo-Scythians, Saka, Huns and Kushans, whose genetic links are still missing. Analysis of autosomal SNP markers suggests that these groups possibly derived their ancestry from some groups of North West India having additional Middle Eastern genetic component and also their separation history suggests very early separation from North West Indian and Gangetic plain Indo-Europeans during late bronze or Iron age, most probably following central India and Godavari basin to South West coast. Higher distribution of west Eurasian mitochondrial haplogroups also points to admixture through maternal lineage. Selection screen using genome wide genealogy approach revealed genetic signatures related to their long-term coastal food habits. Thus, our study suggests that the South West coastal groups with traditional warriors and feudal lords’ status are of a distinct lineage compared to Dravidian and Gangetic plain Indo-Europeans and are remnants of very early migrations from North West India following Godavari basin to Karnataka and Kerala.
Neq2X7: a multi-purpose and open-source fusion DNA polymerase for advanced DNA engineering and diagnostics PCR
Authors: Hernández-Rollán Cristina , Ehrmann Anja K. , Nørholm Morten H. H.
Published: March 2022

Thermostable DNA polymerases, such as Taq isolated from the thermophilic bacterium Thermus aquaticus, enable one-pot exponential DNA amplification known as polymerase chain reaction (PCR). However, other properties than thermostability - such as fidelity, processivity, and compatibility with modified nucleotides - are important in contemporary molecular biology applications. Here, we describe the engineering and characterization of a fusion between a DNA polymerase identified in the marine archaea Nanoarchaeum equitans and a DNA binding domain from the thermophile Sulfolobus solfataricus. The fusion creates a highly active enzyme, Neq2X7, capable of amplifying long and GC-rich DNA and that is unaffected by replacing dTTP with dUTP in PCR. This makes it an attractive DNA polymerase for use e.g., with uracil excision (USER) DNA assembly and for contamination-free diagnostics. Furthermore, Neq2X7 is easy to produce, and the expression plasmid is freely available.

Graphical abstract