bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of Failed Decortications in Post Tuberculous Empyema
Authors: Mohammad Abid Khan  , Abdul Baseer  , Tahir Aslam  , Imran Tahir  , Asif Ahmad
Published: December 2024

Objectives: Treatment of post-Tuberculous empyema remains challenge to clinicians. The objective of this study was to report frequency of failed decortications in post-tuberculous empyema.
Methodology: A cross-sectional observational study was carried out at Thoracoscopic Surgery Department of Lady Reading Hospital Peshawar. Medical records of hospital were reviewed retrospectively from last 5 years (from 2016-2021). Patients with post-tuberculous empyema that underwent decortication were included. Definition of empyema was taken as loculation or septations in pleural space identified on computed tomography. Patients without any decortications were excluded. SPSS was used for data analysis.
Results: From 110 patients, mean age 59.2 ± 19.4 years and 71 (65%) males and 39 (35%) females, mean BMI was 22.3±2.9 kg/m2. All patients had history of pulmonary tuberculosis. Mean duration of symptoms before surgical treatment was 12.7 ± 9.8 days. 34 (31%) were successful while 76 (69%) decortications failed. Decortication as first line of treatment was used in 04 (12%) with successful decortications, while in 47 (62 %) with failed decortications (p<0.001). Mean duration of symptoms to treatment among successful decortications was 12.2 ± 9.5 days while in failed decortications 14.1 ± 10.2 days (p-0.06). Mean duration of hospital stay in successful decortications was 12.3 ± 7.7 days while in failed decortications 13.2 ± 8.1 days (p-0.08). Frequency of drainage fluid >1000 ml in successful decortications was 10 (29 %) while in failed decortications 52 (68 %). 11 (15 %) of patients died among failed decortications.
Conclusion: High frequencies of failed decortications due to post-tuberculous empyema were reported in this study.
Microalbuminuria In Newly Diabetes Mellitus Patients: Diagnosis, Screening and Increasing Public Awareness
Authors: Muhammad Tahir Younas  , Mukhtar Shoaib , Yousaf Sabeeha , Niazi Hira , Younas Sana
Published: December 2024

Abstract
 
Objective:  To promote public awareness about preventing chronic kidney disease by determining the prevalence and diagnosis of microalbuminuria in people with newly diagnosed diabetes.
Methodology: Cross Sectional Survey and analysis study was conducted in Department of Medicine PAF Hospital Islamabad from 1st January 2021 to 30th June 2021. A total of 111 newly diagnosed diabetic patients of both genders were included. All patients were sent to same hospital laboratory for urine test by Pathologist aiming microalbuminuria status. Data was collected regarding microalbuminuria from all patients and was noted as per operational definition.
Results: The Age range in this study was from 18 to 50 years with mean age of 42.504± 5.19 years and mean weight was 82.063±9.37 Kg. Majority of the patients were of male gender (81.1%). 71.2% patients had family history of diabetes. Microalbuminuria was observed in 47.7% patients. Due to a lack of screening and education, a considerable number of individuals with newly diagnosed diabetic patients already had microalbuminuria.
Conclusion: Prevalence of microalbuminuria was high in this patient population of newly diagnosed diabetes mellitus. These findings suggest that healthcare policy or research efforts may focus on reversing microalbuminuria in hopes of improving the prognosis of diabetic patients and preventing chronic kidney disease. Good glycemic control has been proved time and again in preventing cerebrovascular diseases and chronic kidney diseases.
Keywords: Diabetes, Newly Diagnosed, Microalbuminuria, Chronic Kidney Disease
Pattern of OCD Symptoms in Muslim Patients in Tertiary Care Hospital
Authors: Ayub Sher , Ahmad Hussain
Published: December 2024

Objectives: To find the pattern of OCD symptoms in Muslim patients.
Methodology: This study was conducted at the department of psychiatry Khalifa Gulnawaz Teaching Hospital Bannu, Pakistan from January 2022 to December 2022. Those who fulfilled the DSM criteria for obsessive compulsive disorder were included in the study. Those patients who were suffering from medical or neurological illness were excluded from the study.
Results: Ninety-Five Muslim patients (68 males and 27 females) fulfilled the DSM criteria for obsessive compulsive disorder. The mean age of the group was 25.88+7.39. The main themes of obsessions and compulsions were religious (62%), contamination (22%), and orderliness (16%).
Conclusion: This study demonstrates the role of religion in the development of numerous obsessions and compulsions, which may be useful in the early detection and treatment of obsessive compulsive disorder in our culture. Furthermore, in Islamic culture, the implications of these findings on non pharmacological therapeutic methods like exposure and response prevention (ERP) and cognitive behavior therapy (CBT) could be considerable.
Frequency of Lower Urinary Tract Symptoms with Irritable Bowel Syndrome and Their Associated Factors among Women at Urogynecology and Gastroenterology Clinic
Authors: Abrar Saida , Mohsin Raheela
Published: December 2024

Objective: To determine the lower urinary tract symptoms (LUTS) in females with irritable bowel syndrome (IBS) and to find the effect on their Quality of Life (QoL) using the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) Questionnaire.
Methodology: This study included 140 female patients, 80 as cases with diagnosed IBS by the Rome III criteria while 60 without IBS as controls from Urogynecology clinics among which 45 patients had a≤ stage-II pelvic organ prolapse and 15 patients had idiopathic microscopic hematuria. LUTS were evaluated using BFLUTS Questionnaire.
Results: The two groups did not significantly differ in demographic except a high body mass index (BMI) in the IBS group (p-value 0.002). The IBS group also had a significantly higher frequency of chronic hypertension, interstitial cystitis, and chronic depression (p-value 0.02, 0.03, and 0.03 respectively). There was a high frequency of LUTS symptoms in patients with IBS, frequency (p-value <0.001), urgency urinary incontinence (p-value <0.004), hesitancy (p-value <0.02), straining to void (p-value <0.001) and intermittency (p-value <0.001). Also, IBS significantly affected sexual activity (p-value < 0.001) and quality of life especially, daily tasks (p-value <0.01).
Conclusion: Patients with IBS have a higher frequency of storage and voiding LUTS, and it negatively affects their sexual and overall quality of life. Thus it is possible that both share some common underlying pathology and patients with IBS should be screened for LUTS and provided comprehensive care.
Occupational Variations in Vitamin D Status and its Correlation with Serum Lipids in Varying Glycemic Control Groups
Authors: Abbas Zaheer , Waqas Umair , Ali Abid Ali
Published: December 2024

Objective: The study focuses on the evaluation of the difference between the serum vitamin D3 levels, on the basis of sunlight exposure, in indoor and outdoor individuals and to find out the correlation between serum 1,25-OH-D and serum lipids of varying glycemic control subjects.
Methodology: We enrolled 221 participants. The serum 1,25-hydroxy-D3 was quantitated by immuno-fluorescence method. Blood HbA1c amount was analyzed by high performance liquid chromatography. Serum levels of cholesterol, triacylglycerols, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol were estimated by spectrophotometric analysis. Very low-density lipoprotein cholesterol was computed using the Friedewald equation. The Statistical Package for Social Software 20.0 was chosen to statistically analyze the collected data.
Results: A significant dissimilarity in the levels of sun-born vitamin, the calcitriol, was calculated, among the sun-exposed and non-exposed group. The mean vitamin D value was measured higher in sun-exposure group than non-exposed to sun. There came to be known the interlink between glycemic control and vitamin D quantity. Serum vitamin D had an inverse relationship with serum cholesterol, triglycerides, LDL-C and VLDL-C, but a positive relation with HDL-C.
Conclusion: The present expanding insufficiency and deficiency of vitamin-D3 is bringing about the peril of prevalent dyslipidemia and poor glycemic control, hence jeopardizing the health of people. The current unforeseen falling off serum vitamin D levels in the principal part of the population, is needed to be overseen and treated accordingly
Comparison of topical 5% Permethrin with topical 10% Sulphur in the treatment of Scabies
Authors: Nasir Aleena , Khan Abdul Haseeb , Sarwar Sara , Farooq Mahnoor , Sajjad Najia
Published: December 2024

Objective: To compare the efficacy of topical 5% Permethrin and topical 10% Sulphur in the treatment of Scabies.
Design: Randomized controlled trial.
Place and duration of study: This study was conducted at the Department of Dermatology, Combined Military Hospital, Abbottabad, Pakistan, from March 2022 to September 2022.
Patients and methods: A total of 60 patients coming to outpatient department and diagnosed with scabies mites were randomized into two equal groups of 30 patients. Diagnosed patients on odd serial number were allocated to group A, treated with application of topical 5% Permethrin cream twice with one week interval, while patients reporting on even serial number were allocated to group B, treated with 10% Sulphur ointment and were told to apply this for two or three weeks. All patients were followed up at the intervals of 1, 2 and 4 weeks. Primary outcome was the comparison of efficacy of 5% Permethrin cream and 10% Sulphur ointment for the treatment of Scabies.
Results: At the first follow-up  after 1 week, the efficacy of Permethrin was significantly higher (63.33%) compared to Sulphur group where no patient was cured (p< 0.001), while at 2nd follow-up after 2 weeks, the efficacy of Permethrin was 100%, while it was 43.33% in sulfur group (p< 0.001).  However at the end of 3rd follow-up after 4 weeks, efficacy of both treatments was 100%.
Conclusion: The topical application of 5% Permethrin and 10% Sulphur was equally effective in 4 week time, however Permethrin cream showed faster cure in the treatment of Scabies
Disparities in Epilepsy Knowledge, Beliefs and Cost-Effectiveness: A Comparative Analysis of Rural Healthcare Facilities in Bhakkar Hard- to-Reach District in South Punjab- Pakistan
Authors: Haseeb Muhammad , Iftikhar Samia , Masood , Inam Ul Haque , Malik Muhammad Akbar
Published: December 2024

ABSTRACT
Background: Although 80% of the 50million people with epilepsy reside in resource poor, developing countries. Epilepsy care in these regions remains limited and the majority of epilepsy patients go untreated due to various modifiable and non-modifiable factors.
Objective: Comparing the effectiveness of volunteer specialist intervention versus autonomous epilepsy treatment to optimize care strategies and improve patient well-being in rural areas of Bhakkar, Punjab, Pakistan.
Material and Methods: An observational study comparing treatment gap and expenses between two cohorts: one being supported and treated at Rukhsana Shafqat Medical Centre, and their counterpart’s getting treatment from other facilities with spending out of their pocket was carried out June 01, 2023 to January 01, 2024 at RSMC Bhakkar, Punjab.
Results: A comparison of 100 epilepsy cases each from a major medical center (RSMC) and rural healthcare facilities shows demographic and clinical differences. RSMC patients are younger, with different gender ratios and education levels. RSMC reports 31% idiopathic epilepsy, 61% symptomatic, and 8% cryptogenic, contrasting rural centers' 14%, 78%, and 8%. Co morbidities vary, with 49 individuals having none in RSMC and 60 in rural centers. Treatment duration and disease knowledge also differ, with RSMC demonstrating better knowledge (64.57% good knowledge) compared to rural centers (52.63%). Misconceptions are higher in rural areas (50.4%) than at RSMC (36%). Monthly costs are predominantly below 5000 PKR at RSMC (87%) and in 72% of cases in rural centers, with 28% spending more than 5000 PKR.
Conclusion: The community-based rehabilitation model of care can offer an alternative approach to epilepsy care and address the reality of most people with epilepsy living in such areas of poor developing countries.
JUDICIALIZAÇÃO DA SAÚDE E NOVAS POSSIBILIDADES JURÍDICAS
Authors: Schulze Clenio Jair
Published: December 2024

O presente texto pretende indicar medidas para aliviar a tensão gerada da análise dos processos judiciais sobre saúde, bem como permitir que o(a) julgador(a) esteja mais seguro(a) no momento da prolatação da sua decisão. Analisam-se, assim, aspectos destacados que impactam a judicialização da saúde, tais como fast track na Avaliação de Tecnologias em Saúde – ATS, a renovação da prescrição médica e a migração de tecnologias no processo judicial; algumas propostas de custo-efetividade em saúde, aspectos da nota técnica e do laudo pericial, análise de evidências em saúde, consequencialismo, resultados em saúde e saúde baseada em valor. Propõe-se, ao final, normas para combater a judicialização da saúde predatória e também o tratamento adequado para as demandas em saúde.
A AMEAÇA DAS FAKE NEWS PARA A DEMOCRACIA E OS DIREITOS HUMANOS NA ERA DO TECNOPOPULISMO
Authors: Sampaio José Adércio Leite , Bocchino Lavínia Assis
Published: December 2024

Na era do tecnopopulismo, a qualidade epistêmica do debate eleitoral e os direitos humanos estão sob ameaça, devido às manobras de atores populistas para permanecerem no poder, combinadas a uma tecnologia de ponta que atua na coleta indevida dos dados de eleitores, por intermédio das plataformas de mídia, para a criação de propaganda microdirecionada e disseminação de fake news (desinformação) em massa nas redes sociais. Essas técnicas abusam do direito à liberdade de expressão ao manipular a opinião pública e impedir o acesso às informações verídicas, além de violar a privacidade do eleitor. A partir de estudos documentais, bibliográficos e comparativos com outros países para investigar como identificar o problema e pensar em soluções, o presente trabalho visa a encontrar meios eficazes e viáveis para combater esses mecanismos, no âmbito das eleições brasileiras, a fim de assegurar os direitos humanos e a democracia.
A DELEGAÇÃO DE PODERES POLÍTICOS ÀS CORTES CONSTITUCIONAIS
Authors: Beçak Rubens , Fernandes Lucas Paulo
Published: December 2024

O artigo trata da delegação de poder e autoridade políticos às cortes constitucionais. Se, atualmente, tribunais constitucionais possuem características políticas, torna-se relevante observar as causas dessas atribuições. Por isso, partindo do processo de elaboração constitucional, percorrem-se teorias que possam explicar os motivos da delegação de poderes políticos a cortes constitucionais, a fim de discorrer sobre o caráter político-institucional do judicial review. Apesar de ressalvas existentes, o judicial review apresenta-se como uma forma de seguro futuro às classes políticas, as quais projetam nas cortes constitucionais um mecanismo ulterior de realização da própria política. A abordagem é transdisciplinar entre o Direito Constitucional e a Ciência Política, por meio de revisão bibliográfica narrativa e qualitativa, com um enfoque crítico.
O PRINCÍPIO DA SUPLETIVIDADE NOS CONTRATOS EMPRESARIAIS
Authors: Coelho Fábio Ulhoa
Published: December 2024

O princípio da supletividade nos contratos empresariais foi explicitado no direito brasileiro pela Lei da Liberdade Econômica de 2019. Este artigo discute a sua aplicação, tomando, por exemplo, um dispositivo das regras legais sobre o contrato de representação comercial autônoma.
Can AI Finish Poverty? The Role of Artificial Intelligence in Poverty Alleviation
Authors: Kaçer Murat
Published: December 2024

Artificial intelligence has become an integral part of our daily lives, both in discourse and action. Technological developments play a significant role in the recovery of the global economy. Although poverty has decreased proportionally in terms of meeting basic needs due to these advancements, it remains one of the most chronic and significant issues in the world. This study examines the role of artificial intelligence in the fight against poverty. It explores the various roles artificial intelligence plays in microfinance, agriculture, health, and education. While the study emphasizes that artificial intelligence has important functions in this area, it also notes that its contribution may not be inevitable or mandatory; factors such as political conditions and biophysical limits of our planet also play a critical role.
Reflection – a Learning Strategy to Improve a Student’s Performance After Providing Feedback
Authors:   , Špehte Elita
Published: December 2024

Providing feedback is an integral part of the learning process that ensures an effective teaching process. Therefore, the aim of the doctoral thesis is to develop in theory and practice-based a model of the student’s reflective learning process after the teacher’s feedback for the improvement of the learning process. The work includes an analysis of the theoretical aspects of feedback and reflection, as well as their constitutive elements. By evaluating the impact of reflection and feedback on student learning and performance improvement, the pedagogical prerequisites that facilitate the use of student reflection practices in the learning process are described. The development and validation of a model of student reflection in the learning process following teacher feedback has been implemented. The results of this work can be utilized in both schools and higher education institutions, not only in Latvia but also in the European Union.
Resistive switching characteristics of Cu/MgO/MoS2/Cu structure
Authors: HE Xiaolong , CHEN Peng ,   School of Physics Science and Technology, Southwest University, Chongqing 400715, China
Published: December 2024

During the study of resistive switching devices, researchers have found that the influence of the insertion layer cannot be ignored. Many reports have confirmed that the appropriate insertion layer can significantly improve the performance of the resistive switching devices. Therefore, in this work, we use magnetron sputtering to fabricate three devices: Cu/MgO/Cu, Cu/MgO/MoS2/Cu and Cu/MoS2/MgO/Cu. Through the characterization test of each device and the measurement of the I-V curve, it is found that the resistive switching characteristics of the Cu/MgO/Cu device will change greatly after adding an MoS2 insertion layer. The analysis results show that the inserted MoS2 layer does not change the main transmission mechanism (space charge limited conduction) of the device, but affects the regulating function of interfacial potential barrier, the effect also is related to the location of MoS2 inserted into the layer. Among the Cu/MgO/Cu, Cu/MgO/MoS2/Cu and Cu/MoS2/MgO/Cu devices, the Cu/MgO/MoS2/Cu device exhibits a larger switching ratio (about 103) and a lower reset voltage (about 0.21 V), which can be attributed to the regulation of the interface barrier between MgO and MoS2. In addition, when the MoS2 layer is inserted between the bottom electrodes Cu and MgO, the leakage current of the device is significantly reduced. Therefore, Cu/MoS2/MgO/Cu device has the highest commercial value from the point of view of practical applications. Finally, according to the XPS results and XRD results, we establish the conductive filament models for the three devices, and analyze the reasons for the different resistive switching characteristics of the three devices.
130 μJ linear-polarized single-frequency 12-μm-core Er/Yb co-doped fiber amplifier based on pre-shaped seed pulse
Authors: JIANG Peiheng , SHI Chaodu , FU Shijie , TIAN Hao , SHENG Quan , SHI Wei , SHEN Qihao , ZHOU Dingfu , YAO Jianquan ,   School of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin 300072, China,   Key Laboratory of Optoelectronic Information Technology (Ministry of Education), Tianjin University, Tianjin 300072, China,   Southwest Institute of Technical and Physics, Chengdu 610041, China
Published: December 2024

Stimulated Brillouin scattering (SBS) is the major barrier in the process of energy scaling for pulsed single-frequency fiber master oscillator power amplifier (MOPA). Due to gain saturation effect, the laser pulse profile will be gradually distorted with the increase of pump power, which induces steep leading edge and narrower width for the amplified pulses. The resulting laser peak power would increase rapidly and thus the SBS threshold is reached earlier to limit the amplification of pulse energy.

A method to obtain high-energy pulsed single-frequency laser by pulse pre-shaping is demonstrated in this work. By designing the leading edge of the triangular pulse, optimizing its rising trend and the duration of the low-intensity rising part, the pulse width compression phenomenon caused by gain saturation is alleviated effectively. Thereafter, the laser peak power increase process can be retarded to reach the SBS threshold so that higher energy can be amplified for the pulsed single-frequency fiber laser. In the experiment, when the seed pulse is optimized to be a triangular pulse with a low-intensity rising edge of 401 ns and a pulse width of 520 ns, a linear-polarized pulse single-frequency fiber laser of 130.9 μJ is obtained in a 12-μm-core Er/Yb co-doped polarization-maintaining fiber. The pulse width is broadened to 608 ns at the maximum energy. When it is compared with the triangular pulse seed with a rapidly rising leading edge, its maximum energy is increased by about 25%. The optical signal-to-noise ratio and polarization extinction ratio are measured to be 42 dB and 16 dB at the maximum pulse energy, respectively. The corresponding spectral linewidth measured by a delayed self-heterodyne system is 542 kHz. Higher pulse energy can be anticipated by further optimizing the pulse profile and using large-mode-are gain fibers.
Dynamic changes in subplate and cortical plate microstructure at the onset of cortical folding in vivo
Authors: Wilson Siân , Christiaens Daan , Yun Hyukjin , Uus Alena , Cordero-Grande Lucilio , Karolis Vyacheslav , Price Anthony , Deprez Maria , Tournier Jacques-Donald , Rutherford Mary , Grant Ellen , Hajnal Joseph V , Edwards A David , Arichi Tomoki , O’Muircheartaigh Jonathan , Im Kiho
Published: December 2024

Cortical gyrification takes place predominantly during the second to third trimester, alongside other fundamental developmental processes, such as the development of white matter connections, lamination of the cortex and formation of neural circuits. The mechanistic biology that drives the formation cortical folding patterns remains an open question in neuroscience. In our previous work, we modelled the in utero diffusion signal to quantify the maturation of microstructure in transient fetal compartments, identifying patterns of change in diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester. In this work, we apply the same modelling approach to explore whether microstructural maturation of these compartments is correlated with the process of gyrification. We quantify the relationship between sulcal depth and tissue anisotropy within the cortical plate (CP) and underlying subplate (SP), key transient fetal compartments often implicated in mechanistic hypotheses about the onset of gyrification. Using in utero high angular resolution multi-shell diffusion-weighted imaging (HARDI) from the Developing Human Connectome Project (dHCP), our analysis reveals that the anisotropic, tissue component of the diffusion signal in the SP and CP decreases immediately prior to the formation of sulcal pits in the fetal brain. By back-projecting a map of folded brain regions onto the unfolded brain, we find evidence for cytoarchitectural differences between gyral and sulcal areas in the late second trimester, suggesting that regional variation in the microstructure of transient fetal compartments precedes, and thus may have a mechanistic function, in the onset of cortical folding in the developing human brain.
Dynamics of striatal action selection and reinforcement learning
Authors: Lindsey Jack , Markowitz Jeffrey E , Gillis Winthrop F , Datta Sandeep Robert , Litwin-Kumar Ashok
Published: December 2024

Spiny projection neurons (SPNs) in dorsal striatum are often proposed as a locus of reinforcement learning in the basal ganglia. Here, we identify and resolve a fundamental inconsistency between striatal reinforcement learning models and known SPN synaptic plasticity rules. Direct-pathway (dSPN) and indirect-pathway (iSPN) neurons, which promote and suppress actions, respectively, exhibit synaptic plasticity that reinforces activity associated with elevated or suppressed dopamine release. We show that iSPN plasticity prevents successful learning, as it reinforces activity patterns associated with negative outcomes. However, this pathological behavior is reversed if functionally opponent dSPNs and iSPNs, which promote and suppress the current behavior, are simultaneously activated by efferent input following action selection. This prediction is supported by striatal recordings and contrasts with prior models of SPN representations. In our model, learning and action selection signals can be multiplexed without interference, enabling learning algorithms beyond those of standard temporal difference models.
GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation
Authors: Chen Qing , Wu Hui , Xie Shulan , Zhu Fangfang , Xu Fang , Xu Qi , Sun Lihong , Yang Yue , Xie Linghua , Xie Jiaqian , Li Hua , Dai Ange , Zhang Wenxin , Wang Luyang , Jiao Cuicui , Zhang Honghai , Xu Zhen-Zhong , Chen Xinzhong
Published: December 2024

Neuropathic pain, a major health problem affecting 7 - 10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK
+
) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here we showed that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK
+
neurons reversed CCI-induced neuropathic pain. Besides, GPR30 in spinal CCK
+
neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Furthermore, GPR30 was expressed in the spinal CCK
+
neurons receiving direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons is required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK
+
neurons is pivotal for neuropathic pain and mediates descending facilitation by corticospinal direct projections, thereby representing a promising therapeutic target for neuropathic pain.
Multiple and subject-specific roles of uncertainty in reward-guided decision-making
Authors: Paunov Alexander , L’Hôtellier Maëva , Guo Dalin , He Zoe , Yu Angela , Meyniel Florent
Published: December 2024

Decision-making in noisy, changing, and partially observable environments entails a basic tradeoff between immediate reward and longer-term information gain, known as the exploration-exploitation dilemma. Computationally, an effective way to balance this tradeoff is by leveraging uncertainty to guide exploration. Yet, in humans, empirical findings are mixed, from suggesting uncertainty-seeking to indifference and avoidance. In a novel bandit task that better captures uncertainty-driven behavior, we find multiple roles for uncertainty in human choices. First, stable and psychologically meaningful individual differences in uncertainty preferences actually range from seeking to avoidance, which can manifest as null group-level effects. Second, uncertainty modulates the use of basic decision heuristics that imperfectly exploit immediate rewards: a repetition bias and win-stay-lose-shift heuristic. These heuristics interact with uncertainty, favoring heuristic choices under higher uncertainty. These results, highlighting the rich and varied structure of reward-based choice, are a step to understanding its functional basis and dysfunction in psychopathology.
A toolbox for ablating excitatory and inhibitory synapses
Authors: Bareghamyan Aida , Deng Changfeng , Daoudi Sarah , Nawy Scott , Lu Xiaocen , Zhang Wei , Campbell Robert E , Kramer Richard H , Chenoweth David M , Arnold Don B
Published: December 2024

Recombinant optogenetic and chemogenetic proteins that manipulate neuronal activity are potent tools for activating and inhibiting neuronal circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer, HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Loss of Flower/FLWR-1 induces an increase in neuronal excitability and causes defective recycling of synaptic vesicles
Authors: Seidenthal Marius , Redzovic Jasmina , Liewald Jana F , Rentsch Dennis , Shapiguzov Stepan , Schuh Noah , Eimer Stefan , Gottschalk Alexander
Published: December 2024

The Flower protein is proposed to couple synaptic vesicle fusion to recycling in different model organisms. It is supposed to trigger activity-dependent bulk endocytosis by conducting Ca
2+
at endocytic sites. However, this mode of action is debated. Here, we investigate the role of the nematode homolog (FLWR-1) in neurotransmission in
Caenorhabditis elegans
. Our results confirm that FLWR-1 facilitates the recycling of synaptic vesicles at the neuromuscular junction. Ultrastructural analysis of synaptic boutons after hyperstimulation surprisingly reveals an accumulation of endosomal structures in
flwr-1
mutants. These findings do not support a role of FLWR-1 in the formation of bulk endosomes but rather a function in their breakdown following cleavage from the plasma membrane. Unexpectedly, loss of FLWR-1 conveys increased neuronal excitability which causes an excitation-inhibition imbalance. Finally, we obtained evidence that this increased transmission at the neuromuscular junction might be caused by deregulation of MCA-3, the nematode homolog of the plasma membrane Ca
2+
ATPase (PMCA).
Decoding m6Am by simultaneous transcription-start mapping and methylation quantification
Authors: Liu Jianheng Fox , Hawley Ben R , Nicholson Luke S , Jaffrey Samie R
Published: December 2024

N
6
,2’-
O
-dimethyladenosine (m
6
Am) is a modified nucleotide located at the first transcribed position in mRNA and snRNA that is essential for diverse physiological processes. m
6
Am mapping methods assume each gene uses a single start nucleotide. However, gene transcription usually involves multiple start sites, generating numerous 5’ isoforms. Thus, gene levels annotations cannot capture the diversity of m
6
Am modification in the transcriptome. Here we describe CROWN-seq, which simultaneously identifies transcription-start nucleotides and quantifies m
6
Am stoichiometry for each 5’ isoform that initiates with adenosine. Using CROWN-seq, we map the m
6
Am landscape in nine human cell lines. Our findings reveal that m
6
Am is nearly always a high stoichiometry modification, with only a small subset of cellular mRNAs showing lower m
6
Am stoichiometry. We find that m
6
Am is associated with increased transcript expression and provide evidence that m
6
Am may be linked to transcription initiation associated with specific promoter sequences and initiation mechanisms. These data suggest a potential new function for m
6
Am in influencing transcription.
Decoding m6Am by simultaneous transcription-start mapping and methylation quantification
Authors: Liu Jianheng Fox , Hawley Ben R , Nicholson Luke , Jaffrey Samie R
Published: December 2024

N
6
,2’-
O
-dimethyladenosine (m
6
Am) is a modified nucleotide located at the first transcribed position in mRNA and snRNA that is essential for diverse physiological processes. m
6
Am mapping methods assume each gene uses a single start nucleotide. However, gene transcription usually involves multiple start sites, generating numerous 5’ isoforms. Thus, gene levels annotations cannot capture the diversity of m
6
Am modification in the transcriptome. Here we describe CROWN-seq, which simultaneously identifies transcription-start nucleotides and quantifies m
6
Am stoichiometry for each 5’ isoform that initiates with adenosine. Using CROWN-seq, we map the m
6
Am landscape in nine human cell lines. Our findings reveal that m
6
Am is nearly always a high stoichiometry modification, with only a small subset of cellular mRNAs showing lower m
6
Am stoichiometry. We find that m
6
Am is associated with increased transcript expression and provide evidence that m
6
Am may be linked to transcription initiation associated with specific promoter sequences and initiation mechanisms. These data suggest a potential new function for m
6
Am in influencing transcription initiation.
Cognitive control of behavior and hippocampal information processing without medial prefrontal cortex
Authors: Park Eun Hye , O’Reilly Sparks Kally C , Grubbs Griffin , Taborga David , Nicholas Kyndall , Ahmed Armaan S , Ruiz-Pérez Natalie , Kim Natalie , Segura-Carrillo Simon , Fenton André A
Published: December 2024

Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature, and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a “central-computation” hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative “local-computation” hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of spatial information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.
Single-nucleus transcriptomics reveal the differentiation trajectories of periosteal skeletal/stem progenitor cells in bone regeneration
Authors: Perrin Simon , Ethel Maria , Bretegnier Vincent , Goachet Cassandre , Wotawa Cécile-Aurore , Luka Marine , Coulpier Fanny , Masson Cécile , Ménager Mickael , Colnot Céline
Published: December 2024

Bone regeneration is mediated by skeletal stem/progenitor cells (SSPCs) that are mainly recruited from the periosteum after bone injury. The composition of the periosteum and the steps of SSPC activation and differentiation remain poorly understood. Here, we generated a single-nucleus atlas of the periosteum at steady state and of the fracture site during the early stages of bone repair (https://fracture-repair-atlas.cells.ucsc.edu). We identified periosteal SSPCs expressing stemness markers (Pi16 and Ly6a/SCA1) and responding to fracture by adopting an injury-induced fibrogenic cell (IIFC) fate, prior to undergoing osteogenesis or chondrogenesis. We identified distinct gene cores associated with IIFCs and their engagement into osteogenesis and chondrogenesis involving Notch, Wnt, and the circadian clock signaling, respectively. Finally, we show that IIFCs are the main source of paracrine signals in the fracture environment, suggesting a crucial paracrine role of this transient IIFC population during fracture healing. Overall, our study provides a complete temporal topography of the early stages of fracture healing and the dynamic response of periosteal SSPCs to injury, redefining our knowledge of bone regeneration.
Aminoglycoside tolerance in Vibrio cholerae engages translational reprogramming associated with queuosine tRNA modification
Authors: Fruchard Louna , Babosan Anamaria , Carvalho Andre , Lang Manon , Li Blaise , Duchateau Magalie , Giai-Gianetto Quentin , Matondo Mariette , Bonhomme Frédéric , Hatin Isabelle , Arbes Hugo , Fabret Céline , Corler Enora , Sanchez Guillaume , Marchand Virginie , Motorin Yuri , Namy Olivier , de Crécy-Lagard Valérie , Mazel Didier , Baharoglu Zeynep
Published: December 2024

Tgt is the enzyme modifying the guanine (G) in tRNAs with GUN anticodon to queuosine (Q).
tgt
is required for optimal growth of
Vibrio cholerae
in the presence of sub-lethal aminoglycoside concentrations. We further explored here the role of the Q34 in the efficiency of codon decoding upon tobramycin exposure. We characterized its impact on the overall bacterial proteome, and elucidated the molecular mechanisms underlying the effects of Q34 modification in antibiotic translational stress response. Using molecular reporters, we showed that Q34 impacts the efficiency of decoding at tyrosine TAT and TAC codons. Proteomics analyses revealed that the anti-SoxR factor RsxA is better translated in the absence of
tgt
. RsxA displays a codon bias towards tyrosine TAT and overabundance of RsxA leads to decreased expression of genes belonging to SoxR oxidative stress regulon. We also identified conditions that regulate
tgt
expression. We propose that regulation of Q34 modification in response to environmental cues leads to translational reprogramming of transcripts bearing a biased tyrosine codon usage.
In silico
analysis further identified candidate genes which could be subject to such translational regulation, among which DNA repair factors. Such transcripts, fitting the definition of modification tunable transcripts, are central in the bacterial response to antibiotics.
Lineage-specific intersection of endothelin and GDNF signaling in enteric nervous system development
Authors: Poltavski Denise M , Cunha Alexander T , Tan Jaime , Sucov Henry M , Makita Takako
Published: December 2024

Two major ligand-receptor signaling axes – endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret – are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditional Ednrb or conditional Ret alleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+ population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.
Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs
Authors: Chao Shuo , Lu Jun , Li Li-Jun , Guo Hong-Yan , Xu Kuipeng , Wang Ning , Zhao Shu-Xian , Jin Xiao-Wen , Wang Shao-Ge , Yin Shen , Shen Wei , Zhao Ming-Hui , Huang Gui-An , Sun Qing-Yuan , Ge Zhao-Jia
Published: December 2024

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. Here, we found that maternal obesity disrupted the genomic methylation of oocytes using a high-fat diet (HFD) induced mouse model, at least a part of which was transmitted to the F2 oocytes and livers via females. We further examined the metabolome of serum and found that the serum concentration of melatonin was reduced. Exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. These suggest that melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.
Challenges in Malaysian Design Industry
Authors: Ali Abu , Liem Andre , Isa Siti Salwa , Jamaludin Nor Lelawati
Published: December 2024

The Malaysian design industry follows a market-need-driven approach, where marketing-oriented managers guide designers to address anticipated high-demand markets. However, challenges persist in understanding designers' problem-solving approaches due to implicit practices. This research emphasizes the hindrance caused by insufficient communication and collaboration among managers, designers, and researchers, impeding a comprehensive grasp of innovation processes in the manufacturing sector. The paper advocates a pragmatic examination of designers' experiences, highlighting sensemaking, speculative imagination, and improvisation as crucial design activities. Results show Malaysian industrial designers face consistent challenges with management, impacting the development process. The study contributes to formulating a practical solution for fostering creativity among managers, designers, and stakeholders in the design industry.
Upregulation of HPV16E1 and E7 expression and FOXO3a mRNA downregulation in high-grade cervical neoplasia
Authors: Sasivimolrattana Thanayod , Gunawan Aileen , Wattanathavorn Warattaya , Pholpong Chavis , Chaiwongkot Arkom , Bhattarakosol Pattarasinee , Bhattarakosol Parvapan
Published: December 2024

Background

Cervical cancer remains a significant global health concern, ranking as the fourth most prevalent cancer among women worldwide. Human papillomaviruses (HPV) transcribe many genes that might be responsible for cervical cancer development. This study aims to investigate the correlation between the expression of HPV16 early genes and the mRNA expression of human FOXO3a, a tumor suppressor gene, in association with various stages of cervical precancerous lesions.

Methods

Eighty-five positive HPV16 DNA cervical swab samples were recruited and categorized based on cytology stages, i.e., negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cell cannot exclude HSIL (ASC-H), high-grade squamous intraepithelial lesion (HSIL). RT-qPCR was performed to amplify HPV16E1, E4, E6, E6*I, E7, and human FOXO3a mRNA expression in all samples. The relative expression of those genes was calculated using GAPDH as a control. Detection of FOXO3a mRNA expression in the cervical cancer cell line by RT-qPCR and meta-analysis of FOXO3a expression using the RNA-Seq dataset by GEPIA2 were analyzed to support the conclusions.

Results

Among the cervical samples, HPV16E1 and E7 were significantly increased expression correlating to disease severity. HPV16E4 mRNA expression was 100% detected in all LSIL samples, with a significant increase observed from normal to LSIL stages. Conversely, FOXO3a mRNA expression decreased with disease severity, and the lowest expression was observed in HSIL/squamous cell carcinoma (SCC) samples. In addition, similar results of FOXO3a downregulation were also found in the cervical cancer cell line and RNA-Seq dataset of cervical cancer samples.

Conclusion

HPV16 early mRNA levels, including E1 and E7, increase during cancer progression, and downregulation of FOXO3a mRNA is a characteristic of cervical cancer cells and HSIL/SCC. Additionally, HPV16E4 mRNA expression was consistently detected in all LSIL samples, suggesting the presence of active viral replication. These findings might lead to further investigation into the interplay between HPV gene expression and host cell factors for targeted therapeutic strategies in cervical cancer management.